Mucinous Colorectal Adenocarcinoma: Influence of EGFR and E-Cadherin Expression on Clinicopathologic Features and Prognosis.

PubMed

Foda, Abd AlRahman M; AbdelAziz, Azza; El-Hawary, Amira K; Hosni, Ali; Zalata, Khalid R; Gado, Asmaa I

2015-08-01

Previous studies have shown conflicting results on epidermal growth factor receptor (EGFR) and E-cadherin expression in colorectal carcinoma and their prognostic significance. To the best of our knowledge, this study is the first to investigate EGFR and E-cadherin expression, interrelation and relation to clinicopathologic, histologic parameters, and survival in rare colorectal mucinous adenocarcinoma (MA). In this study, we studied tumor tissue specimens from 150 patients with colorectal MA and nonmucinous adenocarcinoma (NMA). High-density manual tissue microarrays were constructed using modified mechanical pencil tips technique, and immunohistochemistry for EGFR and E-cadherin was performed. All relations were analyzed using established statistical methodologies. NMA expressed EGFR and E-cadherin in significantly higher rates with significant heterogenous pattern than MA. EGFR and E-cadherin positivity rates were significantly interrelated in both NMA and MA groups. In the NMA group, high EGFR expression was associated with old age, male sex, multiplicity of tumors, lack of mucinous component, and association with schistosomiasis. However, in the MA group, high EGFR expression was associated only with old age and MA subtype rather than signet ring carcinoma subtype. Conversely, high E-cadherin expression in MA cases was associated with old age, fungating tumor configuration, MA subtype, and negative intratumoral lymphocytic response. However, in the NMA cases, none of these factors was statistically significant. In a univariate analysis, neither EGFR nor E-cadherin expression showed a significant impact on disease-free or overall survival. Targeted therapy against EGFR and E-cadherin may not be useful in patients with MA. Neither EGFR nor E-cadherin is an independent prognostic factor in NMA or MA.

Pro-inflammatory cytokines expression increases following low- and high-magnitude cyclic loading of lumbar ligaments

PubMed Central

D’Ambrosia, Peter; King, Karen; Davidson, Bradley; Zhou, Bing He; Lu, Yun

2010-01-01

Repetitive or overuse disorders of the lumbar spine affect the lives of workers and athletes. We hypothesize that repetitive anterior lumbar flexion–extension under low or high load will result in significantly elevated pro-inflammatory cytokines expression several hours post-activity. High loads will exhibit significantly higher expression than low loads. Lumbar spine of in vivo feline was subjected to cyclic loading at 0.25 Hz for six 10-min periods with 10 min of rest in between. One group was subjected to a low peak load of 20 N, whereas the second group to a high peak load of 60 N. Following a 7-h post-loading rest, the supraspinous ligaments of L-3/4, L-4/5 and L-5/6 and the unstimulated T-10/11 were excised for mRNA analysis and IL-1β, IL-6, IL-8, TNFα and TGFβ1 pro-inflammatory cytokines expression. Creep (laxity) developed in the lumbar spine during the loading and the subsequent 7 h of rest was calculated. A two-way mixed model ANOVA was used to assess difference in each cytokines expression between the two groups and control. Tukey HSD post hoc analysis delineated specific significant effects. Significance was set at 0.05. Low and high-load groups exhibited development of creep throughout the cyclic loading period and gradual recovery throughout the 7-h rest period. Residual creep of 24.8 and 30.2% were present in the low and high-load groups, respectively, 7-h post-loading. Significant increases in expression of all cytokines measured relative to control were obtained for supraspinous ligaments from both low and high-load magnitudes. IL-6, IL-8 and TGFβ1 expression in the high-load group were significantly higher relative to the low-load group. Significant increases in cytokines expression indicating tissue inflammation are observed several hours post-repetitive lumbar flexion–extension regardless of the load magnitude applied. Repetitive occupational and athletic activity, regardless of the load applied, may be associated with the potential of developing acute inflammatory conditions that may convert to chronic inflammation if the viscoelastic tissues are further exposed to repetitive activity over long periods. Appropriate rest periods are a relevant preventive measure. PMID:20336330

High SRPX2 protein expression predicts unfavorable clinical outcome in patients with prostate cancer

PubMed Central

Zhang, Meng; Li, Xiaoli; Fan, Zhirui; Zhao, Jing; Liu, Shuzheng; Zhang, Mingzhi; Li, Huixiang; Goscinski, Mariusz Adam; Fan, Huijie; Suo, Zhenhe

2018-01-01

Background Sushi repeat-containing protein X-linked 2 (SRPX2) is overexpressed in a variety of different tumor tissues and correlated with poor prognosis in patients. Little research focuses on the role of SRPX2 expression in prostate cancer (PCa), and the clinicopathological significance of the protein expression in this tumor is relatively unknown. However, our previous transcriptome data from those cancer stem-like cells indicated the role of SRPX2 in PCa. Materials and methods In this study, RT-PCR and Western blotting were firstly used to examine the SRPX2 expression in three PCa cell lines including LNCaP, DU145, and PC3, and then SRPX2 protein expression was immunohistochemically investigated and statistically analyzed in a series of 106 paraffin-embedded PCa tissue specimens. Results Significantly lower levels of SRPX2 expression were verified in the LNCaP cells, compared with the expression in the aggressive DU145 and PC3 cells, in both mRNA and protein levels. Immunohistochemically, there were variable SRPX2 protein expressions in the clinical samples. Moreover, high levels of SRPX2 expression in the PCa tissues were significantly associated with Gleason score (P=0.008), lymph node metastasis (P=0.009), and distant metastasis (P=0.021). Furthermore, higher levels of SRPX2 expression in the PCa tissues were significantly associated with shorter overall survival (OS) (P<0.001). Conclusion Our results demonstrate that SRPX2 is highly expressed in aggressive PCa cells in vitro, and its protein expression in PCa is significantly associated with malignant clinical features and shorter OS, strongly indicating its prognostic value in prostate cancers. PMID:29881288

Enhanced expressions of FHL2 and iASPP predict poor prognosis in acute myeloid leukemia.

PubMed

Cheng, Zhiheng; Dai, Yifeng; Pang, Yifan; Jiao, Yang; Zhao, Hongmian; Zhang, Zhihui; Qin, Tong; Hu, Ning; Zhang, Yijie; Ke, Xiaoyan; Chen, Yang; Wu, Depei; Shi, Jinlong; Fu, Lin

2018-06-18

iASPP is a negative regulator of the apoptotic function of p53, and it can enhance the ability of hematopoietic stem cells to self-renew and resist chemo- and radiation therapy. Recent study showed that iASPP could impact the proliferation and apoptosis of leukemia cells by interacting with FHL2. However, whether they have prognostic significance in acute myeloid leukemia (AML) is unknown. Eighty-four AML patients with FHL2 and iASPP expression data from The Cancer Genome Atlas database were enrolled in the study. Patients with high expressions of FHL2 and iASPP had significantly shorter event-free survival (EFS) and overall survival (OS) than patients with low expressions (P = 0.005, P = 0.003, respectively). Univariate analysis indicated that high expressions of FHL2 or iASPP were unfavorable for EFS and OS (all P < 0.05), while multivariate analysis confirmed that high FHL2 expression was an independent risk factor for EFS and OS (all P < 0.05). In patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT), however, EFS and OS were not significantly different between FHL2 or iASPP high- and low-expression groups. Our results suggested that high expressions of FHL2 and iASPP were poor prognostic factors for AML, but the prognostic effect might be overcome by allo-HSCT.

Decreased expression of class III β-tubulin is associated with unfavourable prognosis in patients with malignant melanoma.

PubMed

Shimizu, Akira; Kaira, Kyoichi; Yasuda, Masahito; Asao, Takayuki; Ishikawa, Osamu

2016-02-01

Class III β-tubulin (TUBB3) has been recognized as being associated with resistance to taxane-based regimens in several cancers. However, little is known about the clinicopathological significance of TUBB3 expression in patients with cutaneous malignant melanoma. The aim of this study was to examine the prognostic significance of TUBB3 expression in cutaneous malignant melanoma. A total of 106 patients with surgically resected cutaneous malignant melanoma were assessed. Tumour sections were immunohistochemically stained for TUBB3, Ki-67 and microvessel density with CD34. TUBB3 was highly expressed in 80% (85/106) of patients. No statistically significant relationship was observed between the high expression of TUBB3 and any variables. On univariate analysis, ulceration, disease stage, TUBB3 and CD34 revealed a significant relationship with overall survival and progression-free survival. Multivariate analysis confirmed that a low TUBB3 expression was an independent prognostic factor for poor prognosis of cutaneous malignant melanoma. The decreased expression of TUBB3 could be a significant marker for predicting unfavourable prognosis in patients with cutaneous malignant melanoma.

High TRAF6 Expression Is Associated With Esophageal Carcinoma Recurrence and Prompts Cancer Cell Invasion.

PubMed

Liu, Xinyang; Wang, Zhichao; Zhang, Guoliang; Zhu, Qikun; Zeng, Hui; Wang, Tao; Gao, Feng; Qi, Zhan; Zhang, Jinwen; Wang, Rui

2017-04-14

Esophageal cancer is one of the most common types of cancer, and it has a poor prognosis. The molecular mechanisms of esophageal cancer progression remain largely unknown. In this study, we aimed to investigate the clinical significance and biological function of tumor necrosis factor receptor-associated factor 6 (TRAF6) in esophageal cancer. Expression of TRAF6 in esophageal cancer was examined, and its correlation with clinicopathological factors and patient prognosis was analyzed. A series of functional and mechanism assays were performed to further investigate the function and underlying mechanisms in esophageal cancer. Expression of TRAF6 was highly elevated in esophageal cancer tissues, and patients with high TRAF6 expression have a significantly shorter survival time than those with low TRAF6 expression. Furthermore, loss-of-function experiments showed that knockdown of TRAF6 significantly reduced the migration and invasion abilities of esophageal cancer cells. Moreover, the pro-oncogenic effects of TRAF6 in esophageal cancer were mediated by the upregulation of AEP and MMP2. Altogether, our data suggest that high expression of TRAF6 is significant for esophageal cancer progression, and TRAF6 indicates poor prognosis in esophageal cancer patients, which might be a novel prognostic biomarker or potential therapeutic target in esophageal cancer.

High expression of Parkin predicts easier recurrence of patients with adjuvant transarterial chemoembolization.

PubMed

Zhang, Changlie; Song, Zhihong; Yu, Guangji

2017-10-01

To investigate the clinical significance of E3 ubiquitin ligase Parkin in patients with adjuvant transarterial chemoembolization after curative resection of hepatocellular carcinoma. Parkin expression of hepatocellular carcinomas was detected and its correlation with clinicopathological factors was analyzed with χ 2 test. The significance of Parkin in prognosis and recurrence was analyzed with log-rank test and the Cox-regression model. High expression of Parkin could result in lower recurrence-free survival rate instead of overall survival rate. Larger tumor size, positive tumor recurrence, advanced T, N, M and TNM stage were significantly associated with poorer prognosis. Larger tumor size, advanced T and TNM stage could lead to higher recurrence. High Parkin expression could predict easier recurrence to patients with adjuvant transarterial chemoembolization.

Organized metabolic crime in prostate cancer: The coexpression of MCT1 in tumor and MCT4 in stroma is an independent prognosticator for biochemical failure.

PubMed

Andersen, Sigve; Solstad, Ørjan; Moi, Line; Donnem, Tom; Eilertsen, Marte; Nordby, Yngve; Ness, Nora; Richardsen, Elin; Busund, Lill-Tove; Bremnes, Roy M

2015-08-01

Lactate import or export over cell membranes is facilitated by monocarboxylate transporters (MCTs) 1 and 4. Expression profiles can be markers of an oxidative or glycolytic phenotype. Descriptive studies and functional studies in neoplastic cells and fibroblasts in prostate cancer (PC) have suggested a distinct phenotype. We aimed to explore expression of MCT1 and MCT4 in PC cells and surrounding stroma in a large cohort. Additionally, we wanted to find out if distinct expression profiles were associated with biochemical failure-free survival (BFFS). Tissue microarrays were constructed from 535 patients with radical prostatectomies between January 1, 1995, and December 31, 2005. Immunohistochemistry was used to detect expression, and degrees of expression were evaluated semiquantitatively by 2 pathologists using light microscopy. For MCT1, there was only epithelial expression, whereas there was a low level of expression of MCT4 in tumor and stroma. A total of 172 patients had a low expression of MCT1 in tumor and MCT4 in stroma. There were 232 patients who had a high expression of MCT1 and a low expression of MCT4 in stroma. Only 11 patients had a low tumoral MCT1 expression and a high stromal MCT4 expression, and 26 patients (5%) had a high expression of both. Patients with a high-high combination had a significantly reduced BFFS (P = 0.011), and when adjusting for other factors, its effect was significant and independent (HR = 1.99, CI 95%: 1.09-3.62; P = 0.024). This study adds to the current understanding of the reversed Warburg effect to be a significant phenotype in PC. High coexpression of MCT1 in tumor and MCT4 in stroma is independently associated to a worse BFFS, and the strength of this association is as strong as having a Gleason score of ≥9. Copyright © 2015 Elsevier Inc. All rights reserved.

High-level SLP-2 expression and HER-2/neu protein expression are associated with decreased breast cancer patient survival.

PubMed

Cao, Wenfeng; Zhang, Bin; Liu, Yanxue; Li, Hongtao; Zhang, Shiwu; Fu, Li; Niu, Yun; Ning, Liansheng; Cao, Xuchen; Liu, Zhihua; Sun, Baocun

2007-09-01

There is sufficient evidence that human stomatin-like protein 2 (SLP-2) is a novel cancer-related gene. Its protein is overexpressed in many human cancers. SLP-2 can contribute to the promotion of cell growth, cell adhesion, and tumorigenesis in esophageal squamous cell carcinoma and lymph node metastasis in laryngeal squamous cell carcinoma. Immunohistochemical detection of SLP-2, estrogen and progesterone receptors, and HER-2/neu were performed on 263 cases of primary invasive breast cancer with a tissue microarray. Of 263 cases, 138 (52.5%) showed high expression of SLP-2 protein, and 125 (47.5%) showed low or absent expression. In addition, there were significant positive associations between tumor stage and size (P = .020), lymph node metastasis (P < .001), clinical stage (P < .001), distant metastasis (P = .002), and HER-2/neu protein expression (P = .037) and high-level SLP-2 expression. High-level SLP-2 expression was associated with decreased overall survival (P = .011) and was more often found in patients with tumors larger than 20 mm, lymph node metastasis, advanced clinical stage, distant metastasis, and HER-2/neu protein-positive expression. More important, lymph node metastasis, HER-2/neu-positive expression, and high-level SLP-2 expression were associated with significantly decreased survival.

High WT1 expression is an early predictor for relapse in patients with acute promyelocytic leukemia in first remission with negative PML-RARa after anthracycline-based chemotherapy: a single-center cohort study.

PubMed

Yoon, Jae-Ho; Kim, Hee-Je; Kwak, Dae-Hun; Park, Sung-Soo; Jeon, Young-Woo; Lee, Sung-Eun; Cho, Byung-Sik; Eom, Ki-Seong; Kim, Yoo-Jin; Lee, Seok; Min, Chang-Ki; Cho, Seok-Goo; Kim, Dong-Wook; Lee, Jong Wook; Min, Woo-Sung

2017-01-23

Wilms' tumor gene 1 (WT1) expression is a well-known predictor for relapse in acute myeloid leukemia. We monitored WT1 decrement along the treatment course to identify its significant role as a marker for residual disease in acute promyelocytic leukemia (APL) and tried to suggest its significance for relapse prediction. In this single center retrospective study, we serially measured PML-RARa and WT1 expression from 117 APL patients at diagnosis, at post-induction and post-consolidation chemotherapies, and at every 3 months after starting maintenance therapy. All 117 patients were in molecular remission after treatment of at least 2 consolidation chemotherapies. We used WT1 ProfileQuant™ kit (Ipsogen) for WT1 monitoring. High WT1 expression (>120 copies/10 4 ABL1) after consolidation and at early period (3 months) after maintenance therapy significantly predicted subsequent relapse. All paired PML-RARa RQ-PCR were not detected except for one sample with early relapse. Patients with high WT1 expression at 3 months after maintenance therapy (n = 40) showed a significantly higher relapse rate (30.5 vs. 6.9%, P < 0.001) and inferior disease free survival (62.8 vs. 91.4%, P < 0.001). Multivariate analysis revealed that high peak leukocyte counts at diagnosis (HR = 6.4, P < 0.001) and high WT1 expression at 3 months after maintenance therapy (HR = 7.1, P < 0.001) were significant factors for prediction of relapse. Our data showed high post-remission WT1 expression was a reliable marker for prediction of subsequent molecular relapse in APL. In this high-risk group, early intervention with ATRA ± ATO, anti-CD33 antibody therapy, and WT1-specific therapy may be used for relapse prevention. Clinical Research Information Service (CRIS), KCT0002079.

Towards a cognitive resource limitations model of diminished expression in schizotypy.

PubMed

Cohen, Alex S; Morrison, Sean C; Brown, Laura A; Minor, Kyle S

2012-02-01

Diminished expression of speech is a pernicious feature of both schizophrenia and schizotypy--defined as the personality organization reflecting a putative genetic schizophrenia liability. As yet, the mechanism underlying diminished expression is unclear. We tested the hypothesis that diminished expression reflects a cognitive resource issue--that is, as cognitive resources are depleted, expression becomes diminished in individuals with psychometrically defined schizotypy. Acoustic analysis of natural speech was procured during experimentally manipulated baseline and high cognitive-load dual tasks and examined in 38 individuals with psychometrically defined schizotypy and 34 controls. For both groups, expression significantly decreased as a function of increased task demands, although there were no group differences in expression or magnitude of change across baseline to high cognitive-load conditions. Participants with self-reported constricted affect showed significant reductions in expression under high-load versus baseline speaking conditions relative to other schizotypal and control participants. Moreover, psychometrically defined schizotypal participants with poor cognitive performance on the high-load task, suggestive of depleted cognitive resources, also showed expressivity reductions compared with other participants. These findings suggest that diminished expression occurs as a function of limited cognitive resources in psychometrically defined schizotypy. PsycINFO Database Record (c) 2012 APA, all rights reserved.

Prognostic impact of programmed cell death 1 ligand 1 expression in human leukocyte antigen class I-positive hepatocellular carcinoma after curative hepatectomy.

PubMed

Umemoto, Yuichiroh; Okano, Shinji; Matsumoto, Yoshihiro; Nakagawara, Hidekazu; Matono, Rumi; Yoshiya, Shohei; Yamashita, Yo-Ichi; Yoshizumi, Tomoharu; Ikegami, Toru; Soejima, Yuji; Harada, Mamoru; Aishima, Shinichi; Oda, Yoshinao; Shirabe, Ken; Maehara, Yoshihiko

2015-01-01

Hepatocellular carcinoma (HCC) is one of the most common solid tumors worldwide. Surgery is potentially curative, but high recurrence rates worsen patient prognosis. The interaction between the proteins programmed cell death 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1) is an important immune checkpoint. The significance of PD-L1 expression and human leukocyte antigen class I (HLA class I), recognized by CD8 T cells, in the prognosis of patients with HCC remains to be determined. We assessed the levels of PD-L1 and HLA class I expression on HCC samples from 80 patients who had undergone hepatectomy at our institution, and evaluated the correlations between PD-L1 and HLA class I expression and patient prognosis. High HLA class I expression was correlated with significantly better recurrence-free survival (RFS), but not overall survival (OS). Multivariate analysis showed that high HLA class I expression was an independent predictor of improved RFS. Low expression of PD-L1 on HCC tended to predict better OS, but the difference was not statistically significant. PD-L1 expression on HCC correlated with the number of CD163-positive macrophages and HLA class I expression with CD3-positive cell infiltration. Univariable and multivariable analyses showed that combined PD-L1 low/HLA class I high expression on HCCs was prognostic for improved OS and RFS. PD-L1 status may be a good predictor of prognosis in HCC patients with high HLA class I expression. Novel therapies targeting the PD-L1/PD-1 pathway may improve the prognosis of patients with HCC.

Prognostic factors of craniopharyngioma with special reference to autocrine/paracrine signaling: underestimated implication of growth hormone receptor.

PubMed

Ogawa, Yoshikazu; Watanabe, Mika; Tominaga, Teiji

2015-10-01

Craniopharyngioma is a slow-growing tumor classified as benign, but tight adhesion and significant local infiltration to the vital structures are common. In spite of improvement of modern microsurgery techniques and precise anatomical understanding not few cases of this tumor recur, and long-term tumor control and maintenance of quality of life are sometimes difficult. However, very little is known about the effects of the molecular characters of craniopharyngioma on the prognosis. Ninety eight cases of craniopharyngioma surgically treated at the Department of Neurosurgery, Tohoku University Hospital and Kohnan Hospital from April 1996 to May 2014, 45 males and 53 females aged from 2 to 80 years (mean, 40.84 years) were retrospectively reviewed, and postoperative outcomes and the possible involvement of the autocrine/paracrine mechanism were investigated. The patients were followed up at intervals of 6 months to assess tumor recurrence, and clinical outcomes were correlated with the findings of immunohistochemical examinations used growth hormone receptor (GHR) and downstream hormones. The follow-up period ranged from 3 to 209 months. Hormone expression was examined in 88 patients, of which 46 specimens (52.3 %) showed high expression of GHR. The GHR high expression group had a significantly shorter duration of postoperative stable disease compared with the low expression group (logrank test, p = 0.007). Simultaneous high expression of growth hormone (GH) and GHR was found in 33 specimens (37.5 %), and the high expression group had a significantly shorter duration of postoperative stable disease compared with the low expression group (logrank test, p = 0.011). No other hormones showed statistically significant differences in outcomes. High expression of GHR is associated with shorter duration of postoperative stable disease in patients with craniopharyngioma. If the surgical specimens were craniopharyngiomas with high GHR expression, GH supplementation would be introduced quite prudently.

Bile salt receptor TGR5 is highly expressed in esophageal adenocarcinoma and precancerous lesions with significantly worse overall survival and gender differences

PubMed Central

Pang, Chunhong; LaLonde, Amy; Godfrey, Tony E; Que, Jianwen; Sun, Jun; Wu, Tong Tong; Zhou, Zhongren

2017-01-01

Bile acid reflux in the esophagus plays an important role in the carcinogenesis of esophageal adenocarcinoma (EAC). The G-protein coupled bile acid receptor (TGR5) has been associated with the development of gastrointestinal cancer. However, little is known regarding the role of TGR5 in esophageal carcinoma and precancerous lesions. We analyzed genomic DNA from 116 EACs for copy number aberrations via Affymetrix SNP6.0 microarrays. The TGR5 gene locus was amplified in 12.7% (14/116) of the EACs. The TGR5 protein expression was also assessed using immunohistochemistry from tissue microarrays, including Barrett’s esophagus (BE), low-(LGD) and high-grade dysplasia (HGD), columnar cell metaplasia (CM), squamous epithelium (SE), EAC and squamous cell carcinoma. The TGR5 protein was highly expressed in 71% of EAC (75/106), 100% of HGD (11/11), 72% of LGD (13/18), 66% of BE (23/35), 84% of CM (52/62), and 36% of SE (30/83). The patients with high expression of TGR5 exhibited significantly worse overall survival compared to the patients with nonhigh expression. TGR5 high expression was significantly increased in the males compared to the females in all cases with an odds ratio of 1.9 times. The vitamin D receptor (VDR) was significantly correlated with TGR5 expression. Our findings indicated that TGR5 may play an important role in the development and prognosis of EAC through a bile acid ligand. Gender differences in TGR5 and VDR expression may explain why males have a higher incidence of EAC compared to females. PMID:28223834

Identification and expression analysis of cobia (Rachycentron canadum) Toll-like receptor 9 gene.

PubMed

Byadgi, Omkar; Puteri, Dinda; Lee, Yan-Horn; Lee, Jai-Wei; Cheng, Ta-Chih

2014-02-01

Cobia culture is hindered by bacterial infection (Photobacterium damselae subsp. piscicida) and in order to study the effect of P. damselae subsp. piscicida challenge and CpG ODN stimulation on cobia Toll like receptor 9 (RCTLR9), we used PCR to clone RCTLR9 gene and qRT-PCR to quantify gene expression. The results indicated that RCTLR9 cDNA contains 3141 bp. It encodes 1047 amino acids containing 16 typical structures of leucine-rich repeats (LRRs) including an LRRTYP, LRRCT and a motif involved in PAMP binding was identified at position 240-253 amino acid. Broad expression of RCTLR9 was found in larval, juvenile and adult stages irrespective of the tissues. In larval stage, RCTLR9 mRNA expression decreased at 5 d and then increased at 10 dph. At juvenile stage cobia, the expression was significantly high (p < 0.05) in spleen and intestine compared to gill, kidney, liver and skin. However, at adult stage, the significant high expression was found in gill and intestine. Cobia challenged with P. damselae subsp. piscicida showed significant increase in RCTLR9 expression at 24 h post challenge in intestine, spleen and liver, while in kidney the expression was peak at 12 h and later it decreased at 24 h. The highest expression was 40 fold increase in spleen and the lowest expression was ∼3.6 fold increase in liver. Cobia stimulated with CpG oligonucleotides showed that the induction of these genes was CpG ODN type and time dependent. In spleen and liver, CpG ODNs 1668 and 2006 injected group showed high expression of RCTLR9, IL-1β, chemokine CC compared to other groups. Meanwhile, CpG ODN 2006 has induced high expression of IgM. The CpG ODNs 2395 have induced significant high expression of Mx in spleen and liver. These results demonstrates the potential of using CpG ODN to enhance cobia resistance to P. damselae subsp. piscicida infection and use as an adjuvant in vaccine development. Copyright © 2013 Elsevier Ltd. All rights reserved.

Prognostic value of transformer 2β expression in prostate cancer.

PubMed

Diao, Yan; Wu, Dong; Dai, Zhijun; Kang, Huafeng; Wang, Ziming; Wang, Xijing

2015-01-01

Deregulation of transformer 2β (Tra2β) has been implicated in several cancers. However, the role of Tra2β expression in prostate cancer (PCa) is unclear. Therefore, this study was to investigate the expression of Tra2β in PCa and evaluated its association with clinicopathological variables and prognosis. Thirty paired fresh PCa samples were analyzed for Tra2β expression by Western blot analysis. Immunohistochemistry (IHC) assay was performed in 160 PCa samples after radical prostatectomy and adjacent non-cancerous tissues. Tra2β protein expression was divided into high expression group and low expression group by IHC. We also investigated the association of Tra2β expression with clinical and pathologic parameters. Kaplan-Meier plots and Cox proportional hazards regression model were used to analyze the association between Tra2β protein expression and prognosis of PCa patients. Our results showed that Tra2β was significantly upregulated in PCa tissues by western blot and IHC. Our data indicated that high expression of Tra2β was significantly associated with lymph node metastasis (P=0.002), clinical stage (P=0.015), preoperative prostate-specific antigen (P=0.003), Gleason score (P=0.001), and biochemical recurrence (P=0.021). High Tra2β expression was a significant predictor of poor biochemical recurrence free survival and overall survival both in univariate and multivariate analysis. We show that Tra2β was significantly upregulated in PCa patients after radical prostatectomy, and multivariate analysis confirmed Tra2β as an independent prognostic factor.

[Expression and clinical significance of KIAA1199 in primary hepatocellular carcinoma].

PubMed

Gu, C J; Ni, Q C; Ni, K; Zhang, S; Qian, H X

2018-05-29

Objective: To investigate the expression and clinical significance of KIAA1199 in primary hepatocellular carcinoma. Methods: A total of 136 cases of primary hepatocellular carcinoma tissues and paired adjacent tissues were collected. Immunohistochemistry and Western blot were used to detect the expression of KIAA1199 in primary hepatocellular carcinoma tissues and paired adjacent tissues. The relationship between KIAA1199 and clinicopathological parameter of primary hepatocellular carcinoma was analyzed. Results: The positive rate of KIAA1199 in primary hepatocellular carcinoma was 82.3% (112/136), which was higher than that in paired para-cancerous tissues (14.7%, 20/136). High expression of KIAA1199 was significantly correlated with age, cirrhosis history, tumor size, tumor number, degree of differentiation, TNM staging and microvenous invasion (MVI) ( P <0.05), but without gender, drinking alcohol hobby, hepatitis history, family genetic history, tumor location ( P >0.05). The Kaplan-Meier survival curves indicated that high KIAA1199 expression was associated with poor survival ( P <0.01). In addition, Cox proportional hazards model showed that the expression of KIAA1199 was related to age, cirrhosis history, tumor size, tumor number, degree of differentiation, TNM staging and MVI ( P <0.05). Conclusion: The expression of KIAA1199 is up-regulated in primary hepatocellular carcinoma, which is significantly correlated with the clinicopathological features and prognosis, high expression of KIAA1199 increased the risk of death in patients with primary hepatocellular carcinoma.

Matrix Metalloproteinase-20 Over-Expression Is Detrimental to Enamel Development: A Mus musculus Model

PubMed Central

Shin, Masashi; Hu, Yuanyuan; Tye, Coralee E.; Guan, Xiaomu; Deagle, Craig C.; Antone, Jerry V.; Smith, Charles E.; Simmer, James P.; Bartlett, John D.

2014-01-01

Background Matrix metalloproteinase-20 (Mmp20) ablated mice have enamel that is thin and soft with an abnormal rod pattern that abrades from the underlying dentin. We asked if introduction of transgenes expressing Mmp20 would revert this Mmp20 null phenotype back to normal. Unexpectedly, for transgenes expressing medium or high levels of Mmp20, we found opposite enamel phenotypes depending on the genetic background (Mmp20−/− or Mmp20+/+) in which the transgenes were expressed. Methodology/Principal Findings Amelx-promoter-Mmp20 transgenic founder mouse lines were assessed for transgene expression and those expressing low, medium or high levels of Mmp20 were selected for breeding into the Mmp20 null background. Regardless of expression level, each transgene brought the null enamel back to full thickness. However, the high and medium expressing Mmp20 transgenes in the Mmp20 null background had significantly harder more mineralized enamel than did the low transgene expresser. Strikingly, when the high and medium expressing Mmp20 transgenes were present in the wild-type background, the enamel was significantly less well mineralized than normal. Protein gel analysis of enamel matrix proteins from the high and medium expressing transgenes present in the wild-type background demonstrated that greater than normal amounts of cleavage products and smaller quantities of higher molecular weight proteins were present within their enamel matrices. Conclusions/Significance Mmp20 expression levels must be within a specific range for normal enamel development to occur. Creation of a normally thick enamel layer may occur over a wider range of Mmp20 expression levels, but acquisition of normal enamel hardness has a narrower range. Since over-expression of Mmp20 results in decreased enamel hardness, this suggests that a balance exists between cleaved and full-length enamel matrix proteins that are essential for formation of a properly hardened enamel layer. It also suggests that few feedback controls are present in the enamel matrix to prevent excessive MMP20 activity. PMID:24466234

Analysis of expression and prognostic significance of vimentin and the response to temozolomide in glioma patients.

PubMed

Lin, Lin; Wang, Guangzhi; Ming, Jianguang; Meng, Xiangqi; Han, Bo; Sun, Bo; Cai, Jinquan; Jiang, Chuanlu

2016-11-01

Gliomas are the most common primary intracranial malignant tumors in adults. Surgical resection followed by optional radiotherapy and chemotherapy is the current standard therapy for glioma patients. Vimentin, a protein of intermediate filament family, could maintain the cellular integrity and participate in several cell signal pathways to modulate the motility and invasion of cancer cells. The purpose of the present research was to identify the relationship between vimentin expression and clinical characteristics and detect the prognostic and predictive ability of vimentin in patients with glioma. To determine the expression of vimentin in glioma tissues, paraffin-embedded blocks from glioma patients by surgical resection were obtained and evaluated by immunohistochemistry. To further investigate the association of vimentin expression with survival, we employed mRNA expression of vimentin genes from the Chinese Glioma Genome Atlas (CGGA) and the GSE 16011 dataset. Kaplan-Meier analysis and Cox regression model were used to statistical analysis. We detected positive vimentin straining in 84 % of high-grade compared to 47 % in low-grade glioma patients. Additionally, vimentin mRNA expression was correlated with glioma grade in both CGGA and GSE16011 dataset. Patients with low vimentin expression have longer survival than high expression. In multivariate analysis, vimentin was an independent significant prognostic factor for high-grade glioma patients. We also identified that glioblastoma patients with low vimentin expression had a better response to temozolomide therapy. Vimentin expression has a significant association with tumor grade and overall survival of high-grade glioma patients. Low vimentin expression may benefit from temozolomide therapy.

[Expression of C-fos in nasopharyngeal carcinoma and the relationship with chemosensitivity and prognosis].

PubMed

Liu, Y T; Zhao, F P; Miao, H B; Fu, S Z; Zhou, S; Zhang, X G; Qin, G

2018-05-01

Objective: To investigate the expression of C-fos in patients with nasopharyngeal carcinoma(NPC), and analyze the relationship between the expression of C-fos and the clinical characteristics, chemosensitivity and prognosis. Method: Clinical and follow-up data of 75 NPC patients was analyzed retrospectively. The expression of C-fos was detected by immunohistochemical assay, and chemosensitivity was detected by ATP bioluminescent anticancer drug sensitivity detection technology. The relationship between them was studied. Result: The expression of C-fos in NPC was statistically higher than that in the control nasopharyngeal mucosa( P <0.001). It was found that C-fos had no statistical relationship with the gender, age, pathologic type, clinical stage of tumor classification, lymph node status, metastasis status and overall stage of NPC patients( P >0.05). NPC had different chemosensitivity with 8 anticancer drugs( P <0.001).There was a significant difference in chemosensitivity of paclitaxel between the high expression of C-fos group and the low expression of C-fos group( P =0.036). The rate of tumor progression was significantly higher in NPC patients with high expression of C-fos than in the low expression group( P =0.014).There was no significant difference in overall survival between the two groups( P =0.076). Conclusion: C-fos is highly expressed in NPC tissues, and the high expression of C-fos in NPC tissues may be related to tumor progression and resistance to paclitaxel. Copyright© by the Editorial Department of Journal of Clinical Otorhinolaryngology Head and Neck Surgery.

Delta-like ligand 4: A predictor of poor prognosis in clear cell renal cell carcinoma

PubMed Central

WANG, WEI; YU, YI; WANG, YA; LI, XIAOMING; BAO, JUNSHENG; WU, GONGJIN; CHANG, HONG; SHI, TINGKAI; YUE, ZHONGJIN

2014-01-01

Delta-like ligand 4 (Dll4)-Notch signaling is important in tumor angiogenesis; however, the prognostic value of D114 detection in patients with clear cell renal cell carcinoma (CCRCC) remains unclear. The present study aimed to determine whether the presence of high Dll4 expression levels was correlated with poor prognosis in CCRCC following curative resection. The D114 expression levels in four paired samples of CCRCC tissues and adjacent normal renal tissues were assayed by western blotting. Surgical specimens comprised 121 CCRCC tissue samples and 65 normal renal tissue samples, obtained from patients with CCRCC. The specimens were immunohistochemically assessed to determine Dll4 and vascular endothelial growth factor receptor 2 (VEGFR-2) expression levels. The prognostic significance of Dll4 expression levels was evaluated by the Kaplan-Meier method and Cox regression analysis. The correlation between Dll4 expression levels and VEGFR-2 expression levels, tumor stage, tumor grade and metastasis, was examined by χ2 test and multivariate logistic regression. As determined by the western blotting results, Dll4 protein expression levels were significantly increased in CCRCC tissues compared with those in adjacent non-cancerous tissues. From the analysis of the surgical specimens, 53 (43.8%) CCRCC patients exhibited immunohistochemically high Dll4 expression levels and 68 (56.2%) patients exhibited low Dll4 expression levels. The survival curves revealed that the patients with high Dll4 expression levels had significantly shorter survival times than the patients with low Dll4 expression levels (P<0.001). Multivariate survival analysis demonstrated that the presence of high Dll4 expression levels was independently associated with reduced overall survival and progression-free survival times (P=0.021 and 0.034, respectively). A positive correlation was also identified between Dll4 and VEGFR-2 expression levels (P=0.001). In conclusion, the results show that the presence of high Dll4 expression levels was clearly associated with high VEGFR-2 expression levels, tumor grade, tumor stage and poor prognosis in CCRCC patients. Therefore, inhibition of Dll4 may exert potent growth inhibitory effects on tumors resistant to anti-VEGF therapies for CCRCC. PMID:25364440

Prognostic significance of epithelial/stromal caveolin-1 expression in prostatic hyperplasia, high grade prostatic intraepithelial hyperplasia and prostatic carcinoma and its correlation with microvessel density.

PubMed

Mohammed, Dareen A; Helal, Duaa S

2017-03-01

Caveolin-1 may play a role in cancer development and progression. The aim was to record the expression and localization of caveolin-1 in benign prostatic hyperplasia (BPH), high grade prostatic intraepithelial neoplasia (HGPIN) and prostatic carcinoma (PCa). Microvessel density was evaluated with CD34 immunostain. Correlations with known prognostic factors of PCa were recorded. Immunohistochemical expression of caveolin-1 and the MVD was evaluated in 65 cases; BPH (25), HGPIN (20) and PCa (20). Stromal caveolin-1expression was significantly higher in BPH than HGPIN and PCca. There was significant inverse relation between stromal caveolin-1 expression and extension to lymph node and seminal vesicle in carcinoma cases. Epithelial caveolin-1 was significantly higher in carcinomas than in BPH and HGPIN. Epithelial expression in carcinoma was significantly associated with preoperative PSA, Gleason score and lymph node extension. MVD was significantly higher in PCa than in BPH and HGPIN. There were significant relations between MVD and preoperative PSA, Gleason score, lymph node and seminal vesicle extension. Stromal caveolin-1 was associated with low MVD while epithelial caveolin-1 with high MVD. Caveolin-1 plays an important role in prostatic carcinogenesis and metastasis. Stromal expression of caveolin-1 in PCa is lowered in relation to BPH and HGPIN. In PCa; stromal caveolin-1 was associated with good prognostic parameters. Epithelial caveolin-1 is significantly increased in PCa than BPH and HGPIN. It is associated with clinically aggressive disease. Caveolin-1 may play a role in angiogenesis. Copyright © 2017 National Cancer Institute, Cairo University. Production and hosting by Elsevier B.V. All rights reserved.

Long non-coding RNA gastric carcinoma highly expressed transcript 1 promotes cell proliferation and invasion in human head and neck cancer.

PubMed

Liu, Hui; Wu, Yu

2018-05-01

Recent evidence indicates that the long non-coding RNA gastric carcinoma highly expressed transcript 1 (GHET1) is involved in the development and carcinogenesis of several tumor types; however, the exact roles of GHET1 and its underlying mechanisms in head and neck cancer (HNC) remain largely unknown. In the present study, the expression patterns of GHET1 in HNC were determined and its clinical significance was assessed. The expression level of GHET1 was significantly increased in HNC tissues, compared with paired adjacent normal tissues. High GHET1 expression was significantly associated with advanced Tumor-Node-Metastasis stages and poor prognosis. Furthermore, inhibition of GHET1 suppressed cell proliferation, induced cell apoptosis and caused cell cycle arrest in vitro . In addition, GHET1 silencing inhibited cell migration and invasion. Taken together, the results of the present study indicated that GHET1 acts as an oncogene in HNC and may represent a novel therapeutic target.

CXCR4 expression varies significantly among different subtypes of glioblastoma multiforme (GBM) and its low expression or hypermethylation might predict favorable overall survival.

PubMed

Ma, Xinlong; Shang, Feng; Zhu, Weidong; Lin, Qingtang

2017-09-01

CXCR4 is an oncogene in glioblastoma multiforme (GBM) but the mechanism of its dysregulation and its prognostic value in GBM have not been fully understood. Bioinformatic analysis was performed by using R2 and the UCSC Xena browser based on data from GSE16011 in GEO datasets and in GBM cohort in TCGA database (TCGA-GBM). Kaplan Meier curves of overall survival (OS) were generated to assess the association between CXCR4 expression/methylation and OS in patients with GBM. GBM patients with high CXCR4 expression had significantly worse 5 and 10 yrs OS (p < 0.05). Across different GBM subtypes, there was an inverse relationship between overall DNA methylation and CXCR4 expression. CXCR4 expression was significantly lower in CpG island methylation phenotype (CIMP) group than in non CIMP group. Log rank test results showed that patients with high CXCR4 methylation (first tertile) had significantly better 5 yrs OS (p = 0.038). CXCR4 expression is regulated by DNA methylation in GBM and its low expression or hypermethylation might indicate favorable OS in GBM patients.

CES2, ABCG2, TS and Topo-I primary and synchronous metastasis expression and clinical outcome in metastatic colorectal cancer patients treated with first-line FOLFIRI regimen.

PubMed

Silvestris, Nicola; Simone, Giovanni; Partipilo, Giulia; Scarpi, Emanuela; Lorusso, Vito; Brunetti, Anna Elisabetta; Maiello, Evaristo; Paradiso, Angelo; Mangia, Anita

2014-09-05

Enzymatic activation of irinotecan (CPT-11) is due to carboxylesterase (CES), and its pharmacological behavior is influenced by drug resistance-related proteins. We previously reported that the clinical response and prognosis of metastatic colorectal cancer (mCRC) patients did not differ in tumors with different thymidylate synthase (TS) or topoisomerase-I (Topo-I) expression. Using immunohistochemistry (IHC), we evaluated the biological role of CES2 and the expression of breast cancer resistance protein (BCRP/ABCG2) in 58 consecutive mCRC patients, who had undergone a first-line CPT-11/5-FU/leucovirin (FOLFIRI) regimen. The expression of these proteins was also examined in a group of synchronous lymph nodes and liver metastases. Furthermore, all samples were revaluated for TS and Topo-I expression. High expression of CES2, ABCG2, TS and Topo-I was observed in 55%, 56%, 38% and 49% of patients, respectively. There was a significant association between high TS and high ABCG2 expression (p = 0.049). Univariate analysis showed that only TS expression significantly impacted on time to progression (p = 0.005). Moreover, Cox' multivariate analysis revealed that TS expression was significantly associated with overall survival (p = 0.01). No significant correlation was found between investigated markers expression and clinical response. Topo-I expression resulted in being significantly higher in liver metastases with respect to the corresponding primary tumors (p < 0.0001), emphasizing the role of Topo-I expression in metastatic cancer biology. In primary tumor tissues, CES2 expression tended to be higher than that observed in liver metastasis tissues (p = 0.05). These preliminary data may suggest CES2 over-expression as a potential marker of malignant phenotype. In light of these findings, we suggest that Topo-I expression together with TS expression could be associated with metastatic progression of CRC. Further studies are warranted with the aim of evaluating the potential predictive and prognostic role of CES2 and ABCG2 in larger series of patients.

Genome-Wide Survey on Genomic Variation, Expression Divergence, and Evolution in Two Contrasting Rice Genotypes under High Salinity Stress

PubMed Central

Jiang, Shu-Ye; Ma, Ali; Ramamoorthy, Rengasamy; Ramachandran, Srinivasan

2013-01-01

Expression profiling is one of the most important tools for dissecting biological functions of genes and the upregulation or downregulation of gene expression is sufficient for recreating phenotypic differences. Expression divergence of genes significantly contributes to phenotypic variations. However, little is known on the molecular basis of expression divergence and evolution among rice genotypes with contrasting phenotypes. In this study, we have implemented an integrative approach using bioinformatics and experimental analyses to provide insights into genomic variation, expression divergence, and evolution between salinity-sensitive rice variety Nipponbare and tolerant rice line Pokkali under normal and high salinity stress conditions. We have detected thousands of differentially expressed genes between these two genotypes and thousands of up- or downregulated genes under high salinity stress. Many genes were first detected with expression evidence using custom microarray analysis. Some gene families were preferentially regulated by high salinity stress and might play key roles in stress-responsive biological processes. Genomic variations in promoter regions resulted from single nucleotide polymorphisms, indels (1–10 bp of insertion/deletion), and structural variations significantly contributed to the expression divergence and regulation. Our data also showed that tandem and segmental duplication, CACTA and hAT elements played roles in the evolution of gene expression divergence and regulation between these two contrasting genotypes under normal or high salinity stress conditions. PMID:24121498

[The effect of altered oxygen partial pressure on the resisitance to hypoxia and expression of oxygen-sensitive genes in Drosophila melanogaster].

PubMed

Berezovs'kyĭ, V Ia; Chaka, O H; Litovka, I H; Levashov, M I; Ianko, R V

2014-01-01

As a result of resistance test to hypoxia of Drosophilas melanogaster of Oregon strain, we identified a high resistance (Group II) and low resistance (Group III) subpopulations of flies. Flies from groups II and III were incubated in a constant normobaric hypoxia (Po2=62-64 mm Hg) for 10 generations. A highly resistant group (Group IV) were exposed to a shortterm anoxia (Po,=1,5 mm Hg, 5 min) every generation. Larvae from Groups II, III, and IV demonstrated significantly elevated levels of Sir and CG 14740 expression. Larvae from Group II had a significantly higher expression of CG 14740 compared to group III. The restitution time after exposure to anoxia was significantly reduced in Group II (on 31% of the control values) Our results suggest that long-term adaptation to low oxygen partial pressure of highly resistant Drosophila significantly reduces the time of restitution and increases the expression of Sir2 and CG14740 genes.

Vascular endothelial growth factor and soft tissue sarcomas: tumor expression correlates with grade.

PubMed

Chao, C; Al-Saleem, T; Brooks, J J; Rogatko, A; Kraybill, W G; Eisenberg, B

2001-04-01

Vascular endothelial growth factor (VEGF), an endothelial-specific mitogen overexpressed in various epithelial malignancies is thought to be a potent regulator of angiogenesis. We hypothesized that some soft tissue sarcomas, due to their high propensity for hematogenous metastases (1) would overexpress VEGF, (2) that the degree of expression may represent a significant biologic predictor for disease-specific survival, and (3) that recurrent tumor would express as high or higher VEGF compared with the primary tumor. Selected paraffin-embedded tissue of surgical specimens from 79 patients with soft tissue sarcomas, treated between 1989 and 1995 were stained with a rabbit polyclonal anti-VEGF antibody at a concentration of 2 microg/ml. Slides were assessed for VEGF expression as high or low by two investigators blinded to the clinicopathologic data. Twelve patients had VEGF expression of their primary tumors, and their recurrent tumors were compared. The Fishers' exact test assessed for differences in VEGF expression; survival analyses were performed according to the methods of Kaplan and Meier. Seventy-eight percent (29 of 37) of patients who died of disease had high VEGF expression. However, VEGF expression was not an independent predictor of either overall or disease-free survival. Tumor grade correlated with VEGF expression significantly. For the low-grade tumors, 7 of 13 expressed low VEGF, whereas for high-grade tumors, 53 of 66 expressed high VEGF (P = .016). Seven of the 12 paired tumor samples expressed identical VEGF immunostaining. The majority of high-grade soft tissue sarcomas in this study have high intensity VEGF expression. This finding may provide useful information on individual soft tissue sarcomas and offer the basis for therapeutic and biologic targeting in high-risk patients using anti-angiogenesis strategies. However, in our analysis, after accounting for tumor grade, VEGF does not seem to be an independent predictor of clinical outcome.

E2F3a gene expression has prognostic significance in childhood acute lymphoblastic leukemia.

PubMed

Wang, Kai-Ling; Mei, Yan-Yan; Cui, Lei; Zhao, Xiao-Xi; Li, Wei-Jing; Gao, Chao; Liu, Shu-Guang; Jiao, Ying; Liu, Fei-Fei; Wu, Min-Yuan; Ding, Wei; Li, Zhi-Gang

2014-10-01

To study E2F3a expression and its clinical significance in children with acute lymphoblastic leukemia (ALL). We quantified E2F3a expression at diagnosis in 148 children with ALL by real-time PCR. In the test cohort (n = 48), receiver operating characteristic (ROC) curve was used to find the best cut-off point to divide the patients into E2F3a low- and high-expression groups. The prognostic significance of E2F3a expression was investigated in the test cohort and confirmed in the validation cohort (n = 100). The correlations of E2F3a expression with the clinical features and treatment outcome of these patients were analyzed. ROC curve analysis indicated that the best cut-off point of E2F3a expression was 0.3780. In the test cohort, leukemia-free survival (LFS) and event-free survival (EFS) of the low-expression group were lower than those of the high-expression group (log rank: P = 0.026 for both). This finding was verified in the validation cohort. LFS, EFS, and overall survival were also lower in the low-expression group than in the high-expression group (log rank, P = 0.015, 0.008, and 0.002 respectively). E2F3a low expression was correlated with the existence of BCR-ABL fusion. An algorithm composed of E2F3a expression and minimal residual disease (MRD) could predict relapse or induction failure more precisely than current risk stratification. These results were still significant in the ALL patients without BCR-ABL fusion. Low expression of E2F3a was associated with inferior prognosis in childhood ALL. An algorithm composed of E2F3a expression and MRD could predict relapse or induction failure more precisely than that of the current risk stratification. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Identification and prognostic value of anterior gradient protein 2 expression in breast cancer based on tissue microarray.

PubMed

Guo, Jilong; Gong, Guohua; Zhang, Bin

2017-07-01

Breast cancer has attracted substantial attention as one of the major cancers causing death in women. It is crucial to find potential biomarkers of prognostic value in breast cancer. In this study, the expression pattern of anterior gradient protein 2 in breast cancer was identified based on the main molecular subgroups. Through analysis of 69 samples from the Gene Expression Omnibus database, we found that anterior gradient protein 2 expression was significantly higher in non-triple-negative breast cancer tissues compared with normal tissues and triple-negative breast cancer tissues (p < 0.05). The data from a total of 622 patients from The Cancer Genome Atlas were analysed. The data from The Cancer Genome Atlas and results from quantitative reverse transcription polymerase chain reaction also verified the anterior gradient protein 2 expression pattern. Furthermore, we performed immunohistochemical analysis. The quantification results revealed that anterior gradient protein 2 is highly expressed in non-triple-negative breast cancer (grade 3 excluded) and grade 1 + 2 (triple-negative breast cancer excluded) tumours compared with normal tissues. Anterior gradient protein 2 was significantly highly expressed in non-triple-negative breast cancer (grade 3 excluded) and non-triple-negative breast cancer tissues compared with triple-negative breast cancer tissues (p < 0.01). In addition, anterior gradient protein 2 was significantly highly expressed in grade 1 + 2 (triple-negative breast cancer excluded) and grade 1 + 2 tissues compared with grade 3 tissues (p < 0.05). Analysis by Fisher's exact test revealed that anterior gradient protein 2 expression was significantly associated with histologic type, histological grade, oestrogen status and progesterone status. Univariate analysis of clinicopathological variables showed that anterior gradient protein 2 expression, tumour size and lymph node status were significantly correlated with overall survival in patients with grade 1 and 2 tumours. Cox multivariate analysis revealed anterior gradient protein 2 as a putative independent indicator of unfavourable outcomes (p = 0.031). All these data clearly showed that anterior gradient protein 2 is highly expressed in breast cancer and can be regarded as a putative biomarker for breast cancer prognosis.

Exercise reduces adipose tissue via cannabinoid receptor type 1 which is regulated by peroxisome proliferator-activated receptor-delta.

PubMed

Yan, Zhen Cheng; Liu, Dao Yan; Zhang, Li Li; Shen, Chen Yi; Ma, Qun Li; Cao, Ting Bing; Wang, Li Juan; Nie, Hai; Zidek, Walter; Tepel, Martin; Zhu, Zhi Ming

2007-03-09

Obesity is one major cardiovascular risk factor. We tested effects of endurance exercise on cannabinoid receptor type 1 (CB1) and peroxisome proliferator-activated receptor-delta (PPAR-delta)-dependent pathways in adipose tissue. Male Wistar rats were randomly assigned to standard laboratory chow or a high-fat diet without and with regular endurance exercise. Exercise in rats on high-fat diet significantly reduced visceral fat mass, blood pressure, and adipocyte size (each p<0.05). Adipocyte hypertrophy induced by high-fat diet was accompanied by increased CB1 expression in adipose tissue, whereas exercise significantly reduced CB1 expression (each p<0.05). CB1 receptor expression and adipocyte differentiation were directly regulated by PPAR-delta. Adipocyte hypertrophy induced by high-fat diet was accompanied by reduced PPAR-delta. Furthermore, selective silencing of PPAR-delta by RNA interference in 3T3-L1-preadipocyte cells significantly increased CB1 expression from 1.00+/-0.06 (n=3) to 1.91+/-0.06 (n=3; p<0.01) and increased adipocyte differentiation, whereas adenovirus-mediated overexpression of PPAR-delta significantly reduced CB1 expression to 0.39+/-0.03 (n=3; p<0.01) and reduced adipocyte differentiation. In the presence of the CB1 antagonist rimonabant adipocyte differentiation in stimulated 3T3 L1 preadipocyte cells was significantly reduced. The study indicates that high-fat diet-induced hypertrophy of adipocytes is associated with increased CB1 receptor expression which is directly regulated by PPAR-delta. Both CB1 and PPAR-delta are intimately involved in therapeutic interventions against a most important cardiovascular risk factor.

Expression of NLRR3 orphan receptor gene is negatively regulated by MYCN and Miz-1, and its downregulation is associated with unfavorable outcome in neuroblastoma.

PubMed

Akter, Jesmin; Takatori, Atsushi; Hossain, Md Shamim; Ozaki, Toshinori; Nakazawa, Atsuko; Ohira, Miki; Suenaga, Yusuke; Nakagawara, Akira

2011-11-01

Our previous study showed that expression of NLRR3 is significantly high in favorable neuroblastomas (NBL), whereas that of NLRR1 is significantly high in unfavorable NBLs. However, the molecular mechanism of transcriptional regulation of NLRR3 remains elusive. This study was undertaken to clarify the transcriptional regulation of NLRR3 and its association with the prognosis of NBL. NLRR3 and MYCN expressions in NBL cell lines were analyzed after induction of cell differentiation, MYCN knockdown, and overexpression. The transcriptional regulation of NLRR3 was analyzed by luciferase reporter and chromatin immunoprecipitation assays. Quantitative PCR was used for examining the expression of NLRR3, Miz-1, or MYCN in 87 primary NBLs. The expression of NLRR3 mRNA was upregulated during differentiation of NBL cells induced by retinoic acid, accompanied with reduced expression of MYCN, suggesting that NLRR3 expression was inversely correlated with MYCN in differentiation. Indeed, knockdown of MYCN induced NLRR3 expression, whereas exogenously expressed MYCN reduced cellular NLRR3 expression. We found that Miz-1 was highly expressed in favorable NBLs and NLRR3 was induced by Miz-1 expression in NBL cells. MYCN and Miz-1 complexes bound to NLRR3 promoter and showed a negative regulation of NLRR3 expression. In addition, a combination of low expression of NLRR3 and high expression of MYCN was highly associated with poor prognosis. NLRR3 is a direct target of MYCN, which associates with Miz-1 and negatively regulates NLRR3 expression. NLRR3 may play a role in NBL differentiation and the survival of NBL patients by inversely correlating with MYCN amplification. ©2011 AACR

Prognostic significance of NFIA and NFIB in esophageal squamous carcinoma and esophagogastric junction adenocarcinoma.

PubMed

Yang, Bo; Zhou, Zhi-Hang; Chen, Li; Cui, Xiang; Hou, Jun-Yan; Fan, Kai-Jie; Han, Si-Hao; Li, Peng; Yi, Shao-Qiong; Liu, Yang

2018-05-01

The nuclear factor I (NFI) family members, especially NFIA and NFIB, play essential roles in cancers. The roles of NFIA and NFIB in esophageal squamous cell carcinoma (ESCC) and esophagogastric junction adenocarcinoma (EJA) remain poorly known. This study aimed to determine the expression of NFIA and NFIB in ESCC and EJA and elucidate their prognostic significance. The expression of NFIA and NFIB was examined in 163 ESCC samples and 26 EJA samples by immunohistochemistry. The results showed that high NFIA expression correlated significantly with poor differentiation, lymph node metastasis, and advanced TNM stage in patients with ESCC. High NFIB expression only correlated with poor differentiation in patients with ESCC. Survival analysis showed that NFIA but not NFIB associated with short overall survival (OS) and disease-free survival (DFS) of patients with ESCC. On the other hand, high NFIB expression correlated with lymph node metastasis, advanced TNM stage, and short OS and DFS in patients with EJA. Finally, multivariate analysis demonstrated that high NFIA expression was an independent prognostic factor for ESCC. Taken together, these results demonstrated that NFIA and NFIB could serve as prognostic indicators for ESCC and EJA, respectively. © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Both high expression of pyruvate kinase M2 and vascular endothelial growth factor-C predicts poorer prognosis in human breast cancer.

PubMed

Lin, Yang; Liu, Fangfang; Fan, Yu; Qian, Xiaolong; Lang, Ronggang; Gu, Feng; Gu, Jun; Fu, Li

2015-01-01

Pyruvate kinase M2 (PKM2) and vascular endothelial growth factor-C (VEGF-C) have been known to play an important role in tumorigenesis and tumor progression in breast cancer. However, the association between PKM2 and VEGF-C in breast cancer remains unclear. In the present study, a total of 218 specimens from breast cancer patients and 26 paired breast tumors with adjacent normal tissues as well as two breast cancer cell lines were enrolled to investigate the correlation between PKM2 and VEGF-C. We found that PKM2 and VEGF-C mRNA levels were both significantly increasing in breast tumors compared with adjacent normal tissues. Knockdown of PKM2 mRNA expression resulted in VEGF-C mRNA and protein down-regulated as well as cell proliferation inhibited. A positive correlation between PKM2 and VEGF-C expression was identified by immunohistochemical analyses of 218 specimens of patients with breast cancer (P=0.023). PKM2 high expression was significantly correlated with histological grade (P=0.030), lymph node stage (P=0.001), besides VEGF-C high expression was significantly associated with lymphovascular invasion (P=0.012). While combined high expression of PKM2 and VEGF-C was found to be associated with worse histological grade, more lymph node metastasis, more lymphovascular invasion, shorter progression free survival (PFS), and poorer overall survival (OS) in human breast cancer. The results of the present study suggested that PKM2 expression was correlated with VEGF-C expression, and combination of PKM2 and VEGF-C levels had the better prognostic significance in predicting the poor outcome of patients with breast cancer.

GDNF family receptor α-1 in the catfish: Possible implication to brain dopaminergic activity.

PubMed

Mamta, Sajwan-Khatri; Senthilkumaran, Balasubramanian

2018-05-31

Glial cell line-derived neurotrophic factor (GDNF)is a potent trophic factor that preferentially binds to GDNF family receptor α-1 (GFRα-1)by regulating dopaminergic (DA-ergic) neuronsin brain. Present study aimed to evaluate the significance of GFRα-1 expression during early brain development in catfish. Initially, the full-length cDNA of GFRα-1 was cloned from adult brain which showed high homology with other vertebrate counterparts. Quantitative PCR analysis of tissue distribution revealed ubiquitous expression of GFRα-1 in the tissues analyzed with high levels in female brain and ovary. Significant high expression was evident in brain at 75 and 100 days post hatch females than the respective age-match males. Expression of GFRα-1 was high in brain during the spawning phase when compared to other reproductive phases. Localization of GFRα-1 revealed its presence in preoptic area-hypothalamus which correlated well with the expression profile in discrete areas of brain in adult catfish. Transient silencing of GFRα-1through siRNA lowered expression levels of GFRα-1, which further down regulated the expression of certain brain-specific genes. Expression of GFRα-1 in brain declined significantly upon treatment with the 1-methyl-1,2,3,6-tetrahydropyridinecausing neurodegeneration which further correlated with catecholamines (CA), L-3,4-dihydroxyphenylalanine, DA and norepinephrine levels. Taken together, GFRα-1 plausibly entrains gonadotropin-releasing hormone and gonadotropin axiseither directly or indirectly, at least by partially targeting CA-ergic activity. Copyright © 2018 Elsevier Inc. All rights reserved.

MMP-7 expression may influence the rate of distant recurrences and disease-specific survival in HPV-positive oropharyngeal squamous cell carcinoma.

PubMed

Vento, Seija I; Jouhi, Lauri; Mohamed, Hesham; Haglund, Caj; Mäkitie, Antti A; Atula, Timo; Hagström, Jaana; Mäkinen, Laura K

2018-05-02

The objective of this study was to determine if matrix metalloproteinase-7 (MMP-7) expression is related to human papilloma virus (HPV) status, clinical parameters, and outcome in oropharyngeal squamous cell carcinoma (OPSCC). Tumor tissue specimens from 201 OPSCC patients treated with curative intent were available for immunohistochemistry, and the samples were stained with monoclonal MMP-7 antibody. All the patients were followed up at least 3 years or until death. MMP-7 expression did not differ between HPV-positive and HPV-negative patients. MMP-7 was not prognostic among patients with HPV-negative OPSCC. In the HPV-positive subgroup, patients with moderate, high, or very high MMP-7 expression had significantly worse 5-year disease-specific survival (DSS) (56.6%) than patients with absent, or low MMP-7 expression (77.2%), and MMP-7 expression appeared as a prognostic factor in the multivariate analysis. In addition, among HPV-positive OPSCC with moderate, high, or very high MMP-7 expression, the 5-year distant recurrence-free survival was significantly lower (69.6%) than in those who had low or absent MMP-7 expression (97.5%). Our results suggest that among HPV-positive OPSCC patients, high MMP-7 expression is related to worse 5-year DSS and increased rate of distant recurrences.

A High-Fructose-High-Coconut Oil Diet Induces Dysregulating Expressions of Hippocampal Leptin and Stearoyl-CoA Desaturase, and Spatial Memory Deficits in Rats

PubMed Central

Lin, Ching-I; Shen, Chu-Fu; Hsu, Tsui-Han; Lin, Shyh-Hsiang

2017-01-01

We investigated the effects of high-fructose-high-fat diets with different fat compositions on metabolic parameters, hippocampal-dependent cognitive function, and brain leptin (as well as stearoyl-CoA desaturase (SCD1) mRNA expressions). Thirty-two male Wistar rats were divided into 3 groups, a control group (n = 8), a high-fructose soybean oil group (37.5% of fat calories, n = 12), and a high-fructose coconut oil group (37.5% of fat calories, n = 12) for 20 weeks. By the end of the study, the coconut oil group exhibited significantly higher serum fasting glucose, fructosamine, insulin, leptin, and triglyceride levels compared to those of the control and soybean oil groups. However, hippocampal leptin expression and leptin receptor mRNA levels were significantly lower, while SCD1 mRNA was significantly higher in rats fed the high-fructose-high-coconut oil diet than in rats fed the other experimental diets. In addition, the coconut oil group spent significantly less time in the target quadrant on the probe test in the Morris water maze (MWM) task. Rats fed the high-fructose-high-coconut oil diet for 20 weeks were prone to develop hyperglycemia, hyperinsulinemia, hyperleptinemia, and hypertriglyceridemia. These metabolic consequences may contribute to hippocampal-dependent memory impairment, accompanied by a lower central leptin level, and a higher SCD1 gene expression in the brain. PMID:28621759

A High-Fructose-High-Coconut Oil Diet Induces Dysregulating Expressions of Hippocampal Leptin and Stearoyl-CoA Desaturase, and Spatial Memory Deficits in Rats.

PubMed

Lin, Ching-I; Shen, Chu-Fu; Hsu, Tsui-Han; Lin, Shyh-Hsiang

2017-06-16

We investigated the effects of high-fructose-high-fat diets with different fat compositions on metabolic parameters, hippocampal-dependent cognitive function, and brain leptin (as well as stearoyl-CoA desaturase (SCD1) mRNA expressions). Thirty-two male Wistar rats were divided into 3 groups, a control group ( n = 8), a high-fructose soybean oil group (37.5% of fat calories, n = 12), and a high-fructose coconut oil group (37.5% of fat calories, n = 12) for 20 weeks. By the end of the study, the coconut oil group exhibited significantly higher serum fasting glucose, fructosamine, insulin, leptin, and triglyceride levels compared to those of the control and soybean oil groups. However, hippocampal leptin expression and leptin receptor mRNA levels were significantly lower, while SCD1 mRNA was significantly higher in rats fed the high-fructose-high-coconut oil diet than in rats fed the other experimental diets. In addition, the coconut oil group spent significantly less time in the target quadrant on the probe test in the Morris water maze (MWM) task. Rats fed the high-fructose-high-coconut oil diet for 20 weeks were prone to develop hyperglycemia, hyperinsulinemia, hyperleptinemia, and hypertriglyceridemia. These metabolic consequences may contribute to hippocampal-dependent memory impairment, accompanied by a lower central leptin level, and a higher SCD1 gene expression in the brain.

CD10 and osteopontin expression in dentigerous cyst and ameloblastoma.

PubMed

Masloub, Shaimaa M; Abdel-Azim, Adel M; Elhamid, Ehab S Abd

2011-05-24

To investigate the expression of CD10 and osteopontin in dentigerous cyst and ameloblastoma and to correlate their expression with neoplastic potentiality of dentigerous cyst and local invasion and risk of local recurrence in ameloblastoma. CD10 and osteopontin expression was studied by means of immunohistochemistry in 9 cases of dentigerous cysts (DC) and 17 cases of ameloblastoma. There were 7 unicystic ameloblastoma (UCA) and 10 multicystic ameloblastoma (MCA). Positive cases were included in the statistical analysis, carried on the tabulated data using the Open Office Spreadsheet 3.2.1 under Linux operating system. Analysis of variance and correlation studies were performed using "R" under Linux operating system (R Development Core Team (2010). Tukey post-hoc test was also performed as a pair-wise test. The significant level was set at 0.05. High CD10 and osteopontin expression was observed in UCA and MCA, and low CD10 and osteopontin expression was observed in DC. Significant correlation was seen between CD10 and osteopontin expression and neoplastic potentiality of DC and local invasion and risk of recurrences in ameloblastoma. In DC, high CD10 and osteopontin expression may indicate the neoplastic potentiality of certain areas. In UCA & MCA, high CD10 and osteopontin expression may identify areas with locally invasive behavior and high risk of recurrence.

Increased Expression of ALDH1A1 in Prostate Cancer is Correlated With Tumor Aggressiveness: A Tissue Microarray Study of Iranian Patients.

PubMed

Kalantari, Elham; Saadi, Faezeh H; Asgari, Mojgan; Shariftabrizi, Ahmad; Roudi, Raheleh; Madjd, Zahra

2017-09-01

Subpopulations of prostate cancer (PCa) cells expressing putative stem cell markers possess the ability to promote tumor growth, maintenance, and progression. This study aimed to evaluate the expression patterns and clinical significance of putative stem cell marker aldehyde dehydrogenase 1 A1 (ALDH1A1) in prostate tumor tissues. ALDH1A1 expression was examined in a well-defined series of prostate tissues, including 105 (68%) samples of PCa, 21 (13%) samples of high-grade prostatic intraepithelial neoplasia, and 31 (19%) samples of benign prostate hyperplasia, which were embedded in tissue microarray blocks. The correlation of ALDH1A1 expression with clinicopathologic parameters was also assessed. There was a significant difference between the expression level of ALDH1A1 in PCa compared with the high-grade prostatic intraepithelial neoplasia and benign prostate hyperplasia samples (P<0.001). PCa cells expressing ALDH1A1 were more often seen in samples with advanced Gleason score (P=0.05) and high serum prostate specific antigen level (P=0.02). In addition, a positive correlation was found between ALDH1A1 expression and primary tumor stage and regional lymph node involvement (P=0.04 and 0.03, respectively). The significant association between ALDH1A1 expressions with Gleason score indicates the potential role of this protein in PCa tumorigenesis and aggressive behavior; therefore, this cancer stem cell marker can be used as a promising candidate for targeted therapy of PCa, especially those with high Gleason score.

Relationship between expression of gastrin, somatostatin, Fas/FasL and caspases in large intestinal carcinoma.

PubMed

Mao, Jia-Ding; Wu, Pei; Yang, Ying-Lin; Wu, Jian; Huang, He

2008-05-14

To explore the correlation between the mRNAs and protein expression of gastrin (GAS), somatostatin (SS) and apoptosis index (AI), apoptosis regulation gene Fas/FasL and caspases in large intestinal carcinoma (LIC). Expression of GAS and SS mRNAs were detected by nested RT-PCR in 79 cases of LIC. Cell apoptosis was detected by molecular biology in situ apoptosis detecting methods (TUNEL). Immunohistochemical staining for GAS, SS, Fas/FasL, caspase-3 and caspase-8 was performed according to the standard streptavidin-biotin-peroxidase (S-P) method. There was a significant positive correlation between mRNA and protein expression of GAS and SS (GASrs = 0.99, P < 0.01; SSrs = 0.98, P < 0.01). There was significant difference in positive expression rates of GAS, SS mRNAs and protein among different histological differentiation, histological types and Dukes' stage of LIC. The AI in GAS high and moderate expression groups was significantly lower than that in low expression groups (3.75 +/- 2.38 vs 7.82 +/- 2.38, P < 0.01; 5.51 +/- 2.66 vs 7.82 +/- 2.38, P < 0.01), and the AI in SS high and moderate expression groups was significantly higher than that in low expression groups (9.03 +/- 1.76 vs 5.35 +/- 3.00, P < 0.01; 7.44 +/- 2.67 vs 5.35 +/- 3.00, P < 0.01). There was a significant negative correlation between the integral ratio of GAS to SS and the AI (r(s) = -0.41, P < 0.01). The positive expression rate of FasL in GAS high and moderate expression groups was higher than that in low expression group (90.9% and 81.0% vs 53.2%, P < 0.05). The positive expression rates of Fas, caspase-8 and caspase-3 in SS high (90.0%, 90.0% and 100%) and moderate (80.0%, 70.0%, 75.0%) expression groups were higher than that in low expression group (53.1%, 42.9%, 49.0%) (90.0% and 80.0% vs 53.1%, P < 0.05; 90.0% and 70.0% vs 42.9%, P < 0.05; 100.0% and 75.0% vs 49.0%, P < 0.05). There was a significant positive correlation between the integral ratio of GAS to SS and the semiquantitative integral of FasL (rs = 0.32, P < 0.01). GAS and SS play important roles in the regulation and control of cell apoptosis in LIC, and the mechanism may be directly related to the aberrant expression of Fas/FasL. The GAS and SS will be valuable targets of the biological behavior of LIC.

Relationship between expression of gastrin, somatostatin, Fas/FasL and caspases in large intestinal carcinoma

PubMed Central

Mao, Jia-Ding; Wu, Pei; Yang, Ying-Lin; Wu, Jian; Huang, He

2008-01-01

AIM: To explore the correlation between the mRNAs and protein expression of gastrin (GAS), somatostatin (SS) and apoptosis index (AI), apoptosis regulation gene Fas/FasL and caspases in large intestinal carcinoma (LIC). METHODS: Expression of GAS and SS mRNAs were detected by nested RT-PCR in 79 cases of LIC. Cell apoptosis was detected by molecular biology in situ apoptosis detecting methods (TUNEL). Immunohistochemical staining for GAS, SS, Fas/FasL, caspase-3 and caspase-8 was performed according to the standard streptavidin-biotin-peroxidase (S-P) method. RESULTS: There was a significant positive correlation between mRNA and protein expression of GAS and SS (GASrs=0.99, P < 0.01; SSrs = 0.98, P < 0.01). There was significant difference in positive expression rates of GAS, SS mRNAs and protein among different histological differentiation, histological types and Dukes’ stage of LIC. The AI in GAS high and moderate expression groups was significantly lower than that in low expression groups (3.75 ± 2.38 vs 7.82 ± 2.38, P < 0.01; 5.51 ± 2.66 vs 7.82 ± 2.38, P < 0.01), and the AI in SS high and moderate expression groups was significantly higher than that in low expression groups (9.03 ± 1.76 vs 5.35 ± 3.00, P < 0.01; 7.44 ± 2.67 vs 5.35 ± 3.00, P < 0.01). There was a significant negative correlation between the integral ratio of GAS to SS and the AI (rs = -0.41, P < 0.01). The positive expression rate of FasL in GAS high and moderate expression groups was higher than that in low expression group (90.9% and 81.0% vs 53.2%, P < 0.05). The positive expression rates of Fas, caspase-8 and caspase-3 in SS high (90.0%, 90.0% and 100%) and moderate (80.0%, 70.0%, 75.0%) expression groups were higher than that in low expression group (53.1%, 42.9%, 49.0%) (90.0% and 80.0% vs 53.1%, P < 0.05; 90.0% and 70.0% vs 42.9%, P < 0.05; 100.0% and 75.0% vs 49.0%, P < 0.05). There was a significant positive correlation between the integral ratio of GAS to SS and the semiquantitative integral of FasL (rs = 0.32, P < 0.01). CONCLUSION: GAS and SS play important roles in the regulation and control of cell apoptosis in LIC, and the mechanism may be directly related to the aberrant expression of Fas/FasL. The GAS and SS will be valuable targets of the biological behavior of LIC. PMID:18473402

High Nuclear Hypoxia-Inducible Factor 1 Alpha Expression Is a Predictor of Distant Recurrence in Patients With Resected Pancreatic Adenocarcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Colbert, Lauren E.; Winship Cancer Institute, Emory University, Atlanta, Georgia; Memorial Sloan-Kettering Cancer Center, New York, New York

Purpose: To evaluate nuclear hypoxia-inducible factor 1α (HIF-1α) expression as a prognostic factor for distant recurrence (DR) and local recurrence (LR) after pancreatic adenocarcinoma resection. Methods and Materials: Tissue specimens were collected from 98 patients with pancreatic adenocarcinoma who underwent resection without neoadjuvant therapy between January 2000 and December 2011. Local recurrence was defined as radiographic or pathologic evidence of progressive disease in the pancreas, pancreatic bed, or associated nodal regions. Distant recurrence was defined as radiographically or pathologically confirmed recurrent disease in other sites. Immunohistochemical staining was performed and scored by an independent pathologist blinded to patient outcomes. Highmore » HIF-1α overall expression score was defined as high percentage and intensity staining and thus score >1.33. Univariate analysis was performed for HIF-1α score with LR alone and with DR. Multivariate logistic regression was used to determine predictors of LR and DR. Results: Median follow-up time for all patients was 16.3 months. Eight patients (8%) demonstrated isolated LR, 26 patients (26.5%) had isolated DR, and 13 patients had both LR and DR. Fifty-three patients (54%) had high HIF-1α expression, and 45 patients (46%) had low HIF-1α expression. High HIF-1α expression was significantly associated with DR (P=.03), and low HIF-1α expression was significantly associated with isolated LR (P=.03). On multivariate logistic regression analysis, high HIF-1α was the only significant predictor of DR (odds ratio 2.46 [95% confidence interval 1.06-5.72]; P=.03). In patients with a known recurrence, an HIF-1α score ≥2.5 demonstrated a specificity of 100% for DR. Conclusions: High HIF-1α expression is a significant predictor of distant failure versus isolated local failure in patients undergoing resection of pancreatic adenocarcinoma. Expression of HIF-1α may have utility in determining candidates for adjuvant local radiation therapy and systemic chemotherapy.« less

Co-Expression of Putative Cancer Stem Cell Markers CD44 and CD133 in Prostate Carcinomas.

PubMed

Kalantari, Elham; Asgari, Mojgan; Nikpanah, Seyedehmoozhan; Salarieh, Naghme; Asadi Lari, Mohammad Hossein; Madjd, Zahra

2017-10-01

Cancer stem cells (CSCs) are the main players of prostate tumorigenesis thus; characterization of CSCs can pave the way for understanding the early detection, drug resistance, metastasis and relapse. The current study was conducted to evaluate the expression level and clinical significance of the potential CSC markers CD44 and CD133 in a series of prostate tissues. One hundred and forty eight prostate tissues composed of prostate cancer (PCa), high-grade prostatic intraepithelial neoplasia (HGPIN), and benign prostate hyperplasia (BPH) were immunostained for the putative CSC markers CD44 and CD133. Subsequently, the correlation between the expression of these markers and the clinicopathological variables was examined. A higher level of CD44 expression was observed in 42% of PCa, 57% of HGPIN, and 42% BPH tissues. In the case of CD133 expression PCa, HGPIN, and BPH samples demonstrated high immunoreactivity in 46%, 43%, and 42% of cells, respectively. Statistical analysis showed an inverse significant correlation between CD44 expression with Gleason score of PCa (P = 0.02), while no significant correlation was observed between CD133 expression and clinicopathological parameters. A significant reciprocal correlation was observed between the expression of two putative CSC markers CD44 and CD133 in PCa specimens while not indicating clinical significance. Further clinical investigation is required to consider these markers as targets of new therapeutic strategies for PCa.

Chemokine Receptor CXCR4 Expression in Patients With Melanoma and Colorectal Cancer Liver Metastases and the Association With Disease Outcome

PubMed Central

Kim, Joseph; Mori, Takuji; Chen, Steven L.; Amersi, Farin F.; Martinez, Steve R.; Kuo, Christine; Turner, Roderick R.; Ye, Xing; Bilchik, Anton J.; Morton, Donald L.; Hoon, Dave S. B.

2006-01-01

Objective: To determine the role of chemokine receptor (CR) expression in patients with melanoma and colorectal cancer (CRC) liver metastases. Summary Background Data: Murine and in vitro models have identified CR as potential factors in organ-specific metastasis of multiple cancers. Chemokines via their respective receptors have been shown to promote cell migration to distant organs. Methods: Patients who underwent hepatic surgery for melanoma or CRC liver metastases were assessed. Screening cDNA microarrays of melanoma/CRC cell lines and tumor specimens were analyzed to identify CR. Microarray data were validated by quantitative real-time RT-PCR (qRT) in paraffin-embedded liver metastases. Migration assays and immunohistochemistry were performed to verify CR function and confirm CR expression, respectively. Results: Microarray analysis identified CXCR4 as the most common CR expressed by both cancers. qRT demonstrated CXCR4 expression in 24 of 27 (89%) melanoma and 28 of 29 (97%) CRC liver metastases. In vitro treatment of melanoma or CRC cells with CXCL12, the ligand for CXCR4, significantly increased cell migration (P < 0.001). Low versus high CXCR4 expression in CRC liver metastases correlated with a significant difference in overall survival (median 27 months vs. 10 months, respectively; P = 0.036). In melanoma, low versus high CXCR4 expression in liver metastases demonstrated no difference in overall survival (median 11 months vs. 8 months, respectively; P = not significant). Conclusions: CXCR4 is expressed and functional on melanoma and CRC cells. The ligand for CXCR4 is highly expressed in liver and may specifically attract melanoma and CRC CXCR4 (+) cells. Quantitative analysis of CXCR4 gene expression in patients with liver metastases has prognostic significance for disease outcome. PMID:16794396

Expression of Y-box-binding protein YB-1 allows stratification into long- and short-term survivors of head and neck cancer patients.

PubMed

Kolk, A; Jubitz, N; Mengele, K; Mantwill, K; Bissinger, O; Schmitt, M; Kremer, M; Holm, P S

2011-12-06

Histology-based classifications and clinical parameters of head and neck squamous cell carcinoma (HNSCC) are limited in their clinical capacity to provide information on prognosis and treatment choice of HNSCC. The primary aim of this study was to analyse Y-box-binding protein-1 (YB-1) protein expression in different grading groups of HNSCC patients, and to correlate these findings with the disease-specific survival (DSS). We investigated the expression and cellular localisation of the oncogenic transcription/translation factor YB-1 by immunohistochemistry on tissue micro arrays in a total of 365 HNSCC specimens and correlated expression data with clinico-pathological parameters including DSS. Compared with control tissue from healthy individuals, a significantly (P<0.01) increased YB-1 protein expression was observed in high-grade HNSCC patients. By univariate survival data analysis, HNSCC patients with elevated YB-1 protein expression had a significantly (P<0.01) decreased DSS. By multivariate Cox regression analysis, high YB-1 expression and nuclear localisation retained its significance as a statistically independent (P<0.002) prognostic marker for DSS. Within grade 2 group of HNSCC patients, a subgroup defined by high nuclear and cytoplasmic YB-1 levels (co-expression pattern) in the cells of the tumour invasion front had a significantly poorer 5-year DSS rate of only 38% compared with overall 55% for grade 2 patients. Vice versa, the DSS rate was markedly increased to 74% for grade 2 cancer patients with low YB-1 protein expression at the same localisation. Our findings point to the fact that YB-1 expression in combination with histological classification in a double stratification strategy is superior to classical grading in the prediction of tumour progression in HNSCC.

Expression of Y-box-binding protein YB-1 allows stratification into long- and short-term survivors of head and neck cancer patients

PubMed Central

Kolk, A; Jubitz, N; Mengele, K; Mantwill, K; Bissinger, O; Schmitt, M; Kremer, M; Holm, P S

2011-01-01

Background: Histology-based classifications and clinical parameters of head and neck squamous cell carcinoma (HNSCC) are limited in their clinical capacity to provide information on prognosis and treatment choice of HNSCC. The primary aim of this study was to analyse Y-box-binding protein-1 (YB-1) protein expression in different grading groups of HNSCC patients, and to correlate these findings with the disease-specific survival (DSS). Methods: We investigated the expression and cellular localisation of the oncogenic transcription/translation factor YB-1 by immunohistochemistry on tissue micro arrays in a total of 365 HNSCC specimens and correlated expression data with clinico-pathological parameters including DSS. Results: Compared with control tissue from healthy individuals, a significantly (P<0.01) increased YB-1 protein expression was observed in high-grade HNSCC patients. By univariate survival data analysis, HNSCC patients with elevated YB-1 protein expression had a significantly (P<0.01) decreased DSS. By multivariate Cox regression analysis, high YB-1 expression and nuclear localisation retained its significance as a statistically independent (P<0.002) prognostic marker for DSS. Within grade 2 group of HNSCC patients, a subgroup defined by high nuclear and cytoplasmic YB-1 levels (co-expression pattern) in the cells of the tumour invasion front had a significantly poorer 5-year DSS rate of only 38% compared with overall 55% for grade 2 patients. Vice versa, the DSS rate was markedly increased to 74% for grade 2 cancer patients with low YB-1 protein expression at the same localisation. Conclusion: Our findings point to the fact that YB-1 expression in combination with histological classification in a double stratification strategy is superior to classical grading in the prediction of tumour progression in HNSCC. PMID:22095225

Immunohistochemical and Biochemical Expression Patterns of TTF-1, RAGE, GLUT-1 and SOX2 in HCV-Associated Hepatocellular Carcinomas

PubMed Central

Aboushousha, Tarek; Mamdouh, Samah; Hamdy, Hussam; Helal, Noha; Khorshed, Fatma; Safwat, Gehan; Seleem, Mohamed

2018-01-01

Objective: To investigate the expression of TTF-1, RAGE, GLUT1 and SOX2 in HCV-associated HCCs and in surrounding non-tumorous liver tissue. Material and Methods: Tissue material from partial hepatectomy cases for HCC along with corresponding serum samples and 30 control serum samples from healthy volunteers were studied. Biopsies were classified into: non-tumor hepatic tissue (36 sections); HCC (33 sections) and liver cell dysplasia (LCD) (15 sections). All cases were positive for HCV. Immunohistochemistry (IHC), gene extraction and quantitative real-time reverse-transcription assays (qRT-PCR) were applied. Results: By IHC, LCD and HCC showed significantly high percentages of positive cases with all markers. SOX2 showed significant increase with higher HCC grades, while RAGE demonstrated an inverse relation and GLUT-1 and TTF-1 lacked any correlation. In nontumorous-HCV tissue, we found significantly high TTF-1, low RAGE and negative SOX2 expression. RAGE, GLUT-1 and SOX2 show non-significant elevation positivity in high grade HCV compared to low grade lesions. TTF-1, RAGE and SOX2 exhibited low expression in cirrhosis compared to fibrosis. Biochemical studies on serum and tissue extracts revealed significant down-regulation of RAGE, GLUT-1 and SOX2 genes, as well as significant up-regulation of the TTF-1 gene in HCC cases compared to controls. All studied genes show significant correlation with HCC grade. In non-tumor tissue, only TTF-1 gene expression had a significant correlation with the fibrosis score. Conclusion: Higher expression of TTF-1, RAGE, GLUT-1 and SOX2 in HCC and dysplasia compared to non-tumor tissues indicates up-regulation of these markers as early events during the development of HCV-associated HCC. PMID:29373917

Immunohistochemical and Biochemical Expression Patterns of TTF-1, RAGE, GLUT-1 and SOX2 in HCV-Associated Hepatocellular Carcinomas

PubMed

Aboushousha, Tarek; Mamdouh, Samah; Hamdy, Hussam; Helal, Noha; Khorshed, Fatma; Safwat, Gehan; Seleem, Mohamed

2018-01-27

Objective: To investigate the expression of TTF-1, RAGE, GLUT1 and SOX2 in HCV-associated HCCs and in surrounding non-tumorous liver tissue. Material and Methods: Tissue material from partial hepatectomy cases for HCC along with corresponding serum samples and 30 control serum samples from healthy volunteers were studied. Biopsies were classified into: non-tumor hepatic tissue (36 sections); HCC (33 sections) and liver cell dysplasia (LCD) (15 sections). All cases were positive for HCV. Immunohistochemistry (IHC), gene extraction and quantitative real-time reverse-transcription assays (qRT-PCR) were applied. Results: By IHC, LCD and HCC showed significantly high percentages of positive cases with all markers. SOX2 showed significant increase with higher HCC grades, while RAGE demonstrated an inverse relation and GLUT-1 and TTF-1 lacked any correlation. In nontumorous-HCV tissue, we found significantly high TTF-1, low RAGE and negative SOX2 expression. RAGE, GLUT-1 and SOX2 show non-significant elevation positivity in high grade HCV compared to low grade lesions. TTF-1, RAGE and SOX2 exhibited low expression in cirrhosis compared to fibrosis. Biochemical studies on serum and tissue extracts revealed significant down-regulation of RAGE, GLUT-1 and SOX2 genes, as well as significant up-regulation of the TTF-1 gene in HCC cases compared to controls. All studied genes show significant correlation with HCC grade. In non-tumor tissue, only TTF-1 gene expression had a significant correlation with the fibrosis score. Conclusion: Higher expression of TTF-1, RAGE, GLUT-1 and SOX2 in HCC and dysplasia compared to non-tumor tissues indicates up-regulation of these markers as early events during the development of HCV-associated HCC. Creative Commons Attribution License

High glucose induces inflammatory cytokine through protein kinase C-induced toll-like receptor 2 pathway in gingival fibroblasts

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jiang, Shao-Yun, E-mail: jiangshaoyun@yahoo.com; Wei, Cong-Cong; Shang, Ting-Ting

2012-10-26

Highlights: Black-Right-Pointing-Pointer High glucose significantly induced TLR2 expression in gingival fibroblasts. Black-Right-Pointing-Pointer High glucose increased NF-{kappa}B p65 nuclear activity, IL-1{beta} and TNF-{alpha} levels. Black-Right-Pointing-Pointer PKC-{alpha}/{delta}-TLR2 pathway is involved in periodontal inflammation under high glucose. -- Abstract: Toll-like receptors (TLRs) play a key role in innate immune response and inflammation, especially in periodontitis. Meanwhile, hyperglycemia can induce inflammation in diabetes complications. However, the activity of TLRs in periodontitis complicated with hyperglycemia is still unclear. In the present study, high glucose (25 mmol/l) significantly induced TLR2 expression in gingival fibroblasts (p < 0.05). Also, high glucose increased nuclear factor kappa B (NF-{kappa}B)more » p65 nuclear activity, tumor necrosis factor-{alpha} (TNF-{alpha}) and interleukin-l{beta} (IL-1{beta}) levels. Protein kinase C (PKC)-{alpha} and {delta} knockdown with siRNA significantly decreased TLR2 and NF-{kappa}B p65 expression (p < 0.05), whereas inhibition of PKC-{beta} had no effect on TLR2 and NF-{kappa}B p65 under high glucose (p < 0.05). Additional studies revealed that TLR2 knockdown significantly abrogated high-glucose-induced NF-{kappa}B expression and inflammatory cytokine secretion. Collectively, these data suggest that high glucose stimulates TNF-{alpha} and IL-1{beta} secretion via inducing TLR2 through PKC-{alpha} and PKC-{delta} in human gingival fibroblasts.« less

Heterogeneous distribution of P53 immunoreactivity in human lung adenocarcinoma correlates with MDM2 protein expression, rather than with P53 gene mutation.

PubMed

Koga, T; Hashimoto, S; Sugio, K; Yoshino, I; Nakagawa, K; Yonemitsu, Y; Sugimachi, K; Sueishi, K

2001-07-20

Although the tumor suppressor p53 protein (P53) immunoreactivity and its gene (p53) mutation were reported to be significant prognostic indicators for human lung adenocarcinomas, little is known regarding the relationship between the heterogeneous distribution of P53 and its genetic status in each tumor focus and the clinicopathological significance. To determine how P53 is heterogeneously stabilized in patients, we compared P53 expression to both the p53 allelic mutation in exon 2 approximately 9 by polymerase chain reaction-single strand conformation polymorphism using microdissected DNA fractions, and the immunohistochemical MDM2 expression. Of the 48 positive to P53 in 118 lung adenocarcinomas examined, 10 with heterogeneous P53 expression were closely examined. The higher P53 expression foci in 7 of 10 cases were less differentiated, histologically in respective cases, and were frequently associated with fibrous stroma. Two had genetic mutations in exon 7 of the p53 gene in both the high and low P53 expression foci of cancer tissue indicating no apparent correlation between heterogeneous P53 expression and the occurrence of gene mutation. Immunohistochemical expression of MDM2 was significantly lower in high P53 expression areas (p < 0.05, the mean labeling indices of high and low P53 expression areas being 4.2 +/- 5.4% and 13.6 +/- 12.2%, respectively). In addition, among all the 118 cases examined, MDM2 expression was significantly suppressed in cases of p53 gene mutation, simultaneously with P53 overexpression, as compared with cases without both the p53 mutation and expression (p < 0.001). These findings suggest that the heterogeneous stabilization of P53 in human lung adenocarcinomas could be partly due to suppressed MDM2 expression. The overexpression of non-mutated P53 may afford a protective mechanism in human lung adenocarcinomas. Copyright 2001 Wiley-Liss, Inc.

Increased Brahma-related Gene 1 Expression Predicts Distant Metastasis and Shorter Survival in Patients with Invasive Ductal Carcinoma of the Breast.

PubMed

Do, Sung-Im; Yoon, Gun; Kim, Hyun-Soo; Kim, Kyungeun; Lee, Hyunjoo; Do, In-Gu; Kim, Dong-Hoon; Chae, Seoung Wan; Sohn, Jin Hee

2016-09-01

Previous studies have demonstrated aberrant Brahma-related gene 1 (BRG1) expression in various tumor types. Increased BRG1 expression has recently been shown to correlate with aggressive oncogenic behavior in many different types of human cancer. However, the role of BRG1 in breast cancer development and progression is not fully understood. We evaluated BRG1 expression in 224 patients with invasive ductal carcinoma (IDC) of the breast using tissue microarray samples and immunohistochemistry. We also investigated whether BRG1 expression status is associated with clinicopathological characteristics and outcomes of patients with IDC. Among the 224 patients with IDC, 37.5% (84/224) exhibited high BRG1 expression. IDC exhibited significantly higher BRG1 expression compared to ductal carcinoma in situ (p=0.009) and normal breast tissue (p=0.005). High BRG1 expression in IDC significantly correlated with higher histological grade (p=0.035) and presence of distant metastasis (p=0.002). Furthermore, high BRG1 expression was an independent factor for predicting distant metastasis (relative risk=4.079; p=0.007). In addition, high BRG1 expression predicted shorter overall (p=0.011) and recurrence-free (p=0.003) survival in patients with IDC. In particular, BRG1 had a significant prognostic value in predicting recurrence-free survival of patients with IDC with lymph node metastasis or stage III disease. BRG1 is involved in the progression and metastasis of breast cancer and can serve as a novel biomarker predictive of distant metastasis and patient outcomes. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

TROP2 correlates with microvessel density and poor prognosis in hilar cholangiocarcinoma.

PubMed

Ning, Shanglei; Guo, Sen; Xie, Jianjun; Xu, Yunfei; Lu, Xiaofei; Chen, Yuxin

2013-02-01

Trophoblast cell surface antigen 2 (TROP2) was found to be associated with tumor progression and poor prognosis in a variety of epithelial carcinomas. The aim of the study was to investigate TROP2 expression and its prognostic impact in hilar cholangiocarcinoma. Immunohistochemistry and quantitative real-time PCR were used to determine TROP2 expression in surgical specimens from 70 hilar cholangiocarcinoma patients receiving radical resection. The relationship between TROP2 expression and microvessel density was investigated and standard statistical analysis was used to evaluate TROP2 prognosis significance in hilar cholangiocarcinoma. High TROP2 expression by immunohistochemistry was found in 43 (61.4 %) of the 70 tumor specimens. Quantitative real-time PCR confirmed that TROP2 level in tumor was significantly higher than in non-tumoral biliary tissues (P = 0.001). Significant correlations were found between TROP2 expression and histological differentiation (P = 0.016) and tumor T stage (P = 0.031) in hilar cholangiocarcinoma. TROP2 expression correlated with microvessel density in hilar cholangiocarcinoma (P = 0.026). High TROP2 expression patients had a significantly poorer overall survival rate than those with low TROP2 expression (30 vs. 68.5 %, P = 0.001), and multivariate Cox regression analysis indicated TROP2 as an independent prognostic factor for hilar cholangiocarcinoma (P = 0.004). TROP2 expression correlates with microvessel density significantly and is an independent prognostic factor in human hilar cholangiocarcinoma.

Dysregulated B Cell Expression of RANKL and OPG Correlates with Loss of Bone Mineral Density in HIV Infection

PubMed Central

Titanji, Kehmia; Vunnava, Aswani; Sheth, Anandi N.; Delille, Cecile; Lennox, Jeffrey L.; Sanford, Sara E.; Foster, Antonina; Knezevic, Andrea; Easley, Kirk A.

2014-01-01

HIV infection is associated with high rates of osteopenia and osteoporosis, but the mechanisms involved are unclear. We recently reported that bone loss in the HIV transgenic rat model was associated with upregulation of B cell expression of the key osteoclastogenic cytokine receptor-activator of NF-κB ligand (RANKL), compounded by a simultaneous decline in expression of its physiological moderator, osteoprotegerin (OPG). To clinically translate these findings we performed cross-sectional immuno-skeletal profiling of HIV-uninfected and antiretroviral therapy-naïve HIV-infected individuals. Bone resorption and osteopenia were significantly higher in HIV-infected individuals. B cell expression of RANKL was significantly increased, while B cell expression of OPG was significantly diminished, conditions favoring osteoclastic bone resorption. The B cell RANKL/OPG ratio correlated significantly with total hip and femoral neck bone mineral density (BMD), T- and/or Z-scores in HIV infected subjects, but revealed no association at the lumbar spine. B cell subset analyses revealed significant HIV-related increases in RANKL-expressing naïve, resting memory and exhausted tissue-like memory B cells. By contrast, the net B cell OPG decrease in HIV-infected individuals resulted from a significant decline in resting memory B cells, a population containing a high frequency of OPG-expressing cells, concurrent with a significant increase in exhausted tissue-like memory B cells, a population with a lower frequency of OPG-expressing cells. These data validate our pre-clinical findings of an immuno-centric mechanism for accelerated HIV-induced bone loss, aligned with B cell dysfunction. PMID:25393853

Prognostic value of the MicroRNA regulators Dicer and Drosha in non-small-cell lung cancer: co-expression of Drosha and miR-126 predicts poor survival.

PubMed

Lønvik, Kenneth; Sørbye, Sveinung W; Nilsen, Marit N; Paulssen, Ruth H

2014-01-01

Dicer and Drosha are important enzymes for processing microRNAs. Recent studies have exhibited possible links between expression of different miRNAs, levels of miRNA processing enzymes, and cancer prognosis. We have investigated the prognostic impact of Dicer and Drosha and their correlation with miR-126 expression in a large cohort of non-small cell lung cancer (NSCLC) patients. We aimed to find patient groups within the cohort that might have an advantage of receiving adjunctive therapies. Dicer expression in the cytoplasm and Drosha expression in the nucleus were evaluated by manual immunohistochemistry of tissue microarrays (TMAs), including tumor tissue samples from 335 patients with resected stages I to IIIA NSCLC. In addition, in situ hybridizations of TMAs for visualization of miR-126 were performed. Kaplan-Meier analysis was performed, and the log-rank test via SPSS v.22 was used for estimating significance levels. In patients with normal performance status (ECOG = 0, n = 197), high Dicer expression entailed a significantly better prognosis than low Dicer expression (P = 0.024). Dicer had no significant prognostic value in patients with reduced performance status (ECOG = 1-2, n = 138). High Drosha expression was significantly correlated with high levels of the microRNA 126 (miR-126) (P = 0.004). Drosha/miR-126 co-expression had a significant negative impact on the disease-specific survival (DSS) rate (P < 0.001). Multivariate analyses revealed that the interaction Dicer*Histology (P = 0.049) and Drosha/miR-126 co-expression (P = 0.033) were independent prognostic factors. In NSCLC patients with normal performance status, Dicer is a positive prognostic factor. The importance of Drosha as a prognostic factor in our material seems to be related to miR-126 and possibly other microRNAs.

High expression of forkhead box protein C2 is associated with aggressive phenotypes and poor prognosis in clinical hepatocellular carcinoma.

PubMed

Shimoda, Yuki; Ubukata, Yasunari; Handa, Tadashi; Yokobori, Takehiko; Watanabe, Takayoshi; Gantumur, Dolgormaa; Hagiwara, Kei; Yamanaka, Takahiro; Tsukagoshi, Mariko; Igarashi, Takamichi; Watanabe, Akira; Kubo, Norio; Araki, Kenichiro; Harimoto, Norifumi; Katayama, Ayaka; Hikino, Toshiaki; Sano, Takaaki; Ogata, Kyoichi; Kuwano, Hiroyuki; Shirabe, Ken; Oyama, Tetsunari

2018-05-25

Hepatocellular carcinoma (HCC) is one of the major causes of tumor death; thus, the identification of markers related to its diagnosis and prognosis is critical. Previous studies have revealed that epithelial-to-mesenchymal transition (EMT) is involved in tumor invasion and metastasis, and the forkhead box protein C2 (FOXC2) has been shown to promote tumor cell proliferation, invasion, and EMT. In the present study, we examined the clinicopathological significance of FOXC2 and EMT-related markers in clinical HCC specimens and identified factors related to the diagnosis and prognosis of HCC. The expression of FOXC2 and EMT-related markers was evaluated by immunohistochemistry in 84 cases of hepatocellular carcinoma. A high expression of FOXC2 was observed in 26 of 84 cases, and expression was significantly correlated with background liver cirrhosis, poor tumor differentiation, high serum AFP, and elevated cell proliferation markers. In addition, this high expression was related to the induction of the Cadherin switch and vimentin expression and was an independent predictor for poor prognosis. The high expression of FOXC2 in HCC is correlated with tumor malignancy and poor prognosis, suggesting that FOXC2 may be an important prognostic factor for HCC.

High anger expression exacerbates the relationship between age and metabolic syndrome.

PubMed

Boylan, Jennifer Morozink; Ryff, Carol D

2015-01-01

Building on prior work linking high anger expression to poor health, this cross-sectional study addressed whether anger expression exacerbated age-related risk for metabolic syndrome in a national sample of adults, known as MIDUS (Midlife in the United States). Respondents reported anger expression via survey assessments and completed an overnight clinic visit. Unadjusted metabolic syndrome prevalence was 40.6%. Men, less educated individuals, and those who reported not getting regular physical activity were at significantly higher risk for metabolic syndrome. Anger expression did not predict higher risk for metabolic syndrome in main effects models, but it moderated the relationship between age and metabolic syndrome. Age-associated risk for metabolic syndrome was significant only for adults with high anger expression. Among older adults, anger expression predicted higher prevalence of metabolic syndrome. Older adults reporting low anger expression had metabolic syndrome rates comparable to younger adults. Results highlight that failing to show the frequently observed decline in anger expression with age may have pernicious health concomitants. © The Author 2013. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Impact of Secreted Protein Acidic and Rich in Cysteine (SPARC) Expression on Prognosis After Surgical Resection for Biliary Carcinoma.

PubMed

Toyota, Kazuhiro; Murakami, Yoshiaki; Kondo, Naru; Uemura, Kenichiro; Nakagawa, Naoya; Takahashi, Shinya; Sueda, Taijiro

2017-06-01

Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein that influences chemotherapy effectiveness and prognosis. The aim of this study was to investigate whether SPARC expression correlates with the postoperative survival of patients treated with surgical resection for biliary carcinoma. SPARC expression in resected biliary carcinoma specimens was investigated immunohistochemically in 175 patients. The relationship between SPARC expression and prognosis after surgery was evaluated using univariate and multivariate analyses. High SPARC expression in peritumoral stroma was found in 61 (35%) patients. In all patients, stromal SPARC expression was significantly associated with overall survival (OS) (P = 0.006). Multivariate analysis revealed that high stromal SPARC expression was an independent risk factor for poor OS (HR 1.81, P = 0.006). Moreover, high stromal SPARC expression was independently associated with poor prognosis in a subset of 118 patients treated with gemcitabine-based adjuvant chemotherapy (HR 2.04, P = 0.010) but not in the 57 patients who did not receive adjuvant chemotherapy (P = 0.21). Stromal SPARC expression correlated with the prognosis of patients with resectable biliary carcinoma, and its significance was enhanced in patients treated with adjuvant gemcitabine-based chemotherapy.

MicroRNA-130a is highly expressed in the esophageal mucosa of achalasia patients

PubMed Central

Shoji, Hiroyuki; Isomoto, Hajime; Yoshida, Akira; Ikeda, Haruo; Minami, Hitomi; Kanda, Tsutomu; Urabe, Shigetoshi; Matsushima, Kayoko; Takeshima, Fuminao; Nakao, Kazuhiko; Inoue, Haruhiro

2017-01-01

Esophageal achalasia is considered as a risk factor of esophageal cancer. The etiologies of esophageal achalasia remain unknown. Peroral endoscopic myotomy (POEM) has recently been established as a minimally invasive method with high curability. The aims of the present study were to identify the microRNAs (miRs) specific to esophageal achalasia, to determine their potential target genes and to assess their alteration following POEM. RNA was extracted from biopsy samples from middle esophageal mucosa and analyzed using a microarray. Differentially expressed miRs in achalasia patients compared with control samples were identified and analyzed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Correlations between specific miR expression levels and the patients' clinical background were also investigated. In addition, alterations of selected miR expression levels before and after POEM were analyzed. The results of RT-qPCR analysis demonstrated that the miR-130a expression levels were significantly higher in patients with achalasia (P<0.0001). In addition, miR-130a expression was significantly correlated with male sex and smoking history in patients with achalasia. However, no significant change in miR-130a expression was observed between before and after POEM. In conclusion, miR-130a is highly expressed in the esophageal mucosa of patients with achalasia and may be a biomarker of esophageal achalasia. PMID:28810541

MicroRNA-130a is highly expressed in the esophageal mucosa of achalasia patients.

PubMed

Shoji, Hiroyuki; Isomoto, Hajime; Yoshida, Akira; Ikeda, Haruo; Minami, Hitomi; Kanda, Tsutomu; Urabe, Shigetoshi; Matsushima, Kayoko; Takeshima, Fuminao; Nakao, Kazuhiko; Inoue, Haruhiro

2017-08-01

Esophageal achalasia is considered as a risk factor of esophageal cancer. The etiologies of esophageal achalasia remain unknown. Peroral endoscopic myotomy (POEM) has recently been established as a minimally invasive method with high curability. The aims of the present study were to identify the microRNAs (miRs) specific to esophageal achalasia, to determine their potential target genes and to assess their alteration following POEM. RNA was extracted from biopsy samples from middle esophageal mucosa and analyzed using a microarray. Differentially expressed miRs in achalasia patients compared with control samples were identified and analyzed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Correlations between specific miR expression levels and the patients' clinical background were also investigated. In addition, alterations of selected miR expression levels before and after POEM were analyzed. The results of RT-qPCR analysis demonstrated that the miR-130a expression levels were significantly higher in patients with achalasia (P<0.0001). In addition, miR-130a expression was significantly correlated with male sex and smoking history in patients with achalasia. However, no significant change in miR-130a expression was observed between before and after POEM. In conclusion, miR-130a is highly expressed in the esophageal mucosa of patients with achalasia and may be a biomarker of esophageal achalasia.

Elevated expression of FABP3 and FABP4 cooperatively correlates with poor prognosis in non-small cell lung cancer (NSCLC).

PubMed

Tang, Zhiyuan; Shen, Qin; Xie, Hao; Zhou, Xiaoyu; Li, Jun; Feng, Jian; Liu, Hua; Wang, Wei; Zhang, Shu; Ni, Songshi

2016-07-19

Fatty acid binding proteins (FABPs) are intracellular lipid-binding proteins that are involved in a variety of biological cellular processes, including tumorigenesis. In this study, we explored the expression pattern of FABP3 and FABP4 in non-small cell lung cancer (NSCLC) as well as their roles in prognosis. We determined mRNA expression of FABP3 and FABP4 in matched pairs of cancerous and non-cancerous fresh frozen tissues from 30 NSCLC patients. Tissue microarray immunohistochemical analysis (TMA-IHC) was applied to determine the protein expression of FABP3 and FABP4 in 281 cancerous and 121 matched adjacent non-cancerous tissue samples. Our results showed that both mRNA and protein expression of FABP3 and FABP4 were significantly higher in cancerous tissues when compared to non-cancerous tissues. Furthermore, high expression of FABP3 or FABP4 in NSCLC was significantly associated with advanced tumor node metastasis (TNM) stage and had a negative impact on the overall survival of NSCLC patients. Concurrent high expression of FABP3 and FABP4 was significantly related to TNM stage. In conclusion, our research demonstrated that high FABP3 or FABP4 expression had strong prognostic value for overall survival in NSCLC. Detection of FABP3 and FABP4 cooperatively was helpful to predict the prognosis of NSCLC.

Elevated expression of FABP3 and FABP4 cooperatively correlates with poor prognosis in non-small cell lung cancer (NSCLC)

PubMed Central

Tang, Zhiyuan; Shen, Qin; Xie, Hao; Zhou, Xiaoyu; Li, Jun; Feng, Jian; Liu, Hua; Wang, Wei; Zhang, Shu; Ni, Songshi

2016-01-01

Fatty acid binding proteins (FABPs) are intracellular lipid-binding proteins that are involved in a variety of biological cellular processes, including tumorigenesis. In this study, we explored the expression pattern of FABP3 and FABP4 in non-small cell lung cancer (NSCLC) as well as their roles in prognosis. We determined mRNA expression of FABP3 and FABP4 in matched pairs of cancerous and non-cancerous fresh frozen tissues from 30 NSCLC patients. Tissue microarray immunohistochemical analysis (TMA-IHC) was applied to determine the protein expression of FABP3 and FABP4 in 281 cancerous and 121 matched adjacent non-cancerous tissue samples. Our results showed that both mRNA and protein expression of FABP3 and FABP4 were significantly higher in cancerous tissues when compared to non-cancerous tissues. Furthermore, high expression of FABP3 or FABP4 in NSCLC was significantly associated with advanced tumor node metastasis (TNM) stage and had a negative impact on the overall survival of NSCLC patients. Concurrent high expression of FABP3 and FABP4 was significantly related to TNM stage. In conclusion, our research demonstrated that high FABP3 or FABP4 expression had strong prognostic value for overall survival in NSCLC. Detection of FABP3 and FABP4 cooperatively was helpful to predict the prognosis of NSCLC. PMID:27323829

Expression of fibroblast growth factor receptor family members is associated with prognosis in early stage cervical cancer patients.

PubMed

Choi, Chel Hun; Chung, Joon-Yong; Kim, Jae-Hoon; Kim, Byoung-Gie; Hewitt, Stephen M

2016-05-06

The oncogenic role of the fibroblast growth factor receptor (FGFR) has been recognized in a number of different cancer types. However, the prognostic significance of FGFRs has not been elucidated yet in cervical cancer. In the present study, we investigate the expression of FGFRs and their prognostic value in cervical cancer patients. FGFR1, FGFR2, FGFR3, and FGFR4 expression was determined by immunohistochemistry in conjunction with quantitative digital image analysis of 336 formalin-fixed, paraffin-embedded cervical cancer tissues and 61 normal cervical tissues, as well as NCI60 cell microarray. Subsequently, the association between clinicopathological characteristics and patient survival was assessed. FGFRs proteins were differentially expressed in the NCI60 cell line panel and showed considerable correlation between protein and mRNA expression. The expression of FGFR1, FGFR2, and FGFR4 were higher in cancer tissues than in normal tissues, whereas the expression of FGFR3 was higher in normal tissues. FGFR1 was highly expressed in adeno-/adenosquamous carcinoma (P = 0.020), while FGFR2, FGFR3, and FGFR4 expression were more prominent in squamous cell carcinoma (P < 0.001, P < 0.001, and P = 0.020, respectively). FGFR2 expression was significantly higher in small sized tumors (P = 0.020). Additionally, high FGFR2 and FGFR4 were correlated with negative lymph node metastasis (P = 0.048 and P = 0.040, respectively). FGFR1, FGFR2, and FGFR3 were highly expressed in tumors without parametrial involvement (P = 0.030, P = 0.005, and P = 0.010, respectively). In survival analysis, high expressions of FGFR2, FGFR3, and FGFR4 was associated with longer disease-free survival (P = 0.006, P = 0.035, P = 0.001, respectively) and overall survival (P = 0.003, P = 0.002, P = 0.003, respectively). Notably, the co-expression of all three FGFRs was significantly associated with favorable disease-free survival (P < 0.001) and overall survival (P < 0.001), compared to the negative expressions of the three FGFRs. The prognostic significance persisted in the cox regression analysis. The frequent expression of members of the FGFR family in cervical cancer suggests they may have prognostic and therapeutic relevance.

Clinicopathological correlations of Bcl-xL and Bax expression in differentiated thyroid carcinoma.

PubMed

Martínez-Brocca, M Asunción; Castilla, Carolina; Navarro, Elena; Amaya, M José; Travado, Paulino; Japón, Miguel A; Sáez, Carmen

2008-02-01

The Bcl-2 family proteins are essential mediators in the apoptotic process. Our aim was to investigate whether anti-apoptotic Bcl-xL and pro-apoptotic Bax were over-expressed in a large series of differentiated thyroid carcinomas (DTC) and to study their association with tumour presentation at diagnosis and prognosis. We examined the immunohistochemical expression of Bcl-xL and Bax in benign nodular thyroid disease (BNTD) and DTC and their association with clinicopathological parameters. Thyroid tissue samples were collected from an unselected series of patients undergoing surgical resection for DTC (n = 74) or BNTD (n = 15). Among DTC cases, expression of Bcl-xL was found to be high in 43.2% and low or absent in 56.8%. Expression of Bax was high in 75.7% and low or absent in 24.3%. Non-neoplastic thyroid tissue was largely unstained for both proteins. Among BNTD cases, expression of Bcl-xL was high in 13.3% and low or absent in 86.6%. Expression of Bax was high in 14.3% and low or absent in 86.6%. A significant association was found between Bcl-xL expression and the presence of high-risk histological subtype (P < 0.05), and regional lymph node (P < 0.01) and distant metastases (P < 0.01). The association between high Bcl-xL expression levels and a longer time of persistent disease after radioiodine ablation was also significant (P < 0.01). Bcl-xL expression was confirmed as an independent prognostic factor for persistent disease in DTC (relative risk, 2.5; 95% confidence interval, 1.1-5.9; P < 0.05). Immunohistochemical expression of Bcl-xL might be a valuable tool in the prediction of tumour aggressiveness in DTC.

Mining, Validation, and Clinical Significance of Colorectal Cancer (CRC)-Associated lncRNAs.

PubMed

Sun, Xiangwei; Hu, Yingying; Zhang, Liang; Hu, Changyuan; Guo, Gangqiang; Mao, Chenchen; Xu, Jianfeng; Ye, Sisi; Huang, Guanli; Xue, Xiangyang; Guo, Aizhen; Shen, Xian

2016-01-01

Colorectal cancer (CRC) is one of the deadliest tumours, but its pathogenesis remains unclear. The involvement of differentially expressed long non-coding RNAs (lncRNAs) in CRC tumorigenesis makes them suitable tumour biomarkers. Here, we screened 150 cases of CRC and 85 cases of paracancerous tissues in the GEO database for differentially expressed lncRNAs. The levels of lncRNA candidates in 84 CRC and paracancerous tissue samples were validated by qRT-PCR and their clinical significance was analyzed. We identified 15 lncRNAs with differential expression in CRC tumours; among them, AK098081 was significantly up-regulated, whereas AK025209, BC040303, BC037331, AK026659, and CR749831 were down-regulated in CRC. In a receiver operating characteristic curve analysis, the area under the curve for the six lncRNAs was 0.914. High expression of AK098081 and low expression of BC040303, CR749831, and BC037331 indicated poor CRC differentiation. CRC patients with lymph node metastasis had lower expression of BC037331. In addition, the group with high AK098081 expression presented significantly lower overall survival and disease-free survival rates than the low-expression group, confirming AK098081 as an independent risk factor for CRC patients. In conclusion, we have identified multiple CRC-associated lncRNAs from microarray expression profiles that can serve as novel biomarkers for the diagnosis and prognosis of CRC.

Anti-Obesity and Anti-Diabetic Effects of Acacia Polyphenol in Obese Diabetic KKAy Mice Fed High-Fat Diet

PubMed Central

Ikarashi, Nobutomo; Toda, Takahiro; Okaniwa, Takehiro; Ito, Kiyomi; Ochiai, Wataru; Sugiyama, Kiyoshi

2011-01-01

Acacia polyphenol (AP) extracted from the bark of the black wattle tree (Acacia meansii) is rich in unique catechin-like flavan-3-ols, such as robinetinidol and fisetinidol. The present study investigated the anti-obesity/anti-diabetic effects of AP using obese diabetic KKAy mice. KKAy mice received either normal diet, high-fat diet or high-fat diet with additional AP for 7 weeks. After the end of administration, body weight, plasma glucose and insulin were measured. Furthermore, mRNA and protein expression of obesity/diabetic suppression-related genes were measured in skeletal muscle, liver and white adipose tissue. As a result, compared to the high-fat diet group, increases in body weight, plasma glucose and insulin were significantly suppressed for AP groups. Furthermore, compared to the high-fat diet group, mRNA expression of energy expenditure-related genes (PPARα, PPARδ, CPT1, ACO and UCP3) was significantly higher for AP groups in skeletal muscle. Protein expressions of CPT1, ACO and UCP3 for AP groups were also significantly higher when compared to the high-fat diet group. Moreover, AP lowered the expression of fat acid synthesis-related genes (SREBP-1c, ACC and FAS) in the liver. AP also increased mRNA expression of adiponectin and decreased expression of TNF-α in white adipose tissue. In conclusion, the anti-obesity actions of AP are considered attributable to increased expression of energy expenditure-related genes in skeletal muscle, and decreased fatty acid synthesis and fat intake in the liver. These results suggest that AP is expected to be a useful plant extract for alleviating metabolic syndrome. PMID:21799697

Prognostic value of long noncoding RNA ZFAS1 in various carcinomas: a meta-analysis.

PubMed

Dong, Dan; Mu, Zhongyi; Wang, Wei; Xin, Na; Song, Xiaowen; Shao, Yue; Zhao, Chenghai

2017-10-13

A number of studies have revealed that zinc finger antisense 1 (ZFAS1), a long noncoding RNA (lncRNA), is aberrantly regulated in various cancers, and high ZFAS1 expression is associated with poor prognosis and increased risk of lymph node metastasis (LNM). This meta-analysis was conducted to identify the potential value of ZFAS1 as a biomarker for cancer prognosis. We searched electronic database PubMed, Web of Science, and China Wanfang Data (up to June 1, 2017) to collect all relevant studies and explore the association of ZFAS1 expression with overall survival (OS) and LNM. The results showed that cancer patients with high ZFAS1 expression had a worse OS than those with low ZFAS1 expression (HR: 1.94, 95% confidence interval [CI]: 1.41-2.47, P < 0.001), and high ZFAS1 expression was significantly associated with LNM (OR: 2.60, 95% CI: 1.54-4.42, P < 0.001). Subgroup analysis revealed that high ZFAS1 expression was significantly related to high incidence of LNM in subgroups of sample size more than 88 (OR: 3.16, 95% CI: 2.06-4.86, P < 0.001), non-digestive system malignancies (OR: 4.05, 95% CI: 2.49-6.60, P < 0.001), and studies reported in 2017 (OR: 4.86, 95% CI: 2.67-8.84, P < 0.001) without significant heterogeneity. Further meta-regression by the covariates showed that tumor type, sample size, quality score, cut off value and publication year did not result in the inter-study heterogeneity. In conclusion, the present meta-analysis demonstrates that high ZFAS1 expression may potentially serve as a reliable biomarker for poor clinical outcome in various cancers.

Prognostic significance of epidermal growth factor receptor (EGFR) over expression in urothelial carcinoma of urinary bladder.

PubMed

Hashmi, Atif Ali; Hussain, Zubaida Fida; Irfan, Muhammad; Khan, Erum Yousuf; Faridi, Naveen; Naqvi, Hanna; Khan, Amir; Edhi, Muhammad Muzzammil

2018-06-07

Epidermal growth factor receptor (EGFR) has been shown to have abnormal expression in many human cancers and is considered as a marker of poor prognosis. Frequency of over expression in bladder cancer has not been studied in our population; therefore we aimed to evaluate the frequency and prognostic significance of EGFR immunohistochemical expression in locoregional population. We performed EGFR immunohistochemistry on 126 cases of bladder cancer and association of EGFR expression with tumor grade, lamina propria invasion, deep muscle invasion and recurrence of disease was evaluated. High EGFR expression was noted in 26.2% (33 cases), 15.1% (19 cases) and 58.7% (74 cases) revealed low and no EGFR expression respectively. Significant association of EGFR expression was noted with tumor grade, lamina propria invasion, deep muscle invasion and recurrence status while no significant association was seen with age, gender and overall survival. Kaplan- Meier curves revealed significant association of EGFR expression with recurrence while no significant association was seen with overall survival. Significant association of EGFR overexpression with tumor grade, muscularis propria invasion and recurrence signifies its prognostic value; therefore EGFR can be used as a prognostic biomarker in Urothelial bladder carcinoma.

High expression of glucose-regulated protein 78 (GRP78) is associated with metastasis and poor prognosis in patients with esophageal squamous cell carcinoma.

PubMed

Ren, Peng; Chen, Chuangui; Yue, Jie; Zhang, Jianguo; Yu, Zhentao

2017-01-01

Glucose-regulated protein 78 (GRP78) plays an important role in the invasion and metastasis of many human cancers. However, the role of this protein in the progression of invasion and metastasis in esophageal squamous cell carcinoma (ESCC) remains elusive. Immunohistochemistry and Western blot were performed to analyze GRP78 expression in 92 patients with primary ESCC. The correlation of GRP78 expression with clinicopathological factors was analyzed. In vitro, the expression levels of GRP78 were downregulated by small interfering RNA transfection in TE-1 and CaEs-17 ESCC lines. Cell invasion and migration assays were applied to determine the invasion and migratory abilities of ESCC cells. Compared with GRP78 in adjacent normal esophageal tissues, GRP78 was overexpressed in ESCC tissues. High GRP78 expression was significantly correlated with positive lymph node metastasis ( P =0.035) and advanced tumor stage ( P =0.017). Survival analysis revealed that high GRP78 expression was significantly associated with shorter overall survival ( P =0.037). In multivariate analysis, GRP78 overexpression was identified as an independent prognostic factor for overall survival ( P =0.011). si-GRP78 can significantly decrease the GRP78 expression level and reverse the invasion and migratory abilities of ESCC cells in TE-1 and CaEs-17 cell lines. These findings demonstrated that high expression of GRP78 was associated with disease progression and metastasis in ESCC and might serve as a novel prognostic marker for patients with ESCC.

High expression of glucose-regulated protein 78 (GRP78) is associated with metastasis and poor prognosis in patients with esophageal squamous cell carcinoma

PubMed Central

Ren, Peng; Chen, Chuangui; Yue, Jie; Zhang, Jianguo; Yu, Zhentao

2017-01-01

Background Glucose-regulated protein 78 (GRP78) plays an important role in the invasion and metastasis of many human cancers. However, the role of this protein in the progression of invasion and metastasis in esophageal squamous cell carcinoma (ESCC) remains elusive. Patients and methods Immunohistochemistry and Western blot were performed to analyze GRP78 expression in 92 patients with primary ESCC. The correlation of GRP78 expression with clinicopathological factors was analyzed. In vitro, the expression levels of GRP78 were downregulated by small interfering RNA transfection in TE-1 and CaEs-17 ESCC lines. Cell invasion and migration assays were applied to determine the invasion and migratory abilities of ESCC cells. Results Compared with GRP78 in adjacent normal esophageal tissues, GRP78 was overexpressed in ESCC tissues. High GRP78 expression was significantly correlated with positive lymph node metastasis (P=0.035) and advanced tumor stage (P=0.017). Survival analysis revealed that high GRP78 expression was significantly associated with shorter overall survival (P=0.037). In multivariate analysis, GRP78 overexpression was identified as an independent prognostic factor for overall survival (P=0.011). si-GRP78 can significantly decrease the GRP78 expression level and reverse the invasion and migratory abilities of ESCC cells in TE-1 and CaEs-17 cell lines. Conclusion These findings demonstrated that high expression of GRP78 was associated with disease progression and metastasis in ESCC and might serve as a novel prognostic marker for patients with ESCC. PMID:28228658

Experimental non-alcoholic fatty liver disease results in decreased hepatic uptake transporter expression and function in rats

PubMed Central

Fisher, Craig D.; Lickteig, Andrew J.; Augustine, Lisa M.; Oude Elferink, Ronald P.J.; Besselsen, David G.; Erickson, Robert P.; Cherrington, Nathan J.

2009-01-01

Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of diagnoses ranging from simple fatty liver (SFL), to non-alcoholic steatohepatitis (NASH). This study aimed to determine the effect of moderate and severe NAFLD on hepatic transporter expression and function in vivo. Rats were fed a high-fat diet (SFL model) or a methionine-choline-deficient diet (NASH model) for eight weeks. Hepatic uptake transporter function was determined by bromosulfophthalein (BSP) disposition. Transporter expression was determined by branched DNA signal amplification assay and western blotting; inflammation was identified by immunostaining of liver slices for interleukin 1 beta (IL-1β). MC- rats showed significant retention of BSP in the plasma when compared to control rats. Hepatic NTCP, OATP1a1, 1a4, 1b2 and 2b1; and OAT 2 and 3 mRNA levels were significantly decreased in high-fat and MC- diet rats when compared to control. Protein expression of OATP1a1 was significantly decreased in high-fat animals, while OATP1a1 and OATP1b2 expression was significantly lower in MC- rats when compared to control. Liver tissue from high-fat and MC- rats stained positive for IL-1β, a pro-inflammatory cytokine known to decrease expression of NTCP, OATP and OAT transporters, suggesting a plausible mechanism for the observed transporter alterations. These data suggest that different stages of NAFLD result in altered hepatic uptake transporter expression that can lead to a functional impairment of xenobiotic uptake from the blood. Furthermore, NAFLD may alter the plasma retention time of clinically relevant drugs that are reliant on these transporters and may increase the potential drug toxicity. PMID:19358839

Cytoplasmic Hu-Antigen R (HuR) Expression is Associated with Poor Survival in Patients with Surgically Resected Cholangiocarcinoma Treated with Adjuvant Gemcitabine-Based Chemotherapy.

PubMed

Toyota, Kazuhiro; Murakami, Yoshiaki; Kondo, Naru; Uemura, Kenichiro; Nakagawa, Naoya; Takahashi, Shinya; Sueda, Taijiro

2018-05-01

Hu-antigen R (HuR) is an RNA-binding protein that regulates the stability, translation, and nucleus-to-cytoplasm translocation of messenger RNAs (mRNAs). The aim of this study was to investigate the prognostic significance of HuR in cholangiocarcinoma patients who received adjuvant gemcitabine-based chemotherapy (AGC) after surgical resection. Nuclear and cytoplasmic HuR expression was investigated immunohistochemically in 131 patients with resected cholangiocarcinoma, including 91 patients administered AGC and 40 patients who did not receive adjuvant chemotherapy. The correlation between HuR expression and survival was evaluated by statistical analysis. High nuclear and cytoplasmic HuR expression was observed in 67 (51%) and 45 (34%) patients, respectively. Cytoplasmic HuR expression was significantly associated with lymph node metastasis (p < 0.01), while high cytoplasmic HuR expression was significantly associated with poor disease-free survival [DFS] (p = 0.03) and overall survival [OS] (p = 0.001) in the 91 patients who received AGC, but not in the 40 patients who did not receive AGC (DFS p = 0.17; OS p = 0.07). In the multivariate analysis of patients who received AGC, high cytoplasmic HuR expression was an independent predictor of poor DFS (hazard ratio [HR] 1.77; p = 0.04) and OS (HR 2.09; p = 0.02). Nuclear HuR expression did not affect the survival of enrolled patients. High cytoplasmic HuR expression was closely associated with the efficacy of AGC in patients with cholangiocarcinoma. The current findings warrant further investigations to optimize adjuvant chemotherapy regimens for resectable cholangiocarcinoma.

High Phosphohistone H3 Expression Correlates with Adverse Clinical, Biological, and Pathological Factors in Neuroblastomas

PubMed Central

Ramani, Pramila; Taylor, Scott; Miller, Elizabeth; Sowa-Avugrah, Emile; May, Margaret T.

2015-01-01

Phosphohistone H3 (pHH3), a biomarker of the late G2- and M-phase of the cell cycle, provides a powerful indication of the proliferative state of many cancers. We investigated the prognostic significance of pHH3 by immunostaining 80 neuroblastomas and counting the average number of strongly stained nuclei and mitotic figures. The median and 75th percentile pHH3 proliferation indices (PIs) were 0.54% and 1.06% (range, 0.01% to 2.23%) respectively. pHH3 expression was significantly higher in neuroblastomas from patients with adverse clinical characteristics, all unfavorable pathological factors including high mitosis karyorrhexis index (MKI), and adverse biological factors including MYCN oncogene amplification. High pHH3-PIs, at 1% threshold, were significantly associated with a shorter overall survival (OS) and event-free survival (EFS) in the univariable Cox regression analyses. In the multivariable models, high pHH3 counts were significantly associated with worse OS after adjustment for age but were not independent of either high MKI or MYCN amplification. In children less than 18 months of age, high MKIs and high PHH3-PIs were associated with significantly worse OS and EFS. In conclusion, high pHH3 expression correlates strongly with high MKI and MYCN amplification and indicates poor prognosis in neuroblastomas. PMID:25711230

High EVI1 expression is associated with MLL rearrangements and predicts decreased survival in paediatric acute myeloid leukaemia: a report from the children's oncology group.

PubMed

Ho, Phoenix A; Alonzo, Todd A; Gerbing, Robert B; Pollard, Jessica A; Hirsch, Betsy; Raimondi, Susana C; Cooper, Todd; Gamis, Alan S; Meshinchi, Soheil

2013-09-01

Ectopic viral integration site-1 (EVI1) is highly expressed in certain cytogenetic subsets of adult acute myeloid leukaemia (AML), and has been associated with inferior survival. We sought to examine the clinical and biological associations of EVI1(high) , defined as expression in excess of normal controls, in paediatric AML. EVI1 mRNA expression was measured via quantitative real-time polymerase chain reaction in diagnostic specimens obtained from 206 patients. Expression levels were correlated with clinical features and outcome. EVI1(high) was present in 58/206 (28%) patients. MLL rearrangements occurred in 40% of EVI1(high) patients as opposed to 12% of the EVI1(low/absent) patients (P < 0·001). No abnormalities of 3q26 were found in EVI1(high) patients by conventional cytogenetic analysis, nor were cryptic 3q26 abnormalities detected in a subset of patients screened by next-generation sequencing. French-American-British class M7 was enriched in the EVI1(high) group, accounting for 24% of these patients. EVI1(high) patients had significantly lower 5-year overall survival from study entry (51% vs. 68%, P = 0·015). However, in multivariate analysis including other established prognostic markers, EVI1 expression did not retain independent prognostic significance. EVI1 expression is currently being studied in a larger cohort of patients enrolled on subsequent Children's Oncology Group trials, to determine if EVI1(high) has prognostic value in MLL-rearranged or intermediate-risk subsets. © 2013 John Wiley & Sons Ltd.

[Effect of Endomorphin-1 on Maturation and Expression of TLR4 in Peripheral Blood Dendritic Cells Induced by High Glucose].

PubMed

Liu, Chuan-Miao; Yang, Tian-Hua; Huang, Min; Zhou, Cheng; Li, Yong-Hai; Li, Zheng-Hong

2018-06-01

To investigate the effects of endomorphin-1 (EM-1) on the maturation phenotype, cytokine secretion, T cell proliferation and TLR4 expression in human peripheral blood dendritic cells (PBDCs) stimulated and induced by high glucose, and to explore the regulatory mechanism of EM-1 on DC immune function. Peripheral blood mononuclear cells (PBMNCs) were induced into immature dendritic cells (imDCs). The high glucose was used as the stimulating factor, and the EM-1 was used as the interventional factor. Then, the experiments were divided into normal glucose group (NG group), high glucose group (HG group), high glucose plus EM-1 group (EM group) and high glucose plus EM-1 and naloxone group (Nal group), respectively. The PBDC's phenotype changes were detected by flow cytometry; ELISA was used to detect the changes of cytokines secreted by PBDCs co-cultured with autologous lymphocytes; CFSE was used to detect the proliferation of T lymphocytes. TLR4 expression on PBDC surface was detected by RT-PCR. Compared with HG group, the expression of PBDC surface molecules CD86, CCR7 and CD36 was up-regulated in EM group (P<0.01), while the change of CD83 expression was not statistically significant. However, IL-12 and IL-10 secreted by PBDCs and the proliferation index of T-lymphocytes stimulated by PBDCs were both decreased in EM group. Compared with EM group, the expression of CD86, CCR7 and CD36 was decreased in Nal group (P<0.01), while the expression of CD83 was almost unchanged (P>0.05). T-lymphocyte proliferation index was increased very significantly in Nal group (P<0.01). The gray ratio of TLR4 in HG group was higher than that in NG group, while the gray ratio in EM group's was very significantly lower than that in HG group's (P<0.01). These results indicate that the high glucose can promote the expression of PBDC TLR4, while the EM-1 inhibits the expression of TLR4. EM-1 up-regulates the expression of PBDC surface molecules CD86, CCR7 and CD36 stimulated and induced by high glucose, but inhibites the induction of PBDC to maturity by high glucose. And the secreted inflammatory cytokines IL-12 and IL-10 inhibites the proliferation of T lymphocytes derived from PBDCs, while naloxone inhibites the effect of EM-1. EM-1 inhibites the expression of TLR4 on PBDC surface induced by high glucose.

The expression of pigment epithelium-derived factor in bladder transitional cell carcinoma.

PubMed

Jang, Tae Jung; Kim, Sung Woo; Lee, Kyung Seop

2012-06-01

Pigment epithelium-derived factor (PEDF) is an anti-angiogenic factor. The purpose of this study is to examine the involvement of PEDF in the angiogenesis and biological behavior of bladder transitional cell carcinoma (TCC). We examined the expression of PEDF in 99 bladder TCCs and ten non-neoplastic tissues, and evaluated microvessel density (MVD). The positive immunoreactivity for PEDF was seen in normal urothelium in 60% (6/10) and TCC in 13% (13/99). The PEDF expression had a significant correlation with MVD, i.e., a low MVD in 42% (5/12), a middle MVD in 11% (8/76) and a high MVD 0% (0/11) of tumors. The PEDF expression was not significantly correlated with the differentiation and invasion of TCC, but the degree of MVD was significantly higher in both high grade TCC and the pT2 tumors. The degree of PEDF expression is significantly higher in normal bladder urothelium than bladder TCC; it is inversely correlated with the angiogenesis; and it is not related to the differentiation and progression of TCC. It can therefore be concluded that bladder TCC would initially occur if there is a lack of the PEDF expression.

The Expression of Pigment Epithelium-Derived Factor in Bladder Transitional Cell Carcinoma

PubMed Central

Kim, Sung Woo; Lee, Kyung Seop

2012-01-01

Background Pigment epithelium-derived factor (PEDF) is an anti-angiogenic factor. The purpose of this study is to examine the involvement of PEDF in the angiogenesis and biological behavior of bladder transitional cell carcinoma (TCC). Methods We examined the expression of PEDF in 99 bladder TCCs and ten non-neoplastic tissues, and evaluated microvessel density (MVD). Results The positive immunoreactivity for PEDF was seen in normal urothelium in 60% (6/10) and TCC in 13% (13/99). The PEDF expression had a significant correlation with MVD, i.e., a low MVD in 42% (5/12), a middle MVD in 11% (8/76) and a high MVD 0% (0/11) of tumors. The PEDF expression was not significantly correlated with the differentiation and invasion of TCC, but the degree of MVD was significantly higher in both high grade TCC and the pT2 tumors. Conclusions The degree of PEDF expression is significantly higher in normal bladder urothelium than bladder TCC; it is inversely correlated with the angiogenesis; and it is not related to the differentiation and progression of TCC. It can therefore be concluded that bladder TCC would initially occur if there is a lack of the PEDF expression. PMID:23110012

Extent, Causes, and Consequences of Small RNA Expression Variation in Human Adipose Tissue

PubMed Central

Knights, Andrew J.; Abreu-Goodger, Cei; van de Bunt, Martijn; Guerra-Assunção, José Afonso; Bartonicek, Nenad; van Dongen, Stijn; Mägi, Reedik; Nisbet, James; Barrett, Amy; Rantalainen, Mattias; Nica, Alexandra C.; Quail, Michael A.; Small, Kerrin S.; Glass, Daniel; Enright, Anton J.; Winn, John; Deloukas, Panos; Dermitzakis, Emmanouil T.; McCarthy, Mark I.; Spector, Timothy D.; Durbin, Richard; Lindgren, Cecilia M.

2012-01-01

Small RNAs are functional molecules that modulate mRNA transcripts and have been implicated in the aetiology of several common diseases. However, little is known about the extent of their variability within the human population. Here, we characterise the extent, causes, and effects of naturally occurring variation in expression and sequence of small RNAs from adipose tissue in relation to genotype, gene expression, and metabolic traits in the MuTHER reference cohort. We profiled the expression of 15 to 30 base pair RNA molecules in subcutaneous adipose tissue from 131 individuals using high-throughput sequencing, and quantified levels of 591 microRNAs and small nucleolar RNAs. We identified three genetic variants and three RNA editing events. Highly expressed small RNAs are more conserved within mammals than average, as are those with highly variable expression. We identified 14 genetic loci significantly associated with nearby small RNA expression levels, seven of which also regulate an mRNA transcript level in the same region. In addition, these loci are enriched for variants significant in genome-wide association studies for body mass index. Contrary to expectation, we found no evidence for negative correlation between expression level of a microRNA and its target mRNAs. Trunk fat mass, body mass index, and fasting insulin were associated with more than twenty small RNA expression levels each, while fasting glucose had no significant associations. This study highlights the similar genetic complexity and shared genetic control of small RNA and mRNA transcripts, and gives a quantitative picture of small RNA expression variation in the human population. PMID:22589741

Changes in liver PPARalpha mRNA expression in response to two levels of high-safflower-oil diets correlate with changes in adiposity and serum leptin in rats and mice.

PubMed

Hsu, Shan-Ching; Huang, Ching-jang

2007-02-01

The ligand-dependent transcription factor peroxisome proliferator-activated receptor alpha (PPARalpha) is known to be activated by common fatty acids and to regulate the expression of genes of various lipid oxidation pathways and transport. High-fat diets provide more fatty acids, which presumably could enhance lipid catabolism through up-regulation of PPARalpha signaling. However, high intake of fat could also lead to obesity. To examine PPARalpha signaling in high-fat feeding and obesity, this study examined the hepatic mRNA expression of PPARalpha and some of its target genes in Wistar rats and C57BL/6J mice fed two levels (20% or 30% wt/wt) of high-safflower-oil (SFO; oleic-acid-rich) diets until animals showed significantly higher body weight (13 weeks for rats and 22 weeks for mice) than those of control groups fed a 5% SFO diet. At the end of these respective feeding periods, only the rats fed 30% SFO and the mice fed 20% SFO among the two groups fed high-fat diets showed significantly higher body weight, white adipose tissue weight, serum leptin and mRNA expression of PPARalpha (P<.05) compared to the respective control groups. Despite elevated acyl-CoA (a PPARalpha target gene) protein and activity in both groups fed high-fat diets, the mRNA expression level of most PPARalpha target genes examined correlated mainly to PPARalpha mRNA levels and not to fat intake or liver lipid levels. The observation that the liver PPARalpha mRNA expression in groups fed high-fat diets was significantly higher only in obese animals with elevated serum leptin implied that obesity and associated hyperleptinemia might have a stronger impact than dietary SFO intake per se on PPARalpha-regulated mRNA expression in the liver.

Decoy receptor 3 is a prognostic factor in renal cell cancer.

PubMed

Macher-Goeppinger, Stephan; Aulmann, Sebastian; Wagener, Nina; Funke, Benjamin; Tagscherer, Katrin E; Haferkamp, Axel; Hohenfellner, Markus; Kim, Sunghee; Autschbach, Frank; Schirmacher, Peter; Roth, Wilfried

2008-10-01

Decoy receptor 3 (DcR3) is a soluble protein that binds to and inactivates the death ligand CD95L. Here, we studied a possible association between DcR3 expression and prognosis in patients with renal cell carcinomas (RCCs). A tissue microarray containing RCC tumor tissue samples and corresponding normal tissue samples was generated. Decoy receptor 3 expression in tumors of 560 patients was examined by immunohistochemistry. The effect of DcR3 expression on disease-specific survival and progression-free survival was assessed using univariate analysis and multivariate Cox regression analysis. Decoy receptor 3 serum levels were determined by ELISA. High DcR3 expression was associated with high-grade (P = .005) and high-stage (P = .048) RCCs. The incidence of distant metastasis (P = .03) and lymph node metastasis (P = .002) was significantly higher in the group with high DcR3 expression. Decoy receptor 3 expression correlated negatively with disease-specific survival (P < .001) and progression-free survival (P < .001) in univariate analyses. A multivariate Cox regression analysis retained DcR3 expression as an independent prognostic factor that outperformed the Karnofsky performance status. In patients with high-stage RCCs expressing DcR3, the 2-year survival probability was 25%, whereas in patients with DcR3-negative tumors, the survival probability was 65% (P < .001). Moreover, DcR3 serum levels were significantly higher in patients with high-stage localized disease (P = .007) and metastatic disease (P = .001). DcR3 expression is an independent prognostic factor of RCC progression and mortality. Therefore, the assessment of DcR3 expression levels offers valuable prognostic information that could be used to select patients for adjuvant therapy studies.

CD47 expression in Epstein-Barr virus-associated gastric carcinoma: coexistence with tumor immunity lowering the ratio of CD8+/Foxp3+ T cells.

PubMed

Abe, Hiroyuki; Saito, Ruri; Ichimura, Takashi; Iwasaki, Akiko; Yamazawa, Sho; Shinozaki-Ushiku, Aya; Morikawa, Teppei; Ushiku, Tetsuo; Yamashita, Hiroharu; Seto, Yasuyuki; Fukayama, Masashi

2018-04-01

Epstein-Barr virus-associated gastric carcinoma (EBVaGC) frequently harbors dense lymphocytic infiltration, suggesting a specific microenvironment allowing coexistence with tumor immunity. CD47, which mediates the "do not eat me" signal in innate immunity, is also important in adaptive anti-tumor immunity. We investigated the significance of CD47 in EBVaGC compared with EBV-negative gastric cancer and the correlation with various immune cells. By immunohistochemistry of CD47, high, low, and negative expression was observed in 24, 63, and 12% of EBVaGC (n = 41), while 11, 49, and 39% of EBV-negative gastric cancer (n = 262), respectively, indicating that high expression of CD47 in cancer cells was significantly frequent and increased in EBVaGC (P = 0.043). In contrast to EBV-negative gastric carcinoma in which no significant correlation was observed between CD47 and survival, high expression of CD47 correlated significantly with worse disease-specific survival (P = 0.011) and overall survival (P = 0.013) in EBVaGC. To further clarify the role of CD47 expression in EBVaGC, digital image analysis of immune cell infiltration revealed that high CD47 expression was correlated with a lower ratio of CD8 + /Foxp3 + T cells (P = 0.021), a sensitive indicator of tumor immunity. Thus, CD47 lowers anti-tumor immunity in EBVaGC by finely tuning profile of infiltrating T cells, suggesting that CD47 is an additional target for cancer immunotherapy against this virus-driven gastric cancer.

RNA-Seq Mouse Brain Regions Expression Data Analysis: Focus on ApoE Functional Network

PubMed

Babenko, Vladimir N; Smagin, Dmitry A; Kudryavtseva, Natalia N

2017-09-13

ApoE expression status was proved to be a highly specific marker of energy metabolism rate in the brain. Along with its neighbor, Translocase of Outer Mitochondrial Membrane 40 kDa (TOMM40) which is involved in mitochondrial metabolism, the corresponding genomic region constitutes the neuroenergetic hotspot. Using RNA-Seq data from a murine model of chronic stress a significant positive expression coordination of seven neighboring genes in ApoE locus in five brain regions was observed. ApoE maintains one of the highest absolute expression values genome-wide, implying that ApoE can be the driver of the neighboring gene expression alteration observed under stressful loads. Notably, we revealed the highly statistically significant increase of ApoE expression in the hypothalamus of chronically aggressive (FDR < 0.007) and defeated (FDR < 0.001) mice compared to the control. Correlation analysis revealed a close association of ApoE and proopiomelanocortin (Pomc) gene expression profiles implying the putative neuroendocrine stress response background of ApoE expression elevation therein.

Effects of Different Levels of Calcium Intake on Brain Cell Apoptosis in Fluorosis Rat Offspring and Its Molecular Mechanism.

PubMed

Sun, Yan; Ke, Lulu; Zheng, Xiangren; Li, Tao; Ouyang, Wei; Zhang, Zigui

2017-04-01

The purpose of the investigation is to reveal the influence of dietary calcium on fluorosis-induced brain cell apoptosis in rat offspring, as well as the underlying molecular mechanism. Sprague-Dawley (SD) female rats were randomly divided into five groups: control group, fluoride group, low calcium, low calcium fluoride group, and high calcium fluoride group. SD male rats were used for breeding only. After 3 months, male and female rats were mated in a 1:1 ratio. Subsequently, 18-day-old gestation rats and 14- and 28-day-old rats were used as experimental subjects. We determined the blood/urine fluoride, the blood/urine calcium, the apoptosis in the hippocampus, and the expression levels of apoptosis-related genes, namely Bcl-2, caspase 12, and JNK. Blood or blood/urine fluoride levels and apoptotic cells were found significantly increased in fluorosis rat offspring as compared to controls. Furthermore, the Bcl-2 messenger RNA (mRNA) expression levels significantly decreased, and caspase 12 mRNA levels significantly increased in each age group as compared to controls. Compared with the fluoride group, the blood/urine fluoride content and apoptotic cells evidently decreased in the high calcium fluoride group, Bcl-2 mRNA expression significantly increased and caspase 12 mRNA expression significantly decreased in each age group. All results showed no gender difference. Based on these results, the molecular mechanisms of fluorosis-induced brain cell apoptosis in rat offspring may include the decrease in Bcl-2 mRNA expression level and increase in caspase 12 mRNA expression signaling pathways. High calcium intake could reverse these gene expression trends. By contrast, low calcium intake intensified the toxic effects of fluoride on brain cells.

Long noncoding RNA CCAT2 can predict metastasis and poor prognosis: A meta-analysis.

PubMed

Fan, Yang-Hua; Fang, Hua; Ji, Chen-Xing; Xie, Huan; Xiao, Bing; Zhu, Xin-Gen

2017-03-01

It has been reported that Colon cancer-associated transcript 2 (CCAT2) is dysregulated in various cancers. We performed this meta-analysis to clarify its promising functions as a prognosis marker in malignant tumors. Electronic databases, including PubMed, Medline, OVID, Cochrane Library, and Web of Science, were searched from inception to October 20, 2016. The hazard ratio (HR) and 95% confidence interval (CI) were calculated to explore the relationship between CCAT2 expression and survival, which were extracted from the eligible studies. The odds ratio (OR) was calculated to assess the association between CCAT2 expression and pathological parameters using RevMan5.3 software. Six original studies were included in this meta-analysis including 725 cancer patients. The pooled HR suggested that high CCAT2 expression was significantly correlated with overall survival (OS) (HR=2.30, 95% CI: 1.62-3.25, p<0.00001) in cancer patients. Subgroup analysis revealed a significant association between CCAT2 and OS in urogenital system (HR=1.70, 95% CI: 1.27-2.26, p<0.003) and non-urogenital system cancer patients (HR=3.18, 95% CI: 2.09-4.83, p<0.0001). A significant association was observed between high CCAT2 expression and poor progression-free survival (PFS) in cancer patients (pooled HR=2.76, 95% CI: 1.74-4.37). CCAT2 expression was significantly related to lymph node metastasis (LNM) (OR=4.33, 95% CI 2.03-9.22), distant metastasis (DM) (OR=11.66, 95% CI: 5.36-25.37) and tumor stage (OR=2.58, 95% CI 1.86-3.57). This meta-analysis demonstrated that high CCAT2 expression significantly predicts poor OS, poor PFS, LNM, DM and tumor stage, suggesting that high CCAT2 expression may serve as a novel biomarker for poor prognosis and metastasis in cancers. Copyright © 2017 Elsevier B.V. All rights reserved.

Feeding a High Concentrate Diet Down-Regulates Expression of ACACA, LPL and SCD and Modifies Milk Composition in Lactating Goats

PubMed Central

Tao, Hui; Chang, Guangjun; Xu, Tianle; Zhao, Huajian; Zhang, Kai; Shen, Xiangzhen

2015-01-01

High concentrate diets are fed to early and mid-lactation stages dairy ruminants to meet the energy demands for high milk production in modern milk industry. The present study evaluated the effects of a high concentrate diet on milk fat and milk composition, especially, cis-9, trans-11 CLA content in milk and gene expression of lactating goats. Eight mid-lactating goats with rumen fistula were randomly assigned into a high concentrate diet (HCD) group and low concentrate diet (LCD) group. High concentrate diet feeding significantly increased lipopolysaccharides (LPS) in plasma and decreased milk fat content, vaccenic acid (VA) and cis-9, trans-11 CLA in milk of the lactating goats. The mRNA expression levels of sterol regulatory element binding protein B 1c (SREBP1c), lipoprotein lipase (LPL), fatty acid synthetase (FASN) and acetyl-CoA carboxylase α (ACACA, ACCα) involving in lipid metabolism were analyzed, and ACACA and LPL all decreased in their expression level in the mammary glands of goats fed a high concentrate diet. DNA methylation rate of stearoyl-CoA desaturase (SCD) was elevated and decreased, and SCD mRNA and protein expression was reduced significantly in the mammary glands of goats fed a high concentrate diet. In conclusion, feeding a high concentrate diet to lactating goats decreases milk fat and reduced expression of SCD in the mammary gland, which finally induced cis-9, trans-11 CLA content in milk. PMID:26086219

Anti-obesity effects of hot water extract from Wasabi (Wasabia japonica Matsum.) leaves in mice fed high-fat diets

PubMed Central

Ogawa, Tetsuro; Wang, Li; Katsube, Takuya; Yamasaki, Yukikazu; Sun, Xufeng; Shiwaku, Kuninori

2013-01-01

The anti-obesity effects of a hot water extract from wasabi (Wasabia japonica Matsum.) leaves (WLE), without its specific pungent constituents, such as allyl-isothiocyanate, were investigated in high fat-diet induced mice. C57J/BL mice were fed a high-fat diet (control group) or a high-fat diet supplemented with 5% WLE (WLE group). Physical parameters and blood profiles were determined. Gene expression associated with lipid metabolism in liver and white adipose tissue were analyzed. After 120 days of feeding, significantly lower body weight gain, liver weight and epididymal white adipose tissue weight was observed in the WLE group compared to the control group. In liver gene expression within the WLE group, PPARα was significantly enhanced and SREBP-1c was significantly suppressed. Subsequent downstream genes controlled by these regulators were significantly suppressed. In epididymal white adipose tissue of the WLE group, expression of leptin, PPARγ, and C/EBPα were significantly suppressed and adiponectin was significantly enhanced. Acox, related to fatty acid oxidization in adipocytes, was also enhanced. Our results demonstrate that the WLE dietary supplement induces mild suppression of obesity in a high-fat diet induced mice, possibly due to suppression of lipid accumulation in liver and white adipose tissue. PMID:23964313

Anti-obesity effects of hot water extract from Wasabi (Wasabia japonica Matsum.) leaves in mice fed high-fat diets.

PubMed

Yamasaki, Masayuki; Ogawa, Tetsuro; Wang, Li; Katsube, Takuya; Yamasaki, Yukikazu; Sun, Xufeng; Shiwaku, Kuninori

2013-08-01

The anti-obesity effects of a hot water extract from wasabi (Wasabia japonica Matsum.) leaves (WLE), without its specific pungent constituents, such as allyl-isothiocyanate, were investigated in high fat-diet induced mice. C57J/BL mice were fed a high-fat diet (control group) or a high-fat diet supplemented with 5% WLE (WLE group). Physical parameters and blood profiles were determined. Gene expression associated with lipid metabolism in liver and white adipose tissue were analyzed. After 120 days of feeding, significantly lower body weight gain, liver weight and epididymal white adipose tissue weight was observed in the WLE group compared to the control group. In liver gene expression within the WLE group, PPARα was significantly enhanced and SREBP-1c was significantly suppressed. Subsequent downstream genes controlled by these regulators were significantly suppressed. In epididymal white adipose tissue of the WLE group, expression of leptin, PPARγ, and C/EBPα were significantly suppressed and adiponectin was significantly enhanced. Acox, related to fatty acid oxidization in adipocytes, was also enhanced. Our results demonstrate that the WLE dietary supplement induces mild suppression of obesity in a high-fat diet induced mice, possibly due to suppression of lipid accumulation in liver and white adipose tissue.

Sustained expression of steroid receptor coactivator SRC-2/TIF-2 is associated with better prognosis in malignant pleural mesothelioma.

PubMed

Jennings, Cormac J; O'Grady, Anthony; Cummins, Robert; Murer, Bruno; Al-Alawi, Mazen; Madden, Stephen F; Mutti, Luciano; Harvey, Brian J; Thomas, Warren; Kay, Elaine W

2012-01-01

Estrogen receptor beta (ERβ) overexpression by malignant pleural mesothelioma (MPM) tumor cells correlates with enhanced patient survival. ER-regulated transcription is mediated by the p160 family of steroid receptor coactivators (SRCs), and SRC isoform overexpression is associated with worse prognosis in many steroid-related malignancies. The aim of this study was to establish whether SRC isoform expression varied between individual MPM tumors with positive or negative prognostic significance. Immunohistochemical analysis of tumor biopsies from 89 subjects with confirmed histological diagnosis of MPM and biopsies from 3 normal control subjects was performed to detect the expression of SRC-1, SRC-2 (TIF-2), SRC-3 (AIB-1), and ERβ. Allred scores for expression of ERβ and each of the SRCs were determined, and Kaplan-Meier survival curves were calculated to correlate biomarker expression, gender, and histology type with postdiagnosis survival. ERβ and all the SRCs were expressed at high levels in normal pleural mesothelium, and expression of each biomarker was reduced or lost in a subset of the MPM subjects; however, postdiagnosis survival only significantly correlated with TIF-2 expression. Low or intermediate expression of TIF-2 correlated with reduced median postdiagnosis survival (9 months) compared with those subjects whose tumors highly expressed TIF-2 (20 months) (p = 0.036, log-rank test). Maintained high expression of TIF-2 in tumor cells is a positive prognostic indicator for postdiagnosis survival in patients with confirmed MPM. This is the first clinical study to correlate high TIF-2 expression with improved patient prognosis in any malignancy.

S100A8 Production in CXCR2-Expressing CD11b+Gr-1high Cells Aggravates Hepatitis in Mice Fed a High-Fat and High-Cholesterol Diet.

PubMed

Mukai, Kaori; Miyagi, Takuya; Nishio, Kumiko; Yokoyama, Yoshinobu; Yoshioka, Teppei; Saito, Yoshinobu; Tanaka, Satoshi; Shigekawa, Minoru; Nawa, Takatoshi; Hikita, Hayato; Sakamori, Ryotaro; Yoshihara, Harumasa; Imai, Yasuharu; Hiramatsu, Naoki; Tatsumi, Tomohide; Takehara, Tetsuo

2016-01-01

Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease with a spectrum of presentations. S100A8 has been suggested to play a pivotal role as an endogenous immune-activator in inflammatory diseases. In this study, we investigated the involvement of S100A8 in the development of NAFLD. We used a diet model of NAFLD, in which mice were fed either a high-fat and high-cholesterol diet (HFHCD) or a normal diet (ND) as a control. We also assessed liver tissues from patients with NAFLD, including patients with nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). HFHCD-fed mice, but not ND-fed mice, developed steatohepatitis. S100A8 expression was significantly elevated in the livers of HFHCD-fed mice compared with the controls. S100A8 was exclusively expressed in CXCR2-expressing CD11b(+)Gr-1(high) cells, which significantly increased in the livers of HFHCD-fed mice. These cells were F4/80 negative and did not possess a suppressor function. TNF-α expression was enhanced by S100A8 in primary liver leukocytes or a hepatocyte cell line and significantly elevated in the livers of HFHCD-fed mice. TNF-α was primarily produced from CD11b(+)F4/80(+) cells in liver leukocytes in response to S100A8. TNF-α deficiency attenuated hepatitis in HFHCD-fed mice. S100A8 was significantly more expressed in the liver tissues of patients with NASH than in those of patients with NAFL. In conclusion, these results suggest that S100A8 is primarily produced from CXCR2-expressing CD11b(+)Gr-1(high) cells, and it upregulates TNF-α production in CD11b(+)F4/80(+) cells through cellular cross-talk, which is an important mechanism in the development of NAFLD. Copyright © 2015 by The American Association of Immunologists, Inc.

High expression of NKG2A/CD94 and low expression of granzyme B are associated with reduced cord blood NK cell activity.

PubMed

Wang, Yanyan; Xu, Han; Zheng, Xiaodong; Wei, Haiming; Sun, Rui; Tian, Zhigang

2007-10-01

Human umbilical cord blood (CB) has recently been used as a source of stem cells in transplantation. NK cells derived from CB are the key effector cells involved in graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL). It was reported that the activity of CB NK cells was lower than that of adult peripheral blood (PB) NK cells. In this study, we analyzed the expression of some NK cell receptors and cytotoxicity-related molecules in CB and PB NK cells. The expressions of activating NK receptors, CD16, NKG2D and NKp46, did not show significant difference between CB and PB NK cells. But the expression of inhibitory receptor NKG2A/CD94 was significantly higher on CB NK cells. As to the effector function molecules, granzyme B was expressed significantly lower in CB NK cells, but the expressions of intracellular perforin, IFN-gamma, TNF-alpha and cell surface FasL and TRAIL did not show difference between CB and PB NK cells. The results indicated that the high expression of NKG2A/CD94 and low expression of granzyme B may be related with the reduced activity of CB NK cells.

Expression of p53, Bcl-2, VEGF, Ki67 and PCNA and prognostic significance in hepatocellular carcinoma.

PubMed

Stroescu, Cezar; Dragnea, Adrian; Ivanov, Bogdan; Pechianu, Catalin; Herlea, Vlad; Sgarbura, Olivia; Popescu, Andra; Popescu, Irinel

2008-12-01

Hepatocellular carcinoma is one of the most common malignant tumors that carry a poor prognosis. To improve the long-term outlook for HCC, an accurate prognosis is important. To study the immunohistochemical expressions of p53, Ki67, Bcl-2, VEGF and PCNA and their potential role as prognostic factors in patients with radical resection of hepatocellular carcinoma. Forty-seven formalin-fixed paraffin-embedded tumor samples from patients with HCC receiving liver resection were investigated immunohistochemically for the expression of cellular proliferation markers PCNA, Ki67, p53, Bcl-2 and VEGF and their correlation with tumor characteristics and survival time after resection. p53 was expressed in a higher percentage (85.7 vs. 42.1%) in undifferentiated histological tumor grades (Edmondson Steiner G3/G4 vs. G1/G2). Patients with p53 accumulating tumors showed a worse survival than patients with p53 non-accumulating tumors (median 9.5 vs. 16.5 months). Over-expression of VEGF was found in 38.3% of all HCCs. VEGF expression was significantly correlated with p53 expression and recurrence rates. The results showed that the labeling index of PCNA and expression of p53 are correlated. The high labeling index of PCNA or over-expression of p53 resulted in high risk of tumor recurrence, more aggressive growth and poor survival. High labeling index of PCNA, p53 nuclear accumulation and VEGF high expression are associated with poor survival in patients with HCC.

Postnatal changes and sexual dimorphism in collagen expression in mouse skin

PubMed Central

Arai, Koji Y.; Hara, Takuya; Nagatsuka, Toyofumi; Kudo, Chikako; Tsuchiya, Sho; Nomura, Yoshihiro; Nishiyama, Toshio

2017-01-01

To investigate sexual dimorphism and postnatal changes in skin collagen expression, mRNA levels of collagens and their regulatory factors in male and female skin were examined during the first 120 days of age by quantitative realtime PCR. Levels of mRNAs encoding extracellular matrices did not show any differences between male and female mice until day 15. Col1a1 and Col1a2 mRNAs noticeably increased at day 30 and remained at high levels until day 120 in male mice, while those in female mice remained at low levels during the period. Consistent with the mRNA expression, pepsin-soluble type I collagen contents in skin was very high in mature male as compared to female. Col3a1 mRNA in male mice also showed significantly high level at day 120 as compared to female. On the other hand, expression of mRNAs encoding TGF-ßs and their receptors did not show apparent sexual dimorphism although small significant differences were observed at some points. Castration at 60 days of age resulted in a significant decrease in type I collagen mRNA expression within 3 days, and noticeably decreased expression of all fibril collagen mRNAs examined within 14 days, while administration of testosterone tube maintained the mRNA expression at high levels. Despite the in vivo effect of testosterone, administration of physiological concentrations of testosterone did not affect fibril collagen mRNA expression in either human or mouse skin fibroblasts in vitro, suggesting that testosterone does not directly affect collagen expression in fibroblasts. In summary, present study demonstrated dynamic postnatal changes in expression of collagens and their regulatory factors, and suggest that testosterone and its effects on collagen expression are responsible for the skin sexual dimorphism but the effects of testosterone is not due to direct action on dermal fibroblasts. PMID:28494009

High Expression of EphA4 Predicted Lesser Degree of Tumor Regression after Neoadjuvant Chemoradiotherapy in Rectal Cancer.

PubMed

Lin, Ching-Yih; Lee, Ying-En; Tian, Yu-Feng; Sun, Ding-Ping; Sheu, Ming-Jen; Lin, Chen-Yi; Li, Chien-Feng; Lee, Sung-Wei; Lin, Li-Ching; Chang, I-Wei; Wang, Chieh-Tien; He, Hong-Lin

2017-01-01

Background: Numerous transmembrane receptor tyrosine kinase pathways have been found to play an important role in tumor progression in some cancers. This study was aimed to evaluate the clinical impact of Eph receptor A4 (EphA4) in patients with rectal cancer treated with neoadjuvant concurrent chemoradiotherapy (CCRT) combined with mesorectal excision, with special emphasis on tumor regression. Methods: Analysis of the publicly available expression profiling dataset of rectal cancer disclosed that EphA4 was the top-ranking, significantly upregulated, transmembrane receptor tyrosine kinase pathway-associated gene in the non-responders to CCRT, compared with the responders. Immunohistochemical study was conducted to assess the EphA4 expression in pre-treatment biopsy specimens from 172 rectal cancer patients without distant metastasis. The relationships between EphA4 expression and various clinicopathological factors or survival were statistically analyzed. Results: EphA4 expression was significantly associated with vascular invasion ( P =0.015), post-treatment depth of tumor invasion ( P =0.006), pre-treatment and post-treatment lymph node metastasis ( P =0.004 and P =0.011, respectively). More importantly, high EphA4 expression was significantly predictive for lesser degree of tumor regression after CCRT ( P =0.031). At univariate analysis, high EphA4 expression was a negative prognosticator for disease-specific survival ( P =0.0009) and metastasis-free survival ( P =0.0001). At multivariate analysis, high expression of EphA4 still served as an independent adverse prognostic factor for disease-specific survival (HR, 2.528; 95% CI, 1.131-5.651; P =0.024) and metastasis-free survival (HR, 3.908; 95% CI, 1.590-9.601; P =0.003). Conclusion: High expression of EphA4 predicted lesser degree of tumor regression after CCRT and served as an independent negative prognostic factor in patients with rectal cancer.

Pontin Acts as a Potential Biomarker for Poor Clinical Outcome and Promotes Tumor Invasion in Hilar Cholangiocarcinoma.

PubMed

Sun, Qi; Li, Fanni; Yu, Songyang; Zhang, Xiang; Shi, Feiyu; She, Junjun

2018-01-01

Hilar cholangiocarcinoma (HC) is a devastating malignancy that carries a poor overall prognosis. As a member of the AAA+ superfamily, Pontin becomes highly expressed in several malignant tumors, which contributes to tumor progression and influences tumor prognosis. In our research, Pontin expression in tumor specimens resected from 86 HC patients was detected by immunohistochemistry. Interestingly, high expression of Pontin was significantly associated with lymph node metastasis ( p = 0.011) and tumor node metastasis (TNM) stage ( p = 0.005). The Kaplan-Meier overall survival rate and multivariate analyses were performed to evaluate the prognosis of patients with HC. Patients with high Pontin expression had significantly poorer overall survival outcomes. Multivariate analyses found that Pontin was an independent prognostic factor ( p = 0.001). Moreover, bioinformatics analysis confirmed the increase in Pontin mRNA expression levels in cholangiocarcinoma tissues. In addition, in vitro experiments showed that Pontin expression was inhibited at the mRNA as well as protein levels after transfection with Pontin siRNA in human cholangiocarcinoma cell lines. Moreover, significant suppression of cell invasion was observed after the downregulation of Pontin. Taken together, the present study suggested that Pontin could act as a potential prognostic predictor, which might be a new valuable molecular candidate for the prevention and treatment of HC.

High expression of B7-H6 in human glioma tissues promotes tumor progression.

PubMed

Jiang, Tianwei; Wu, Wei; Zhang, Huasheng; Zhang, Xiangsheng; Zhang, Dingding; Wang, Qiang; Huang, Lei; Wang, Ye; Hang, Chunhua

2017-06-06

B7-H6, a new member of B7-family ligand, also known as NCR3LG1, plays an important role in NK cells mediated immune responses. Many studies have shown that it is highly expressed in various human cancers, and its expression levels are significantly associated with cancer patients' clinicopathological parameters and postoperative prognoses. But, still the exact role of B7-H6 expression in human glioma remains elusive. In the present study, we have characterized the B7-H6 expression in the human glioma tissues as well as glioma cell lines, U87 and U251. We observed that B7-H6 was highly expressed in the human glioma tissues, and its expression was significantly associated with cancer progression. By using the RNA interference technology, we successfully ablated B7-H6 expression in human glioma cell lines to further study its contribution towards various biological features of this malignancy. Our study identified that the B7-H6 knockdown in U87 and U251 glioma cells significantly suppressed cell proliferation, migration, invasion, and enhanced apoptosis along with induction of cell cycle arrest. It thus suggested that B7-H6 play an important role in the regulation of the biological behavior of these glioma cells. However, the detailed mechanism of B7-H6 mediated regulation of glioma cancer cell transformation and its prognostic value merits further investigation.

Randomized controlled trial of expressive writing for psychological and physical health: the moderating role of emotional expressivity.

PubMed

Niles, Andrea N; Haltom, Kate E Byrne; Mulvenna, Catherine M; Lieberman, Matthew D; Stanton, Annette L

2014-01-01

The current study assessed main effects and moderators (including emotional expressiveness, emotional processing, and ambivalence over emotional expression) of the effects of expressive writing in a sample of healthy adults. Young adult participants (N=116) were randomly assigned to write for 20 minutes on four occasions about deepest thoughts and feelings regarding their most stressful/traumatic event in the past five years (expressive writing) or about a control topic (control). Dependent variables were indicators of anxiety, depression, and physical symptoms. No significant effects of writing condition were evident on anxiety, depressive symptoms, or physical symptoms. Emotional expressiveness emerged as a significant moderator of anxiety outcomes, however. Within the expressive writing group, participants high in expressiveness evidenced a significant reduction in anxiety at three-month follow-up, and participants low in expressiveness showed a significant increase in anxiety. Expressiveness did not predict change in anxiety in the control group. These findings on anxiety are consistent with the matching hypothesis, which suggests that matching a person's naturally elected coping approach with an assigned intervention is beneficial. These findings also suggest that expressive writing about a stressful event may be contraindicated for individuals who do not typically express emotions.

Effects of Expressive Writing on Psychological and Physical Health: The Moderating Role of Emotional Expressivity

PubMed Central

Haltom, Kate E.; Mulvenna, Catherine M.; Lieberman, Matthew D.; Stanton, Annette L.

2013-01-01

The current study assessed main effects and moderators (including emotional expressiveness, emotional processing and ambivalence over emotional expression) of the effects of expressive writing in a sample of healthy adults. Young adult participants (N = 116) were randomly assigned to write for 20 minutes on four occasions about deepest thoughts and feelings regarding their most stressful/traumatic event in the past five years (expressive writing) or about a control topic (control). Dependent variables were indicators of anxiety, depression, and physical symptoms. No significant effects of writing condition were evident on anxiety, depressive symptoms, or physical symptoms. Emotional expressiveness emerged as a significant moderator of anxiety outcomes, however. Within the expressive writing group, participants high in expressiveness evidenced a significant reduction in anxiety at three-month follow-up, and participants low in expressiveness showed a significant increase in anxiety. Expressiveness did not predict change in anxiety in the control group. These findings on anxiety are consistent with the matching hypothesis, which suggests that matching a person’s naturally elected coping approach with an assigned intervention is beneficial. These findings also suggest that expressive writing about a stressful event may be contraindicated for individuals who do not typically express emotions. PMID:23742666

[DAB2IP expression in bladder transitional cell carcinoma and its correlation with clinical outcome].

PubMed

Zhu, Jian-Ning; Wu, Kai-Jie; Guan, Zhen-Feng; Liu, Li-Xia; Ning, Zhong-Yun; Zhou, Jian-Cheng; Wang, Xin-Yang; Fan, Jin-Hai

2014-07-01

To investigate the expression of DAB2IP in bladder transitional cell carcinoma (BTCC) and its correlation with clinical characteristics and prognosis of BTCC patients. Immunohistochemical staining was applied to detect DAB2IP protein level in 79 cases of TCCB tissues and 11 cases of normal bladder tissues, and the relationships of the staining results with pathological grade, stage, lymph node metastasis, gender, age and the 3-year survival rate of the patients were analyzed. The expression of DAB2IP in BTCC tissues was significantly lower than that in normal bladder epithelium, and the expression score and rate of DAB2IP in the high-grade, invasive and metastatic BTCC were significantly lower than those in low-grade, superficial and non-metastatic BTCC (P < 0.05). The 3-year survival rate of the patients with high DAB2IP expression was significantly higher than that of the patients with low DAB2IP expression. DAB2IP may be one of the important inhibitory factors during the occurrence and progression of BTCC.

Ectopic expression of Arabidopsis Target of Rapamycin (AtTOR) improves water-use efficiency and yield potential in rice

NASA Astrophysics Data System (ADS)

Bakshi, Achala; Moin, Mazahar; Kumar, M. Udaya; Reddy, Aramati Bindu Madhava; Ren, Maozhi; Datla, Raju; Siddiq, E. A.; Kirti, P. B.

2017-02-01

The target of Rapamycin (TOR) present in all eukaryotes is a multifunctional protein, regulating growth, development, protein translation, ribosome biogenesis, nutrient, and energy signaling. In the present study, ectopic expression of TOR gene of Arabidopsis thaliana in a widely cultivated indica rice resulted in enhanced plant growth under water-limiting conditions conferring agronomically important water-use efficiency (WUE) trait. The AtTOR high expression lines of rice exhibited profuse tillering, increased panicle length, increased plant height, high photosynthetic efficiency, chlorophyll content and low Δ13C. Δ13C, which is inversely related to high WUE, was as low as 17‰ in two AtTOR high expression lines. These lines were also insensitive to the ABA-mediated inhibition of seed germination. The significant upregulation of 15 stress-specific genes in high expression lines indicates their contribution to abiotic stress tolerance. The constitutive expression of AtTOR is also associated with significant transcriptional upregulation of putative TOR complex-1 components, OsRaptor and OsLST8. Glucose-mediated transcriptional activation of AtTOR gene enhanced lateral root formation. Taken together, our findings indicate that TOR, in addition to its multiple cellular functions, also plays an important role in response to abiotic stress and potentially enhances WUE and yield related attributes.

Clinical significance of CXCL16/CXCR6 expression in patients with prostate cancer.

PubMed

Ha, Hong Koo; Lee, Wan; Park, Hyun Jun; Lee, Sang Don; Lee, Jeong Zoo; Chung, Moon Kee

2011-01-01

We hypothesized that the CXCL16-CXCR6 ligand-receptor system may play an important role in prostate cancer progression. Levels of CXCL16 and CXCR6 expression were evaluated in prostate cancer cell lines (PC-3 and LNCaP) and normal prostate epithelial cells (PrEC), as well as in tissues from 354 patients. The immunohistochemical expression of CXCL16/CXCR6 was greater in the PC-3/LNCaP cells than in the PrEC cell line. The expression of CXCL16/CXCR6 was significantly higher in prostate cancer than in benign prostatic hypertrophy. Using RT-PCR, the expression of CXCL16/CXCR6 was found to be greater in the PC-3/LNCaP cells than in the PrEC cell line. CXCL16/CXCR6 was weakly detected in lung and liver tissues, whereas CXCL16 was highly expressed in specimens of bone metastasis. CXCL16 immunostaining was related to Gleason score, T stage, tumor volume, perineural invasion and lymph node metastasis. However, biochemical PSA recurrence was not related to the expression of CXCL16/CXCR6. High CXCL16/CXCR6 expression may be related to aggressive cancer behavior, and high CXCL16 expression to bone metastases.

AAA+ ATPases Reptin and Pontin as potential diagnostic and prognostic biomarkers in salivary gland cancer - a short report.

PubMed

Mikesch, Jan-Henrik; Hartmann, Wolfgang; Angenendt, Linus; Huber, Otmar; Schliemann, Christoph; Arteaga, Maria Francisca; Wardelmann, Eva; Rudack, Claudia; Berdel, Wolfgang E; Stenner, Markus; Grünewald, Inga

2018-06-05

Salivary gland cancer (SGC) is a rare and heterogeneous disease with significant differences in recurrence and metastasis characteristics. As yet, little is known about the mechanisms underlying the initiation and/or progression of these diverse tumors. In recent years, the AAA+ ATPase family members Pontin (RuvBL1, Tip49a) and Reptin (RuvBL2, Tip49b) have been implicated in various processes, including transcription regulation, chromatin remodeling and DNA damage repair, that are frequently deregulated in cancer. The aim of this study was to assess the clinical and functional significance of Reptin and Pontin expression in SGC. Immunohistochemical staining of Pontin, Reptin, β-catenin, Cyclin D1, TP53 and MIB-1 was performed on a collection of 94 SGC tumor samples comprising 13 different histological subtypes using tissue microarrays. We found that Reptin and Pontin were expressed in the majority of SGC samples across all histological subtypes. Patients with a high Reptin expression showed a significantly inferior 5-year overall survival rate compared to patients with a low Reptin expression (47.7% versus 78.3%; p = 0.033), whereas no such difference was observed for Pontin. A high Reptin expression strongly correlated with a high expression of the proliferation marker MIB-1 (p = 0.003), the cell cycle regulator Cyclin D1 (p = 0.006), accumulation of TP53 as a surrogate p53 mutation marker (p = 0.042) and cytoplasmic β-catenin expression (p = 0.002). Increased Pontin expression was found to significantly correlate with both cytoplasmic and nuclear β-catenin expression (p = 0.037 and p = 0.018, respectively), which is indicative for its oncogenic function. Our results suggest a role of Reptin and Pontin in SGC tumor progression and/or patient survival. Therefore, SGC patients exhibiting a high Reptin expression may benefit from more aggressive therapeutic regimens. Future studies should clarify whether such patients may be considered for more radical surgery, extended adjuvant therapy and/or targeted therapy.

[Expression and clinical significance of 5hmC in bladder urothelial carcinoma].

PubMed

Li, Jie; Xu, Yuqiao; Zhang, Zhiwen; Zhang, Ming; Zhang, Zhekai; Zhang, Feng; Li, Qing

2016-02-01

To investigate the expression of 5-hydroxymethylcytosine (5hmC) in bladder urothelial carcinoma (UC) and its clinical significance. The expression of 5hmC in 21 cases of UC tissues and pericarcinous urinary tract epithelium was detected by immunohistochemical staining. Then the expression of 5hmC in the surgical resection of UC tissues in 92 cases was also surveyed. Non parametric U Mann-Whitney test was used to analyze the correlation between 5hmC expression and clinical data. Single factor survival analysis was performed by Kaplan-Meier test. The expression of 5hmC in normal urinary tract epithelium and UC tissues was significantly different, but there was no significant difference in the expression of 5hmC between low and high grades of UC tissues as well as between different TNM grades. Kaplan-Meier single factor survival analysis showed that there was no significant correlation between the 5hmC expression level and the survival rate or the recurrence-free survival of UC patients. The expression level of 5hmC in UC tissues is significantly lower than that in pericarcinous urinary tract epithelium. There is no correlation between the 5hmC expression and the progression, prognosis and recurrence of UC.

Prognostic significance of MYCN gene amplification and protein expression in primary brain tumors: Astrocytoma and meningioma.

PubMed

Estiar, Mehrdad Asghari; Javan, Firouzeh; Zekri, Ali; Mehrazin, Masoud; Mehdipour, Parvin

2017-07-04

Astrocytoma and meningioma are the most common primary brain tumors. MYCN as a member of MYC proto-oncogenes has recently appeared as an attractive therapeutic target. Functions of MYCN are critical for growth of nervous system and neural differentiation. We examined MYCN amplification and protein expression in astrocytoma and meningioma cases. In this study, we used real-time PCR, FISH assay and flowcytometry to analyze DNA amplification and protein expression of MYCN. Among 30 samples of brain tumor, 14 cases (46.6%) revealed MYCN amplification. High-protein expression of MYCN was also observed in 43.3% of patients. There was a significant correlation between MYCN gene amplification and protein expression (r= 0.523; p= 0.003), interestingly five case showed discrepancy between the gene amplification and protein expression. Although MYCN amplification fails to show correlation with poor prognosis (p= 0.305), protein high-expression of MYCN significantly reduce disease-free survival (p= 0.019). Our results challenge the concept of the neural specificity of MYCN by demonstrating contribution of MYCN in meningioma. Moreover, this study highlights the importance of research at both level of DNA and protein, to determine the biological functions and medical impacts of MYCN.

Long non-coding RNA PVT1 as a novel potential biomarker for predicting the prognosis of colorectal cancer.

PubMed

Fan, Heng; Zhu, Jian-Hua; Yao, Xue-Qing

2018-05-01

Long non-coding RNA (lncRNA) plays a very important role in the occurrence and development of various tumors, and is a potential biomarker for cancer diagnosis and prognosis. The purpose of this study was to investigate the relationship between the expression of lncRNA plasmacytoma variant translocation 1 (PVT1) and the prognostic significance in patients with colorectal cancer. The expression of PVT1 was measured by real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) in cancerous and adjacent tissues of 210 colorectal cancer patients. The disease-free survival and overall survival of colorectal cancer patients were evaluated by Kaplan-Meier analysis, and univariate and multivariate analysis were performed by Cox proportional-hazards model. Our results revealed that PVT1 expression in cancer tissues of colorectal cancer was significantly higher than that of adjacent tissues ( P<0.001). High PVT1 expression was increased by 51.4% (108/210), which was significantly correlated with the tumor differentiation, the depth of invasion, the stage of tumor, node, metastasis (TNM), and lymphatic metastasis. The Kaplan-Meier analysis showed that high PVT1 expression resulted in a shorter disease-free survival (Log-rank test P<0.001) and overall survival (Log-rank test P<0.001) compared with the low PVT1 expression group in colorectal cancer patients, whether at TNM I/II stage or at TNM III/IV stage. A multivariate Cox regression analysis demonstrated that high PVT1 expression was an independent predictor of poor prognosis in colorectal cancer patients. Our results suggest that high PVT1 expression might be a potential biomarker for assessing tumor recurrence and prognosis in colorectal cancer patients.

Overexpression of Pofut1 and activated Notch1 may be associated with poor prognosis in breast cancer.

PubMed

Wan, Guoxing; Tian, Lin; Yu, Yuandong; Li, Fang; Wang, Xuanbin; Li, Chen; Deng, Shouheng; Yu, Xiongjie; Cai, Xiaojun; Zuo, Zhigang; Cao, Fengjun

2017-09-09

The present study was to evaluate the prognostic value of protein expression of Pofut1 and Notch1 signaling in breast cancer. Formalin-fixed paraffin-embedded 314 breast specimens including 174 infiltrating ductal carcinoma(IDC), 50 ductal carcinoma in situ(DCIS) and 90 adjacent normal tissue(ANT) were immunohistochemically examined to evaluate the protein expression of Pofut1, activated Notch1(N1IC) and Slug on specimens. Survival analysis was performed by Kaplan-Meier method and Cox's proportional-hazards model. A online database was computationally used to further explore the prognostic role of Pofut1 and Notch1 mRNA expression by Kaplan-Meier Plotter. Pofut1, Slug and N1IC expression were significantly increased in IDC compared to ANT(all p < 0.05). High expression of Pofut1, Slug and N1IC were associated with tumor aggressiveness including lymph node metastasis (LNM: p = 0.005 for Pofut1, p < 0.001 for N1IC, p = 0.017 for Slug), advanced stage(p = 0.039 for Pofut1, p = 0.025 for N1IC) and higher histological grade(p = 0.001 for N1IC). Additionally, high expression of Pofut1 was found to be significantly associated with high expressions of N1IC and Slug in IDC(r = 0.244, p = 0.001; r = 0.374, p < 0.001, respectively), similar correlation was also observed between high N1IC and Slug expression(r = 0.496, p < 0.001). Moreover, Kaplan-Meier and Cox's regression analysis indicated the significant prognostic value of elevated Pofut1, N1IC, Slug expressions, positive LNM and advanced tumor stage for the prediction of a shorter disease-free survival (DFS) and overall survival(OS). The web-based analysis also suggested a significant association of high Pofut1 and Notch1 mRNA expression with worse survival outcome. Our findings suggested that overexpression of Pofut1 and activated Notch1 signaling may be associated with a poor prognosis in breast cancer. Copyright © 2017 Elsevier Inc. All rights reserved.

Advanced colorectal adenoma related gene expression signature may predict prognostic for colorectal cancer patients with adenoma-carcinoma sequence.

PubMed

Li, Bing; Shi, Xiao-Yu; Liao, Dai-Xiang; Cao, Bang-Rong; Luo, Cheng-Hua; Cheng, Shu-Jun

2015-01-01

There are still no absolute parameters predicting progression of adenoma into cancer. The present study aimed to characterize functional differences on the multistep carcinogenetic process from the adenoma-carcinoma sequence. All samples were collected and mRNA expression profiling was performed by using Agilent Microarray high-throughput gene-chip technology. Then, the characteristics of mRNA expression profiles of adenoma-carcinoma sequence were described with bioinformatics software, and we analyzed the relationship between gene expression profiles of adenoma-adenocarcinoma sequence and clinical prognosis of colorectal cancer. The mRNA expressions of adenoma-carcinoma sequence were significantly different between high-grade intraepithelial neoplasia group and adenocarcinoma group. The biological process of gene ontology function enrichment analysis on differentially expressed genes between high-grade intraepithelial neoplasia group and adenocarcinoma group showed that genes enriched in the extracellular structure organization, skeletal system development, biological adhesion and itself regulated growth regulation, with the P value after FDR correction of less than 0.05. In addition, IPR-related protein mainly focused on the insulin-like growth factor binding proteins. The variable trends of gene expression profiles for adenoma-carcinoma sequence were mainly concentrated in high-grade intraepithelial neoplasia and adenocarcinoma. The differentially expressed genes are significantly correlated between high-grade intraepithelial neoplasia group and adenocarcinoma group. Bioinformatics analysis is an effective way to study the gene expression profiles in the adenoma-carcinoma sequence, and may provide an effective tool to involve colorectal cancer research strategy into colorectal adenoma or advanced adenoma.

CD146 Expression Influences Periapical Cyst Mesenchymal Stem Cell Properties.

PubMed

Paduano, Francesco; Marrelli, Massimo; Palmieri, Francesca; Tatullo, Marco

2016-10-01

Recent studies have identified a new human dental derived progenitor cell population with multi-lineage differentiation potential referred to as human periapical cyst mesenchymal stem cells (hPCy-MSCs). In the present study, we compared two subpopulations of hPCy-MSCs characterised by the low or high expression of CD146 to establish whether this expression can regulate their stem cell properties. Using flow cytometry, we evaluated the stem cell marker profile of hPCy-MSCs during passaging. Furthermore, CD146 Low and CD146 High cells were sorted by magnetic beads and subsequently both cell populations were evaluated for differences in their proliferation, self-renewal, stem cell surface markers, stemness genes expression and osteogenic differentiation potential.We found that hPCy-MSCs possessed a stable expression of several mesenchymal stem cell surface markers, whereas CD146 expression declined during passaging.In addition, sorted CD146 Low cells proliferated significantly faster, displayed higher colony-forming unit-fibroblast capacity and showed higher expression of Klf4 when compared to the CD146 High subset. Significantly, the osteogenic potential of hPCy-MSCs was greater in the CD146 Low than in CD146 High population. These results demonstrate that CD146 is spontaneously downregulated with passaging at both mRNA and protein levels and that the high expression of CD146 reduces the proliferative, self-renewal and osteogenic differentiation potential of hPCy-MSCs. In conclusion, our study demonstrates that changes in the expression of CD146 can influence the stem cell properties of hPCy-MSCs.

Living high training low induces physiological cardiac hypertrophy accompanied by down-regulation and redistribution of the renin-angiotensin system

PubMed Central

Shi, Wei; Meszaros, J Gary; Zeng, Shao-ju; Sun, Ying-yu; Zuo, Ming-xue

2013-01-01

Aim: Living high training low” (LHTL) is an exercise-training protocol that refers living in hypoxia stress and training at normal level of O2. In this study, we investigated whether LHTL caused physiological heart hypertrophy accompanied by changes of biomarkers in renin-angiotensin system in rats. Methods: Adult male SD rats were randomly assigned into 4 groups, and trained on living low-sedentary (LLS, control), living low-training low (LLTL), living high-sedentary (LHS) and living high-training low (LHTL) protocols, respectively, for 4 weeks. Hematological parameters, hemodynamic measurement, heart hypertrophy and plasma angiotensin II (Ang II) level of the rats were measured. The gene and protein expression of angiotensin-converting enzyme (ACE), angiotensinogen (AGT) and angiotensin II receptor I (AT1) in heart tissue was assessed using RT-PCR and immunohistochemistry, respectively. Results: LLTL, LHS and LHTL significantly improved cardiac function, increased hemoglobin concentration and RBC. At the molecular level, LLTL, LHS and LHTL significantly decreased the expression of ACE, AGT and AT1 genes, but increased the expression of ACE and AT1 proteins in heart tissue. Moreover, ACE and AT1 protein expression was significantly increased in the endocardium, but unchanged in the epicardium. Conclusion: LHTL training protocol suppresses ACE, AGT and AT1 gene expression in heart tissue, but increases ACE and AT1 protein expression specifically in the endocardium, suggesting that the physiological heart hypertrophy induced by LHTL is regulated by region-specific expression of renin-angiotensin system components. PMID:23377552

Effect of compound Maqin decoction on TGF-β1/Smad proteins and IL-10 and IL-17 content in lung tissue of asthmatic rats.

PubMed

Xie, Y H; Li, X P; Xu, Z X; Qian, P; Li, X L; Wang, Y Q

2016-09-02

In this research, compound Maqin decoction (CMD) has been shown to positively affect in airway inflammation of asthma models. We evaluated the effects of CMD on the expression of transforming growth factor (TGF)-β1/Smad proteins, interleukin (IL)-17, and IL-10 in lung tissue of asthmatic rats. Asthma was induced in a rat model using ovalbumin. After a 4-week treatment with CMD, rats were killed to evaluate the expression of TGF-β1 and Smad proteins in lung tissue. IL-10 and IL-17 levels in lung tissue homogenates were determined by ELISA. The expression of TGF-β1 and Smad3 protein increased, whereas expression of Smad7 protein decreased upon high-dose or low-dose treatment with CMD or by intervention with dexamethasone, compared to the control. There was a significant difference between treatment with a high dose CMD and the control treatment, but no significant difference was found between high-dose CMD treatment and dexamethasone intervention. The expression of TGF-β1 and Smad7 protein increased, whereas the expression of Smad3 protein decreased in the model group compared to other groups. In the CMD high-dose group, low-dose group, and dexamethasone intervention group, the IL-17 concentrations in lung tissue homogenates were decreased, while IL-10 levels were increased. Again, there was a significant difference between CMD high-dose and control treatment, but not between CMD high-dose treatment and dexamethasone intervention. Thus, positive effects of CMD against asthmatic airway remodeling may be due to its regulatory effect on TGF-β1, Smad3, and Smad7 protein levels and on cytokines such as IL-10 and IL-17.

Expression and clinical significance of connective tissue growth factor in advanced head and neck squamous cell cancer.

PubMed

Kikuchi, Ryoko; Kikuchi, Yoshihiro; Tsuda, Hitoshi; Maekawa, Hitoshi; Kozaki, Ken-Ichi; Imoto, Issei; Tamai, Seiichi; Shiotani, Akihiro; Iwaya, Keiichi; Sakamoto, Masaru; Sekiya, Takao; Matsubara, Osamu

2014-07-01

Connective tissue growth factor (CTGF) has been reported to play critical roles in the tumorigenesis of several human malignancies. This study was performed to evaluate CTGF protein expression in head and neck squamous cell carcinoma (HNSCC). Surgical specimens from 76 primary HNSCC were obtained with written informed consents and the expression level of CTGF was immunohistochemically evaluated. The cytoplasmic immunoreactivity of CTGF in cancer cells was semiquantitatively classified into low and high expression. Among all 76 cases with or without neoadjuvant therapy, low CTGF showed significantly longer (P = 0.0282) overall survival (OS), but not disease-free survival (DFS) than high CTGF. Although low CTGF in patients with stage I, II and III did not result in any significant difference of the OS and DFS, stage IV HNSCC patients with low CTGF showed significantly longer OS (P = 0.032) and DFS (P = 0.0107) than those with high CTGF. These differences in stage IV cases were also confirmed using multivariate analyses. These results suggest that low CTGF in stage IV HNSCC is an independent prognostic factor, despite with or without neoadjuvant therapy.

High expression of SALL4 and fascin, and loss of E-cadherin expression in undifferentiated/dedifferentiated carcinomas of the endometrium

PubMed Central

Onder, Semen; Taskin, Orhun Cig; Sen, Fatma; Topuz, Samet; Kucucuk, Seden; Sozen, Hamdullah; Ilhan, Ridvan; Tuzlali, Sitki; Yavuz, Ekrem

2017-01-01

Abstract Undifferentiated/dedifferentiated endometrial carcinomas (UCE/DCEs) of the endometrium are rare tumors with poor prognosis. There are few clinicopathologic studies with detailed immunohistochemical analysis regarding UCE/DCEs. We evaluated the diagnostic value of a selected tumor stem-cell marker and epithelial-mesenchymal transition (EMT) markers, in addition to previously studied markers in identifying UCE/DCEs from other types of high-grade endometrial carcinomas. Eleven cases of UCE/DCEs with complete clinical follow-up that were diagnosed between 2006 and 2015 were included in the study. For immunohistochemical comparison, 11 clinically matched cases for each type of other high-grade endometrial carcinomas (high-grade endometrioid (F3-EC), serous [SC], and clear cell carcinoma [CCC]) were used as a control group. An immunohistochemical analysis including fascin, SALL4, E-cadherin, and β-catenin, in addition to epithelial and neuroendocrine markers was performed in each case. The majority of UCE/DCEs displayed diffuse expression of fascin (81.9%) and loss of E-cadherin expression (54.5%). SALL4 expression was detected in 36.3% of the UCE/DCE cases. SALL4 expression was significantly more frequent in UCE/DCEs than all other high-grade carcinomas (P < 0.001). Loss of E-cadherin and fascin expression was significantly more frequent in UCE/DCEs than high-grade endometrioid and clear cell adenocarcinomas (P = 0.012, 0.014 and P = 0.01, 0.003, respectively). We suggest that loss of E-cadherin expression together with fascin and SALL4 immunopositivity in addition to morphologic features have an impact in differential diagnosis of UCE/DCEs from other high-grade endometrial carcinomas. PMID:28272224

Jejunal gluconeogenesis associated with insulin resistance level and its evolution after Roux-en-Y gastric bypass.

PubMed

Gutierrez-Repiso, Carolina; Garcia-Serrano, Sara; Moreno-Ruiz, Francisco J; Alcain-Martinez, Guillermo; Rodriguez-Pacheco, Francisca; Garcia-Fuentes, Eduardo

2017-04-01

Intestinal gluconeogenesis (GNG) may play an important role in glucose homeostasis, but there is little information about the condition in humans. To study the relationship between intestinal GNG and insulin resistance, its association with the evolution of morbidly obese patients after bariatric surgery, and the effect of insulin and or leptin. Regional university hospital, Malaga (Spain). Jejunal mRNA expression of genes involved in GNG was analyzed in 3 groups of morbidly obese patients who underwent Roux-en-Y gastric bypass: with low insulin resistance (MO-low-IR), with high insulin resistance (MO-high-IR), and with type 2 diabetes treated with metformin (MO-metf-T2D). Also, intestinal epithelial cells (IEC) from MO-low-IR were incubated with different doses of insulin and or leptin. In MO-high-IR, glutaminase, phosphoenolpyruvate carboxykinase (PEPCK), glucose 6-phosphatase (G6 Pase), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 α), and sterol regulatory element-binding proteins 1 c (SREBP-1 c) expressions were significantly higher than in MO-low-IR. In MO-metf-T2 D, only PEPCK was significantly lower than in MO-high-IR. In IEC, an incubation with a high glucose and insulin dose produced an increase of PEPCK and SREBP-1 c, and a decrease of glutaminase, fructose 1,6-bisphosphatase (FBPase), and PGC-1 α expression. At high doses of leptin, G6 Pase and FBPase were significantly increased. The improvement of insulin resistance 3 months after bariatric surgery was positively associated with high G6 Pase and FBPase expression. mRNA expression of genes involved in GNG is increased in the jejunum of MO-high-IR, and regulated by insulin and or leptin. High mRNA expression of genes involved in GNG is associated with a better evolution of insulin resistance after bariatric surgery. Copyright © 2016 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.

Hematopoietic lineage cell-specific protein 1 immunoreactivity indicates an increased risk of poor overall survival in patients with ovarian carcinoma.

PubMed

Liu, Wenting; Kajiyama, Hiroaki; Shibata, Kiyosumi; Koya, Yoshihiro; Senga, Takeshi; Kikkawa, Fumitaka

2018-06-01

Hematopoietic lineage cell-specific protein 1 (HS1) is a 75-kDa intracellular protein that is expressed primarily in hematopoietic cells. Several previous studies have demonstrated the association between HS1 expression and a poor prognosis in hematopoietic malignancies; however, in solid tumors, no studies not been reported. The present study examined the distribution and expression of HS1 in human epithelial ovarian carcinoma (EOC) to determine its clinical significance. Paraffin sections were obtained from EOC tissues and immunostained with HS1 antibody, and then the staining intensities were evaluated. Overall survival (OS) was determined using the Kaplan-Meier estimator method, and multivariate analysis was performed using the Cox proportional hazards analysis. In total, 195 patients with EOC (median age, 56 years) were enrolled into the present study. HS1 immunoreactivity was categorized based on expression levels: Low (89/195; 45.6%) and high (106/195; 54.4%). Results demonstrated no association between expression level(s) and any clinicopathological parameter including age, International Federation of Gynecology and Obstetrics (FIGO) staging, type of chemotherapy or type of surgery received. The 5-year OS rates of patients who demonstrated low (n=89) and high (n=106) HS1 expression were 90.4 and 66.7%, respectively. The OS times for patients with high HS1 expression were significantly shorter compared with those for patients exhibiting low HS1 expression (P=0.0065). Results obtained from the multivariate analysis demonstrated that the FIGO stage and the amount of HS1 expressed were significant independent prognostic markers for poorer OS (hazard ratio, 3.539; 95% confidence interval, 1.221-12.811; P=0.0187). High HS1 expression levels may serve as a useful biomarker in patients with EOC who are likely to exhibit an unfavorable clinical outcome.

Urban-rural differences in the gene expression profiles of Ghanaian children.

PubMed

Amoah, A S; Obeng, B B; May, L; Kruize, Y C; Larbi, I A; Kabesch, M; Wilson, M D; Hartgers, F C; Boakye, D A; Yazdanbakhsh, M

2014-01-01

Recent studies indicate that urbanization is having a pronounced effect on disease patterns in developing countries. To understand the immunological basis of this, we examined mRNA expression in whole blood of genes involved in immune activation and regulation in 151 children aged 5-13 years attending rural, urban low socioeconomic status (SES) and urban high-SES schools in Ghana. Samples were also collected to detect helminth and malaria infections. Marked differences in gene expression were observed between the rural and urban areas as well as within the urban area. The expression of both interleukin (IL)-10 and programmed cell death protein 1 increased significantly across the schools from urban high SES to urban low SES to rural (P-trend <0.001). Although IL-10 gene expression was significantly elevated in the rural compared with the urban schools (P<0.001), this was not associated with parasitic infection. Significant differences in the expression of toll-like receptors (TLRs) and their signaling genes were seen between the two urban schools. Genetic differences could not fully account for the gene expression profiles in the different groups as shown by analysis of IL-10, TLR-2 and TLR-4 gene polymorphisms. Immune gene expression patterns are strongly influenced by environmental determinants and may underlie the effects of urbanization seen on health outcomes.

The specific social costs of expressive negative symptoms in schizophrenia: reduced smiling predicts interactional outcome.

PubMed

Riehle, M; Mehl, S; Lincoln, T M

2018-04-17

We tested whether people with schizophrenia and prominent expressive negative symptoms (ENS) show reduced facial expressions in face-to-face social interactions and whether this expressive reduction explains negative social evaluations of these persons. We compared participants with schizophrenia with high ENS (n = 18) with participants with schizophrenia with low ENS (n = 30) and with healthy controls (n = 39). Participants engaged in an affiliative role-play that was coded for the frequency of positive and negative facial expression and rated for social performance skills and willingness for future interactions with the respective role-play partner. Participants with schizophrenia with high ENS showed significantly fewer positive facial expressions than those with low ENS and controls and were also rated significantly lower on social performance skills and willingness for future interactions. Participants with schizophrenia with low ENS did not differ from controls on these measures. The group difference in willingness for future interactions was significantly and independently mediated by the reduced positive facial expressions and social performance skills. Reduced facial expressiveness in schizophrenia is specifically related to ENS and has negative social consequences. These findings highlight the need to develop aetiological models and targeted interventions for ENS and its social consequences. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Elevated expression of LSD1 (Lysine-specific demethylase 1) during tumour progression from pre-invasive to invasive ductal carcinoma of the breast

PubMed Central

2012-01-01

Background Lysine-specific demethylase1 (LSD1) is a nuclear protein which belongs to the aminooxidase-enzymes playing an important role in controlling gene expression. It has also been found highly expressed in several human malignancies including breast carcinoma. Our aim was to detect LSD1 expression also in pre-invasive neoplasias of the breast. In the current study we therefore analysed LSD1 protein expression in ductal carcinoma in situ (DCIS) in comparison to invasive ductal breast cancer (IDC). Methods Using immunohistochemistry we systematically analysed LSD1 expression in low grade DCIS (n = 27), intermediate grade DCIS (n = 30), high grade DCIS (n = 31) and in invasive ductal breast cancer (n = 32). SPSS version 18.0 was used for statistical analysis. Results LSD1 was differentially expressed in DCIS and invasive ductal breast cancer. Interestingly, LSD1 was significantly overexpressed in high grade DCIS versus low grade DCIS. Differences in LSD1 expression levels were also statistically significant between low/intermediate DCIS and invasive ductal breast carcinoma. Conclusions LSD1 is also expressed in pre-invasive neoplasias of the breast. Additionally, there is a gradual increase of LSD1 expression within tumour progression from pre-invasive DCIS to invasive ductal breast carcinoma. Therefore upregulation of LSD1 may be an early tumour promoting event. PMID:22920283

Elevated expression of LSD1 (Lysine-specific demethylase 1) during tumour progression from pre-invasive to invasive ductal carcinoma of the breast.

PubMed

Serce, Nuran; Gnatzy, Annette; Steiner, Susanne; Lorenzen, Henning; Kirfel, Jutta; Buettner, Reinhard

2012-08-24

Lysine-specific demethylase1 (LSD1) is a nuclear protein which belongs to the aminooxidase-enzymes playing an important role in controlling gene expression. It has also been found highly expressed in several human malignancies including breast carcinoma. Our aim was to detect LSD1 expression also in pre-invasive neoplasias of the breast. In the current study we therefore analysed LSD1 protein expression in ductal carcinoma in situ (DCIS) in comparison to invasive ductal breast cancer (IDC). Using immunohistochemistry we systematically analysed LSD1 expression in low grade DCIS (n = 27), intermediate grade DCIS (n = 30), high grade DCIS (n = 31) and in invasive ductal breast cancer (n = 32). SPSS version 18.0 was used for statistical analysis. LSD1 was differentially expressed in DCIS and invasive ductal breast cancer. Interestingly, LSD1 was significantly overexpressed in high grade DCIS versus low grade DCIS. Differences in LSD1 expression levels were also statistically significant between low/intermediate DCIS and invasive ductal breast carcinoma. LSD1 is also expressed in pre-invasive neoplasias of the breast. Additionally, there is a gradual increase of LSD1 expression within tumour progression from pre-invasive DCIS to invasive ductal breast carcinoma. Therefore upregulation of LSD1 may be an early tumour promoting event.

The effects of either resveratrol or exercise on macrophage infiltration and switching from M1 to M2 in high fat diet mice.

PubMed

Jeong, Jun Hyun; Lee, Young Ran; Park, Hee Geun; Lee, Wang Lok

2015-06-01

The aim of this study was to compare the effectiveness of either resveratrol supplementation or exercise training on macrophage infiltration and switching from M1 to M2 kupffer cells in high fat diet mice. C57BL/6 mice were separated into 5 groups: normal diet (ND; n = 6), high-fat diet (HD; n = 6), high-fat diet with resveratrol (HR; n = 6), high-fat diet with exercise (HE; n = 6) or high-fat diet with resveratrol and exercise (HRE; n = 6). Resveratrol supplementation mice were orally gavaged with resveratrol (25mg/kg of body weight) dissolved in 50% propylene glycol. Exercise mice ran on a treadmill at 12-20 m/min for 30-60 min/day, 5 times/week for 12 weeks. After 12 weeks of intervention, the liver was analyzed. F4/80 expression was evaluated by western blot while CD11c and CD163 mRNA expressions were evaluated by RT-PCR. The weights of the body and liver were significantly increased in the HD and HR group compared to the ND group (p < 0.01). However, the weights were most effectively reduced in the HE and HRE groups compared to the HD group (p < 0.05). The macrophage marker, F4/80 expression was significantly lower in the HE and HRE groups compared to the HD group (p < 0.05). mRNA expression of the M1 macrophage marker, CD11c, in the HD group was significantly increased compared to the ND group (p < 0.01). mRNA expression of the M2 macrophage specific marker, CD163, in the HE and HRE groups were significantly increased compared to the HD group (p < 0.05). The mRNA expressions of TLR4, ICAM-1 and VCAM-1, which induce pro-inflammatory cytokine production, were strongly decreased in the HR, HE, and HRE groups compared to the HD group. These results suggest that moderate exercise training inhibits macrophage infiltration and up regulation of CD163 expression. However, resveratrol supplementation is not enough to ameliorate obesity-induced macrophage infiltration and switching.

Cloning and characterization of an adenoviral vector for highly efficient and doxycycline – suppressible expression of bioactive human single – chain interleukin 12 in colon cancer

PubMed Central

Wulff, Holger; Krieger, Thorsten; Krüger, Karen; Stahmer, Ingrid; Thaiss, Friedrich; Schäfer, Hansjörg; Block, Andreas

2007-01-01

Background Interleukin-12 (IL-12) is well characterized to induce cellular antitumoral immunity by activation of NK-cells and T-lymphocytes. However, systemic administration of recombinant human IL-12 resulted in severe toxicity without perceptible therapeutic benefit. Even though intratumoral expression of IL-12 leads to tumor regression and long-term survival in a variety of animal models, clinical trials have not yet shown a significant therapeutic benefit. One major obstacle in the treatment with IL-12 is to overcome the relatively low expression of the therapeutic gene without compromising the safety of such an approach. Our objective was to generate an adenoviral vector system enabling the regulated expression of very high levels of bioactive, human IL-12. Results High gene expression was obtained utilizing the VP16 herpes simplex transactivator. Strong regulation of gene expression was realized by fusion of the VP16 to a tetracycline repressor with binding of the fusion protein to a flanking tetracycline operator and further enhanced by auto-regulated expression of its fusion gene within a bicistronic promoter construct. Infection of human colon cancer cells (HT29) at a multiplicity of infection (m.o.i.) of 10 resulted in the production of up to 8000 ng/106 cells in 48 h, thus exceeding any published vector system so far. Doxycycline concentrations as low as 30 ng/ml resulted in up to 5000-fold suppression, enabling significant reduction of gene expression in a possible clinical setting. Bioactivity of the human single-chain IL-12 was similar to purified human heterodimeric IL-12. Frozen sections of human colon cancer showed high expression of the coxsackie adenovirus receptor with significant production of human single chain IL-12 in colon cancer biopsies after infection with 3*107 p.f.u. Ad.3r-scIL12. Doxycycline mediated suppression of gene expression was up to 9000-fold in the infected colon cancer tissue. Conclusion VP16 transactivator-mediated and doxycycline-regulated expression of the human interleukin-12 gene enables highly efficient and tightly controlled cytokine expression in human cancer. These data illustrate the potential of the described adenoviral vector system for the safe and superior expression of therapeutic genes in the treatment of colorectal cancer and other malignancies. PMID:17594499

Diffusion Profiling via a Histogram Approach Distinguishes Low-grade from High-grade Meningiomas, Can Reflect the Respective Proliferative Potential and Progesterone Receptor Status.

PubMed

Gihr, Georg Alexander; Horvath-Rizea, Diana; Garnov, Nikita; Kohlhof-Meinecke, Patricia; Ganslandt, Oliver; Henkes, Hans; Meyer, Hans Jonas; Hoffmann, Karl-Titus; Surov, Alexey; Schob, Stefan

2018-02-01

Presurgical grading, estimation of growth kinetics, and other prognostic factors are becoming increasingly important for selecting the best therapeutic approach for meningioma patients. Diffusion-weighted imaging (DWI) provides microstructural information and reflects tumor biology. A novel DWI approach, histogram profiling of apparent diffusion coefficient (ADC) volumes, provides more distinct information than conventional DWI. Therefore, our study investigated whether ADC histogram profiling distinguishes low-grade from high-grade lesions and reflects Ki-67 expression and progesterone receptor status. Pretreatment ADC volumes of 37 meningioma patients (28 low-grade, 9 high-grade) were used for histogram profiling. WHO grade, Ki-67 expression, and progesterone receptor status were evaluated. Comparative and correlative statistics investigating the association between histogram profiling and neuropathology were performed. The entire ADC profile (p10, p25, p75, p90, mean, median) was significantly lower in high-grade versus low-grade meningiomas. The lower percentiles, mean, and modus showed significant correlations with Ki-67 expression. Skewness and entropy of the ADC volumes were significantly associated with progesterone receptor status and Ki-67 expression. ROC analysis revealed entropy to be the most accurate parameter distinguishing low-grade from high-grade meningiomas. ADC histogram profiling provides a distinct set of parameters, which help differentiate low-grade versus high-grade meningiomas. Also, histogram metrics correlate significantly with histological surrogates of the respective proliferative potential. More specifically, entropy revealed to be the most promising imaging biomarker for presurgical grading. Both, entropy and skewness were significantly associated with progesterone receptor status and Ki-67 expression and therefore should be investigated further as predictors for prognostically relevant tumor biological features. Since absolute ADC values vary between MRI scanners of different vendors and field strengths, their use is more limited in the presurgical setting.

High blood sugar levels significantly impact the prognosis of colorectal cancer patients through down-regulation of microRNA-16 by targeting Myb and VEGFR2

PubMed Central

Huang, Ching-Wen; Lu, Chien-Yu; Miao, Zhi-Feng; Chang, Se-Fen; Juo, Suh-Hang Hank; Wang, Jaw-Yuan

2016-01-01

The high prevalence of type 2 diabetes mellitus in colorectal cancer patients is a crucial public health issue worldwide. The deregulation of microRNAs has been shown to be associated with the progression of CRC; however, the effects of high blood sugar levels on miR deregulation and, in turn, CRC remain unexplored. In this study, 520 CRC patients were classified into two groups according to their blood sugar levels (≧110 or <110 mg/dL). Clinicopathologic features, clinical outcomes, and serum miR-16 levels of the two groups were then analyzed, while cell cycles, cell proliferation, migration, and cellular miR-16 expression were investigated via D-(+)-glucose administration. Additionally, the target genes of miR-16 were identified. Through multivariate analysis, both the disease-free survival and overall survival of the CRC patients were found to be associated with the UICC stage, perineural invasion, and blood glucose levels (P < 0.05). Serum miR-16 levels were significantly lower in the high blood glucose patients than in the normal blood glucose patients (P = 0.0329). With D-(+)-glucose administration, the proliferation and migration of CRC cells in vitro increased remarkably (P < 0.05), while their accumulation in the G1 phase decreased significantly. Cellular miR-16 expression was suppressed by D-(+)-glucose administration. The expression levels of two target genes, Myb and VEGFR2, were affected significantly by miR-16, while glucose administration inhibited miR-16 expression and enhanced tumor cell proliferation and migration. Hyperglycemia can impact the clinical outcomes of CRC patients, likely by inhibiting miR-16 expression and the expression of its downstream genes Myb and VEGFR2. PMID:26934556

High maysin corn silk extract reduces body weight and fat deposition in C57BL/6J mice fed high-fat diets.

PubMed

Lee, Eun Young; Kim, Sun Lim; Kang, Hyeon Jung; Kim, Myung Hwan; Ha, Ae Wha; Kim, Woo Kyoung

2016-12-01

The study was performed to investigate the effects and mechanisms of action of high maysin corn silk extract on body weight and fat deposition in experimental animals. A total of 30 male C57BL/6J mice, 4-weeks-old, were purchased and divided into three groups by weight using a randomized block design. The normal-fat (NF) group received 7% fat (diet weight basis), the high-fat (HF) group received 25% fat and 0.5% cholesterol, and the high-fat corn silk (HFCS) group received high-fat diet and high maysin corn silk extract at 100 mg/kg body weight through daily oral administration. Body weight and body fat were measured, and mRNA expression levels of proteins involved in adipocyte differentiation, fat accumulation, fat synthesis, lipolysis, and fat oxidation in adipose tissue and the liver were measured. After experimental diet intake for 8 weeks, body weight was significantly lower in the HFCS group compared to the HF group ( P < 0.05), and kidney fat and epididymal fat pad weights were significantly lower in the HFCS group compared to the HF group ( P < 0.05). In the HFCS group, CCAAT/enhancer binding protein-β, peroxisome proliferator-activated receptor-γ1 (PPAR-γ1), and PPAR-γ2 mRNA expression levels were significantly reduced ( P < 0.05) in the epididymal fat pad, whereas cluster of differentiation 36, lipoprotein lipase, acetyl-CoA carboxylase-1, sterol regulatory element binding protein-1c, pyruvate dehydrogenase kinase, isozyme-4, glucose-6-phosphate dehydrogenase, and stearoyl-CoA desaturase-1 mRNA expression levels were significantly decreased in liver and adipose tissues ( P < 0.05). In the HFCS group, mRNA expression levels of AMP-activated protein kinase, hormone-sensitive lipase, and carnitine palmitoyltransferase-1 were elevated ( P < 0.05). It can be concluded that high maysin corn silk extract inhibits expression of genes involved in adipocyte differentiation, fat accumulation, and fat synthesis as well as promotes expression of genes involved in lipolysis and fat oxidation, further inhibiting body fat accumulation and body weight elevation in experimental animals.

Emotional facial and vocal expressions during story retelling by children and adolescents with high-functioning autism.

PubMed

Grossman, Ruth B; Edelson, Lisa R; Tager-Flusberg, Helen

2013-06-01

People with high-functioning autism (HFA) have qualitative differences in facial expression and prosody production, which are rarely systematically quantified. The authors' goals were to qualitatively and quantitatively analyze prosody and facial expression productions in children and adolescents with HFA. Participants were 22 male children and adolescents with HFA and 18 typically developing (TD) controls (17 males, 1 female). The authors used a story retelling task to elicit emotionally laden narratives, which were analyzed through the use of acoustic measures and perceptual codes. Naïve listeners coded all productions for emotion type, degree of expressiveness, and awkwardness. The group with HFA was not significantly different in accuracy or expressiveness of facial productions, but was significantly more awkward than the TD group. Participants with HFA were significantly more expressive in their vocal productions, with a trend for greater awkwardness. Severity of social communication impairment, as captured by the Autism Diagnostic Observation Schedule (ADOS; Lord, Rutter, DiLavore, & Risi, 1999), was correlated with greater vocal and facial awkwardness. Facial and vocal expressions of participants with HFA were as recognizable as those of their TD peers but were qualitatively different, particularly when listeners coded samples with intact dynamic properties. These preliminary data show qualitative differences in nonverbal communication that may have significant negative impact on the social communication success of children and adolescents with HFA.

Clinical Significance of SASH1 Expression in Glioma.

PubMed

Yang, Liu; Zhang, Haitao; Yao, Qi; Yan, Yingying; Wu, Ronghua; Liu, Mei

2015-01-01

SAM and SH3 domain containing 1 (SASH1) is a recently discovered tumor suppressor gene. The role of SASH1 in glioma has not yet been described. We investigated SASH1 expression in glioma cases to determine its clinical significance on glioma pathogenesis and prognosis. We produced tissue microarrays using 121 patient-derived glioma samples and 30 patient-derived nontumor cerebral samples. Immunohistochemistry and Western blotting were used to evaluate SASH1 expression. We used Fisher's exact tests to determine relationships between SASH1 expression and clinicopathological characteristics; Cox regression analysis to evaluate the independency of different SASH1 expression; Kaplan-Meier analysis to determine any correlation of SASH1 expression with survival rate. SASH1 expression was closely correlated with the WHO glioma grade. Of the 121 cases, 66.9% with low SASH1 expression were mostly grade III-IV cases, whereas 33.1% with high SASH1 expression were mostly grades I-II. Kaplan-Meier analysis revealed a significant positive correlation between SASH1 expression and postoperative survival. SASH1 was widely expressed in normal and low-grade glioma tissues. SASH1 expression strongly correlated with glioma grades, showing higher expression at a lower grade, which decreased significantly as grade increased. Furthermore, SASH1 expression was positively correlated with better postoperative survival in patients with glioma.

miR-150 influences B-cell receptor signaling in chronic lymphocytic leukemia by regulating expression of GAB1 and FOXP1

PubMed Central

Mraz, Marek; Chen, Liguang; Rassenti, Laura Z.; Ghia, Emanuela M.; Li, Hongying; Jepsen, Kristen; Smith, Erin N.; Messer, Karen; Frazer, Kelly A.; Kipps, Thomas J.

2014-01-01

We examined the microRNAs (miRNAs) expressed in chronic lymphocytic leukemia (CLL) and identified miR-150 as the most abundant, but with leukemia cell expression levels that varied among patients. CLL cells that expressed ζ-chain–associated protein of 70 kDa (ZAP-70) or that used unmutated immunoglobulin heavy chain variable (IGHV) genes, each had a median expression level of miR-150 that was significantly lower than that of ZAP-70–negative CLL cells or those that used mutated IGHV genes. In samples stratified for expression of miR-150, CLL cells with low-level miR-150 expressed relatively higher levels of forkhead box P1 (FOXP1) and GRB2-associated binding protein 1 (GAB1), genes with 3′ untranslated regions having evolutionary-conserved binding sites for miR-150. High-level expression of miR-150 could repress expression of these genes, which encode proteins that enhance B-cell receptor signaling, a putative CLL-growth/survival signal. Also, high-level expression of miR-150 was a significant independent predictor of longer treatment-free survival or overall survival, whereas an inverse association was observed for high-level expression of GAB1 or FOXP1 for overall survival. This study demonstrates that expression of miR-150 can influence the relative expression of GAB1 and FOXP1 and the signaling potential of the B-cell receptor, thereby possibly accounting for the noted association of expression of miR-150 and disease outcome. PMID:24787006

miR-150 influences B-cell receptor signaling in chronic lymphocytic leukemia by regulating expression of GAB1 and FOXP1.

PubMed

Mraz, Marek; Chen, Liguang; Rassenti, Laura Z; Ghia, Emanuela M; Li, Hongying; Jepsen, Kristen; Smith, Erin N; Messer, Karen; Frazer, Kelly A; Kipps, Thomas J

2014-07-03

We examined the microRNAs (miRNAs) expressed in chronic lymphocytic leukemia (CLL) and identified miR-150 as the most abundant, but with leukemia cell expression levels that varied among patients. CLL cells that expressed ζ-chain-associated protein of 70 kDa (ZAP-70) or that used unmutated immunoglobulin heavy chain variable (IGHV) genes, each had a median expression level of miR-150 that was significantly lower than that of ZAP-70-negative CLL cells or those that used mutated IGHV genes. In samples stratified for expression of miR-150, CLL cells with low-level miR-150 expressed relatively higher levels of forkhead box P1 (FOXP1) and GRB2-associated binding protein 1 (GAB1), genes with 3' untranslated regions having evolutionary-conserved binding sites for miR-150. High-level expression of miR-150 could repress expression of these genes, which encode proteins that enhance B-cell receptor signaling, a putative CLL-growth/survival signal. Also, high-level expression of miR-150 was a significant independent predictor of longer treatment-free survival or overall survival, whereas an inverse association was observed for high-level expression of GAB1 or FOXP1 for overall survival. This study demonstrates that expression of miR-150 can influence the relative expression of GAB1 and FOXP1 and the signaling potential of the B-cell receptor, thereby possibly accounting for the noted association of expression of miR-150 and disease outcome. © 2014 by The American Society of Hematology.

Expression and prognostic relevance of PRAME in primary osteosarcoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tan, Pingxian; Zou, Changye; Yong, Bicheng

2012-03-23

Graphical abstract: High PRAME expression was associated with osteosarcoma patients' poor prognosis and lung metastasis. Highlights: Black-Right-Pointing-Pointer We analyzed and verified the role of PRAME in primary osteosarcoma. Black-Right-Pointing-Pointer High PRAME expression in osteosarcoma correlated to poor prognosis and lung metastasis. Black-Right-Pointing-Pointer PRAME siRNA knockdown significantly suppressed the proliferation, colony formation, and G1 cell cycle arrest in U-2OS cells. -- Abstract: The preferentially expressed antigen of melanoma (PRAME), a cancer-testis antigen with unknown function, is expressed in many human malignancies and is considered an attractive potential target for tumor immunotherapy. However, studies of its expression and function in osteosarcoma havemore » rarely been reported. In this study, we found that PRAME is expressed in five osteosarcoma cell lines and in more than 70% of osteosarcoma patient specimens. In addition, an immunohistochemical analysis showed that high PRAME expression was associated with poor prognosis and lung metastasis. Furthermore, PRAME siRNA knockdown significantly suppressed the proliferation, colony formation, and G1 cell cycle arrest in U-2OS cells. Our results suggest that PRAME plays an important role in cell proliferation and disease progression in osteosarcoma. However, the detail mechanisms of PRAME function in osteosarcoma require further investigation.« less

Overexpression of Pokemon in non-small cell lung cancer and foreshowing tumor biological behavior as well as clinical results.

PubMed

Zhao, Zhi-Hong; Wang, Sheng-Fa; Yu, Liang; Wang, Ju; Chang, Hao; Yan, Wei-Li; Zhang, Jian; Fu, Kai

2008-10-01

Transcription factor Pokemon, a central regulation gene of the important tumor suppressor alternative reading frame (ARF), exerted its activity by acting upstream of many tumor-suppressing genes and proto-oncogenes. Its expression in non-small cell lung cancer (NSCLC) and its clinical significance remains unclear. The aim of this study was to investigate the expression of Pokemon in non-small cell lung cancer and to explore its correlation with the clinical pathological characteristics and its influence on patients' prognosis. Observe the expression of Pokemon in NSCLC and investigate its mechanism and clinical significance. Determine the expression of Pokemon in human NSCLC cell lines as well as 55 cases of NSCLC tumor tissues, tumor adjacent tissues and surrounding tissues by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot, and analyze the relationship between Pokemon expression in NSCLC tumor tissues and clinicopathological features. Determine 62 NSCLC tumor tissues (5 years ago) and p14(ARF) expression with immunohistochemical technique, discuss the correlation between them and assess the effect of Pokemon on prognosis of patients with lung cancer. Pokemon mRNA and protein took on high expression in lung cancer cell lines, and the expression difference between cancer tissues, tumor adjacent tissues and surrounding tissues had statistical significance (P<0.05). Pokemon expression and p14(ARF) expression were negatively correlated (r=-0.287). The expression of Pokemon was determined not to be associated with the patient's sex, age, smoking condition, tumor differentiation degree, histology and lymph node metastasis condition. However, its relationship with TNM staging was established (P<0.05). Furthermore, it was shown that the survival rate of patients with negative Pokemon expression was significantly higher than that of those with positive Pokemon expression (P=0.004), therefore, the expression of Pokemon is believed to be an independent factor affecting prognosis (P=0.034). There was high expression of Pokemon in NSCLC, Pokemon exerted carcinogenesis by inhibiting ARF and had some clinical significance for prognostic evaluation of the patients with NSCLC.

[Correlation between EGLN1 gene, protein express in lung tissue of rats and pulmonary artery pressure at different altitude].

PubMed

Li, S H; Li, S; Sun, L; Bai, Z Z; Yang, Q Y; Ga, Q; Jin, G E

2016-08-23

To investigate the correlation between pulmonary artery pressure (PAP) and the expression level of Egl nine homologue 1 (EGLN1) gene or its protein in lung tissue of rats at different altitudes. Totally 121 male Wistar rats were randomly divided into low altitude group (n=11), moderate altitude group and high altitude group, the rats in moderate altitude and high altitude group were further divided into 1(st) day, 3(rd) days, 7(th) days, 15(th) day and 30(th) day group according to the exposure time to hypoxic environment, each group 11 rats. The low altitude group, the PAP of rats were determined by physiological signal acquisition system, and tissue samples were collected in liquid nitrogen container for storage at an altitude of 498 m area. Moderate altitude group rats were placed in altitude of 2 260 meters of natural environment, 5 high altitude groups rats were placed in the hypobaric hypoxic chamber, simulating altitude of 4 500 meters. The PAP of rats in moderate altitude group and high altitude group were also determined by physiological signal acquisition system, and tissue samples were collected when rats were exposed to hypoxia at 1(st), 3(rd), 7(th), 15(th) and 30(th) day; Western blot was used to determine expression levels of EGLN1 protein, and person correlation analysis was used to analyze whether the protein was related to the formation of pulmonary arterial hypertension (PH) under hypoxia. Real-time quantitive PCR method determined expression levels of EGLN1 mRNA in lung tissues, and the relative expression method was used to analyze PCR data, and finally assess whether the EGLN1 gene was the initial cause of the formation of PH during hypoxia. The mean PAP of rats was (20.0±3.2) mmHg (1 mmHg=0.133 kPa) in low altitude group; in moderate altitude group, mean PAP began to increase slightly when rats were exposed to hypoxia on the 15(th) day and reached at (22.7±4.1) mmHg on hypoxic 30(th) day, but compared with the low altitude group, there was no statistical difference (P> 0.05); the mean PAP of rats in high altitude group began to rise on the 7(th) day (28.7±7.7) mmHg, which was higher than that in low altitude group (P<0.05), and significantly increased to (42.3±9.1) mmHg (P<0.001) on hypoxic 30(th) day; it was significantly proportional with exposure to hypoxic time, and compared to low altitude group and moderate altitude group, there was significant difference (P<0.05). EGLN1 protein expression in the lung tissue of rats had no significant difference between the low altitude group and moderate altitude group, and its expression level in the high altitude group were significantly decreased, furthermore, the expression level decreased with the increase of hypoxia exposure time (P<0.05); PAP and EGLN1 protein expression levels showed a negative correlation (r=-0.662). The transcription level of mRNA EGLN1 in high altitude group was significantly increased under hypobaric hypoxia, it was 72 times more than that of the moderate altitude group, and nearly 300 times than that of the low altitude group, respectively (both P<0.001=. EGLN1 gene expression in lung tissue of rat is affected by hypoxia, the expression level increases with the increase of the altitude; but the protein expression level, in contrast with gene expression level, is decreased with the increase of altitude and is significantly negatively correlated with mean PAP.

Lgr5High/DCLK1High phenotype is more common in early stage and intestinal subtypes of gastric carcinomas.

PubMed

Kalantari, Elham; Asadi Lari, Mohammad Hossein; Roudi, Raheleh; Korourian, Alireza; Madjd, Zahra

2017-12-06

Gastric carcinoma is the third most common malignancy and is one of the main causes of cancer deaths worldwide. Cancer stem cells (CSCs) are a subpopulation of tumour cells capable of self-renewal and differentiation, likely responsible for the initiation, recurrence, metastasis and chemo/radio-resistance. This study was conducted to evaluate the expression patterns and clinicopathologic significance of putative CSC markers, Lgr5 and DCLK1, in gastric carcinoma. The expression levels of Lgr5 and DCLK1 were examined in a well-defined series of gastric carcinoma tissues, including 75 (80%) from intestinal and 19 (20%) from diffuse subtypes, using tissue microarray (TMA). In addition, the correlation of the expression of these markers with clinicopathological factors was explored. Higher expressions of Lgr5 and DCLK1 were mainly detected in intestinal subtypes of gastric carcinomas compared to diffuse subtypes (P= 0.005 and P= 0.050, respectively). We also found a higher expression of Lgr5 and DCLK1 more frequently in well-differentiated gastric carcinoma cases (P< 0.001 and P= 0.007). The combined analysis demonstrated that the co-expression of Lgr5 and DCLK1 (Lgr5High/DCLK1High) was more common in intestinal subtypes (P= 0.025) and well-differentiated gastric carcinoma samples (P< 0.001). Interestingly, there was a significant correlation between Lgr5High/DCLK1High phenotype and early-stage gastric carcinoma specimens (P= 0.045). Our findings indicated that the Lgr5High/DCLK1High expression pattern may be considered as a signature phenotype for intestinal subtypes of gastric carcinoma.

Vocational Preference Inventory High Point Codes Versus Expressed Choices as Predictors of College Major and Career Entry

ERIC Educational Resources Information Center

Gade, Eldon M.; Soliah, David

1975-01-01

For 151 male graduates of the University of North Dakota, expressed choices measured by preferences made as high school seniors on the ACT Student Profile Section were significantly more accurate predictors of graduating college major and of career entry occupation than were their Vocational Preference Inventory high point codes. (Author)

Beneficial effects of (pGlu-Gln)-CCK-8 on energy intake and metabolism in high fat fed mice are associated with alterations of hypothalamic gene expression.

PubMed

Montgomery, I A; Irwin, N; Flatt, P R

2013-06-01

Cholecystokinin (CCK) is a gastrointestinal hormone with potential therapeutic promise for obesity-diabetes. The present study examined the effects of twice daily administration of the N-terminally modified stable CCK-8 analogue, (pGlu-Gln)-CCK-8, on metabolic control and hypothalamic gene expression in high fat fed mice. Sub-chronic twice daily injection of (pGlu-Gln)-CCK-8 for 16 days significantly decreased body weight (p<0.05), energy intake (p<0.01), circulating blood glucose (p<0.001), and plasma insulin (p<0.001) compared to high fat controls. Furthermore, (pGlu-Gln)-CCK-8 markedly improved glucose tolerance (p<0.05) and insulin sensitivity (p<0.05). Assessment of hypothalamic gene expression on day 16 revealed significantly elevated NPY (p<0.05) and reduced POMC (p<0.05) and MC4R (p<0.05) mRNA expression in (pGlu-Gln)-CCK-8 treated mice. High fat feeding or (pGlu-Gln)-CCK-8 treatment had no significant effects on hypothalamic gene expression of receptors for leptin, CCK₁ and GLP-1. These studies underscore the potential of (pGlu-Gln)-CCK-8 for the treatment of obesity-diabetes and suggest modulation of NPY and melanocortin related pathways may be involved in the observed beneficial effects. © Georg Thieme Verlag KG Stuttgart · New York.

How distinct is the coding of face identity and expression? Evidence for some common dimensions in face space.

PubMed

Rhodes, Gillian; Pond, Stephen; Burton, Nichola; Kloth, Nadine; Jeffery, Linda; Bell, Jason; Ewing, Louise; Calder, Andrew J; Palermo, Romina

2015-09-01

Traditional models of face perception emphasize distinct routes for processing face identity and expression. These models have been highly influential in guiding neural and behavioural research on the mechanisms of face perception. However, it is becoming clear that specialised brain areas for coding identity and expression may respond to both attributes and that identity and expression perception can interact. Here we use perceptual aftereffects to demonstrate the existence of dimensions in perceptual face space that code both identity and expression, further challenging the traditional view. Specifically, we find a significant positive association between face identity aftereffects and expression aftereffects, which dissociates from other face (gaze) and non-face (tilt) aftereffects. Importantly, individual variation in the adaptive calibration of these common dimensions significantly predicts ability to recognize both identity and expression. These results highlight the role of common dimensions in our ability to recognize identity and expression, and show why the high-level visual processing of these attributes is not entirely distinct. Copyright © 2015 Elsevier B.V. All rights reserved.

A novel dual-marker expression panel for easy and accurate risk stratification of patients with gastric cancer.

PubMed

Kanda, Mitsuro; Murotani, Kenta; Tanaka, Haruyoshi; Miwa, Takashi; Umeda, Shinichi; Tanaka, Chie; Kobayashi, Daisuke; Hayashi, Masamichi; Hattori, Norifumi; Suenaga, Masaya; Yamada, Suguru; Nakayama, Goro; Fujiwara, Michitaka; Kodera, Yasuhiro

2018-05-07

Development of specific biomarkers is necessary for individualized management of patients with gastric cancer. The aim of this study was to design a simple expression panel comprising novel molecular markers for precise risk stratification. Patients (n = 200) who underwent gastrectomy for gastric cancer were randomly assigned into learning and validation sets. Tissue mRNA expression levels of 15 candidate molecular markers were determined using quantitative PCR analysis. A dual-marker expression panel was created according to concordance index (C-index) values of overall survival for all 105 combinations of two markers in the learning set. The reproducibility and clinical significance of the dual-marker expression panel were evaluated in the validation set. The patient characteristics of the learning and validation sets were well balanced. The C-index values of combinations were significantly higher compared with those of single markers. The panel with the highest C-index (0.718) of the learning set comprised SYT8 and MAGED2, which clearly stratified patients into low-, intermediate-, and high-risk groups. The reproducibility of the panel was demonstrated in the validation set. High expression scores were significantly associated with larger tumor size, vascular invasion, lymph node metastasis, peritoneal metastasis, and advanced disease. The dual-marker expression panel provides a simple tool that clearly stratifies patients with gastric cancer into low-, intermediate-, and high risk after gastrectomy. © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Histopathological and molecular prognostic markers in medulloblastoma: c-myc, N-myc, TrkC, and anaplasia.

PubMed

Eberhart, Charles G; Kratz, John; Wang, Yunyue; Summers, Krista; Stearns, Duncan; Cohen, Kenneth; Dang, Chi V; Burger, Peter C

2004-05-01

Several molecular and histopathological prognostic markers have been proposed for the therapeutic stratification of medulloblastoma patients. Amplification of the c-myc oncogene, elevated levels of c-myc mRNA, or tumor anaplasia have been associated with worse clinical outcomes. In contrast, high TrkC mRNA expression generally presages longer survival. The goal of this study was to evaluate the prognostic value of c-myc, N-myc and TrkC expression in medulloblastomas and compare them to histopathological classification. We used in situ hybridization to measure expression of these molecular markers. c-myc mRNA was detected in 18 of 59 (31%) cases, and was significantly associated with shorter patient survival times on both univariate and multivariate analyses (p = 0.04). The presence of c-myc mRNA was also significantly associated with tumor anaplasia. While survival rates were higher for patients with low N-myc or high TrkC expression, these differences were not statistically significant. The group of patients with either moderate or severely anaplastic tumors showed only a trend towards shorter survival (p = 0.11). However, severe anaplasia alone was significantly prognostic (p = 0.002). Given the prognostic import of c-myc, we investigated 2 potential mechanisms by which its expression might be regulated: Wnt signaling and Mxi-1 mutation. Nuclear translocation of beta-catenin, a marker of Wnt pathway activation, was more common in medulloblastomas with high c-myc than in tumors overall, but the difference was not statistically significant. No Mxi-1 mutations were detected in the 22 cases examined. The association we describe between c-myc expression, tumor anaplasia, and worse clinical outcomes provides further evidence for the importance of this oncogene in medulloblastoma pathobiology.

High BAALC expression associates with other molecular prognostic markers, poor outcome, and a distinct gene-expression signature in cytogenetically normal patients younger than 60 years with acute myeloid leukemia: a Cancer and Leukemia Group B (CALGB) study

PubMed Central

Langer, Christian; Radmacher, Michael D.; Ruppert, Amy S.; Whitman, Susan P.; Paschka, Peter; Mrózek, Krzysztof; Baldus, Claudia D.; Vukosavljevic, Tamara; Liu, Chang-Gong; Ross, Mary E.; Powell, Bayard L.; de la Chapelle, Albert; Kolitz, Jonathan E.; Larson, Richard A.; Marcucci, Guido

2008-01-01

BAALC expression is considered an independent prognostic factor in cytogenetically normal acute myeloid leukemia (CN-AML), but has yet to be investigated together with multiple other established prognostic molecular markers in CN-AML. We analyzed BAALC expression in 172 primary CN-AML patients younger than 60 years of age, treated similarly on CALGB protocols. High BAALC expression was associated with FLT3-ITD (P = .04), wild-type NPM1 (P < .001), mutated CEBPA (P = .003), MLL-PTD (P = .009), absent FLT3-TKD (P = .005), and high ERG expression (P = .05). In multivariable analysis, high BAALC expression independently predicted lower complete remission rates (P = .04) when adjusting for ERG expression and age, and shorter survival (P = .04) when adjusting for FLT3-ITD, NPM1, CEBPA, and white blood cell count. A gene-expression signature of 312 probe sets differentiating high from low BAALC expressers was identified. High BAALC expression was associated with overexpression of genes involved in drug resistance (MDR1) and stem cell markers (CD133, CD34, KIT). Global microRNA-expression analysis did not reveal significant differences between BAALC expression groups. However, an analysis of microRNAs that putatively target BAALC revealed a potentially interesting inverse association between expression of miR-148a and BAALC. We conclude that high BAALC expression is an independent adverse prognostic factor and is associated with a specific gene-expression profile. PMID:18378853

Dissociation between PGC-1alpha and GLUT-4 expression in skeletal muscle of rats fed a high-fat diet.

PubMed

Higashida, Kazuhiko; Higuchi, Mitsuru; Terada, Shin

2009-12-01

It has recently been reported that a 4-wk high-fat diet gradually increases skeletal muscle peroxisome proliferator activated receptor (PPAR) gamma coactivator-1alpha (PGC-1alpha) protein content, which has been suggested to regulate GLUT-4 gene transcription. However, it has not been reported that a high-fat diet enhances GLUT-4 mRNA expression and protein content in skeletal muscle, suggesting that an increase in PGC-1alpha protein content is not sufficient to induce muscle GLUT-4 biogenesis in a high-fat fed animal. Therefore, we first evaluated the relationship between PGC-1alpha and GLUT-4 expression in skeletal muscle of rats fed a high-fat diet for 4 wk. The PGC-1alpha protein content in rat epitrochlearis muscle significantly increased by twofold after the 4-wk high-fat diet feeding. However, the high-fat diet had no effect on GLUT-4 protein content and induced a 30% decrease in GLUT-4 mRNA expression in rat skeletal muscle (p<0.05). To clarify the mechanism by which a high-fat diet downregulates GLUT-4 mRNA expression, we next examined the effect of PPARdelta activation, which is known to occur in response to a high-fat diet, on GLUT-4 mRNA expression in L6 myotubes. Incubation with 500 nM GW501516 (PPARdelta activator) for 24 h significantly decreased GLUT-4 mRNA in L6 myotubes. Taken together, these findings suggest that a high-fat diet downregulates GLUT-4 mRNA, possibly through the activation of PPARdelta, despite an increase in PGC-1alpha protein content in rat skeletal muscle, and that a posttranscriptional regulatory mechanism maintains GLUT-4 protein content in skeletal muscle of rats fed a high-fat diet.

Cyclophosphamide Alters the Gene Expression Profile in Patients Treated with High Doses Prior to Stem Cell Transplantation

PubMed Central

El-Serafi, Ibrahim; Abedi-Valugerdi, Manuchehr; Potácová, Zuzana; Afsharian, Parvaneh; Mattsson, Jonas; Moshfegh, Ali; Hassan, Moustapha

2014-01-01

Background Hematopoietic stem cell transplantation is a curative treatment for several haematological malignancies. However, treatment related morbidity and mortality still is a limiting factor. Cyclophosphamide is widely used in condition regimens either in combination with other chemotherapy or with total body irradiation. Methods We present the gene expression profile during cyclophosphamide treatment in 11 patients conditioned with cyclophosphamide for 2 days followed by total body irradiation prior to hematopoietic stem cell transplantation. 299 genes were identified as specific for cyclophosphamide treatment and were arranged into 4 clusters highly down-regulated genes, highly up-regulated genes, early up-regulated but later normalized genes and moderately up-regulated genes. Results Cyclophosphamide treatment down-regulated expression of several genes mapped to immune/autoimmune activation and graft rejection including CD3, CD28, CTLA4, MHC II, PRF1, GZMB and IL-2R, and up-regulated immune-related receptor genes, e.g. IL1R2, IL18R1, and FLT3. Moreover, a high and significant expression of ANGPTL1 and c-JUN genes was observed independent of cyclophosphamide treatment. Conclusion This is the first investigation to provide significant information about alterations in gene expression following cyclophosphamide treatment that may increase our understanding of the cyclophosphamide mechanism of action and hence, in part, avoid its toxicity. Furthermore, ANGPTL1 remained highly expressed throughout the treatment and, in contrast to several other alkylating agents, cyclophosphamide did not influence c-JUN expression. PMID:24466173

Cyclophosphamide alters the gene expression profile in patients treated with high doses prior to stem cell transplantation.

PubMed

El-Serafi, Ibrahim; Abedi-Valugerdi, Manuchehr; Potácová, Zuzana; Afsharian, Parvaneh; Mattsson, Jonas; Moshfegh, Ali; Hassan, Moustapha

2014-01-01

Hematopoietic stem cell transplantation is a curative treatment for several haematological malignancies. However, treatment related morbidity and mortality still is a limiting factor. Cyclophosphamide is widely used in condition regimens either in combination with other chemotherapy or with total body irradiation. We present the gene expression profile during cyclophosphamide treatment in 11 patients conditioned with cyclophosphamide for 2 days followed by total body irradiation prior to hematopoietic stem cell transplantation. 299 genes were identified as specific for cyclophosphamide treatment and were arranged into 4 clusters highly down-regulated genes, highly up-regulated genes, early up-regulated but later normalized genes and moderately up-regulated genes. Cyclophosphamide treatment down-regulated expression of several genes mapped to immune/autoimmune activation and graft rejection including CD3, CD28, CTLA4, MHC II, PRF1, GZMB and IL-2R, and up-regulated immune-related receptor genes, e.g. IL1R2, IL18R1, and FLT3. Moreover, a high and significant expression of ANGPTL1 and c-JUN genes was observed independent of cyclophosphamide treatment. This is the first investigation to provide significant information about alterations in gene expression following cyclophosphamide treatment that may increase our understanding of the cyclophosphamide mechanism of action and hence, in part, avoid its toxicity. Furthermore, ANGPTL1 remained highly expressed throughout the treatment and, in contrast to several other alkylating agents, cyclophosphamide did not influence c-JUN expression.

The regulatory effects of fish oil and chitosan on hepatic lipogenic signals in high-fat diet-induced obese rats.

PubMed

Chiu, Chen-Yuan; Chang, Tien-Chia; Liu, Shing-Hwa; Chiang, Meng-Tsan

2017-10-01

The present study investigated the regulatory effects of fish oil and chitosan on the signals of hepatic lipid metabolism and the postulated mechanism in high-fat diet-induced obese rats. Diet supplementation of chitosan and fish oil efficiently suppressed the increased weights in body and livers of high-fat diet-fed rats. Supplementation of chitosan and fish oil significantly decreased the activities of hepatic lipid biosynthesis-related enzymes and efficiently regulated plasma lipoprotein homeostasis. Both chitosan and fish oil significantly ameliorated the alterations in the protein expressions of hepatic lipogenic transcription factors (LXRα and PPARα), and could also significantly regulate the downstream hepatic lipogenic genes (FAS, HMGCR, CYP7A1, FATP, FABP, AOX, and ABCA) expressions in high-fat diet-fed rats. These results suggest that both fish oil and chitosan exerts downregulative effects on hepatic lipid metabolism in high-fat diet-induced obese rats via the LXRα inhibition and PPARα activation, which further affect the expressions of hepatic lipogenesis-associated genes. Copyright © 2017. Published by Elsevier B.V.

[Elevated expression of CLOCK is associated with poor prognosis in hepatocellular carcinoma].

PubMed

Li, Bo; Yang, Xiliang; Li, Jiaqi; Yang, Yi; Yan, Zhaoyong; Zhang, Hongxin; Mu, Jiao

2018-02-01

Objective To evaluate the expression of circadian locomotor output cycles kaput (CLOCK) and its effects on cell growth in hepatocellular carcinoma (HCC). Methods The expression of CLOCK in 158 pairs of human HCC tissues and matched noncancerous samples was detected by immunohistochemical (IHC) staining. The expression of CLOCK in HCC patients was also verified using the data from GEO and TCGA (a total of 356 cases). The relationship between CLOCK expression and clinicopathological features of HCC patients was analyzed by single factor statistical analysis. Kaplan-Meier survival curves of HCC patients were drawn to study the relationship between the expression level of CLOCK and the survival state. The effect of CLOCK on the growth of HepG2 cells was detected by MTS assay. Results The expression of CLOCK in HCC tissues was significantly higher than that in the adjacent tissues, and the up-regulation of CLOCK expression in HCC tissue was also confirmed in the public data of HCC (356 cases). HCC patients were divided into low CLOCK expression group and high CLOCK expression group. Univariate analysis showed that the expression of CLOCK was related to tumor size, TNM stage, and portal vein invasion in HCC patients. HCC patients with low CLOCK expression had longer overall survival time and relapse-free survival time than those with high CLOCK expression. The proliferation of cells significantly decreased after the expression of CLOCK was knocked down in HepG2 cells. Conclusion The expression of CLOCK in HCC tissues was much higher than that in normal liver tissues, and the high expression of CLOCK indicated the poor prognosis. The knockdown of CLOCK in HCC cells could inhibit the proliferation of HepG2 cells.

Predictive value of Sox2 expression in transurethral resection specimens in patients with T1 bladder cancer.

PubMed

Ruan, Jun; Wei, Bingbing; Xu, Zhuoqun; Yang, Shudong; Zhou, You; Yu, Minhong; Liang, Jiabei; Jin, Ke; Huang, Xing; Lu, Peng; Cheng, Huan

2013-03-01

Sox2 is thought to be an important regulator of self-renewal in embryonic stem cell. According to the cancer stem cell (CSC) theory, the overexpression of Sox2 is potentially involved in carcinogenesis and could affect tumor recurrence and metastasis. Previous study proved Sox2 might be prognostic marker for multiple human malignancies. The purpose of this study was to investigate the clinicopathological significance of Sox2 expression in human non-muscle-invasive bladder cancer. We examined Sox2 expression in 32 paired non-muscle-invasive bladder cancer tissues and adjacent non-cancerous tissues by quantitative real-time RT-PCR (qrtRT-PCR). In addition, we analyzed Sox2 and Ki-67 expression in 126 non-muscle-invasive bladder cancer samples and bladder cancer cell line T24 by immunohistochemistry and immunofluorescence assays. The recurrence-free survival was determined by Kaplan-Meier method and log-rank test. Cox regression was adopted for univariate and multivariate analyses of prognostic factors. The expression of Sox2 was significantly increased in non-muscle-invasive bladder cancer tissues. Sox2 expression was significantly correlated with that of Ki-67 (P < 0.001). The expression of Sox2 was significantly associated with tumor size (P = 0.006), tumor number (P = 0.037), and tumor grade (P < 0.001). Patients with high Sox2 expression had significantly poorer recurrence-free survival (P = 0.0002) when compared with patients with the low expression of Sox2. On multivariate analysis, Sox2 expression and tumor grade were found to be independent prognostic factors for recurrence-free survival (P < 0.05). Our data suggested for the first time that the high expression of Sox2 may contribute to the development of non-muscle-invasive bladder cancer and serve as a novel prognostic marker in patients with T1 bladder cancer.

Clinical and Pathological Significance of ER Stress Marker (BiP/GRP78 and PERK) Expression in Malignant Melanoma.

PubMed

Shimizu, Akira; Kaira, Kyoichi; Yasuda, Masahito; Asao, Takayuki; Ishikawa, Osamu

2017-01-01

Glucose-regulated protein of 78 kD (GRP78) also referred to as immunoglobulin heavy chain binding protein (BiP/GRP78) plays an important role in the endoplasmic reticulum (ER) stress. The level of BiP/GRP78 is highly elevated in various human cancers. The purpose of this study is to examine the prognostic significance of BiP/GRP78 expression in patients with malignant melanoma. A total of 133 malignant melanoma patients were analyzed, and tumor specimens were stained by immunohistochemistry for BiP/GRP78, PKR-like endoplasmic reticulum kinase (PERK), Ki-67, p53 and microvessel density (MVD) determined by CD34. BiP/GRP78 and PERK were highly expressed in 40 % (53/133) and 78 % (104/133), respectively. BiP/GRP78 disclosed a significant relationship with PERK expression, thickness, T factor, N factor, disease staging, cell proliferation (Ki-67) and MVD (CD34). By multivariate analysis, the high expression of BiP/GRP78 was identified as an independent prognostic factor for predicting poor survival against malignant melanoma. The increased BiP/GRP78 expression was clarified as an independent prognostic marker for predicting worse outcome. ER stress marker, BiP/GRP78 could be a powerful molecular target for the treatment of malignant melanoma.

SOX9 expression predicts relapse of stage II colon cancer patients.

PubMed

Marcker Espersen, Maiken Lise; Linnemann, Dorte; Christensen, Ib Jarle; Alamili, Mahdi; Troelsen, Jesper T; Høgdall, Estrid

2016-06-01

The aim of this study was to investigate if the protein expression of sex-determining region y-box 9 (SOX9) in primary tumors could predict relapse of stage II colon cancer patients. One hundred forty-four patients with stage II primary colon cancer were retrospectively enrolled in the study. SOX9 expression was evaluated by immunohistochemistry, and mismatch repair status was assessed by both immunohistochemistry and promoter hypermethylation assay. High SOX9 expression at the invasive front was significantly associated with lower risk of relapse when including the SOX9 expression as a continuous variable (from low to high expression) in univariate (hazard ratio [HR], 0.73; 95% confidence interval [CI], 0.56-0.94; P = .01) and multivariate Cox proportional hazards analyses (HR, 0.75; 95% CI, 0.58-0.96; P = .02), adjusting for mismatch repair deficiency and histopathologic risk factors. Conversely, low SOX9 expression at the invasive front was significantly associated with high risk of relapse, when including SOX9 expression as a dichotomous variable, in univariate (HR, 2.32; 95% CI, 1.14-4.69; P = .02) and multivariate analyses (HR, 2.32; 95% CI, 1.14-4.69; P = .02), adjusting for histopathologic risk factors and mismatch repair deficiency. In conclusion, high levels of SOX9 of primary stage II colon tumors predict low risk of relapse, whereas low levels of SOX9 predict high risk of relapse. SOX9 may have an important value as a biomarker when evaluating risk of relapse for personalized treatment. Copyright © 2016 Elsevier Inc. All rights reserved.

[Effect of Bushen Huoxue Compound on Retinal Müller Cells in High Glucose or AGEs Conditions].

PubMed

Xie, Xue-jun; Song, Ming-xia; Zhang, Mei; Qin, Wei; Wan, Li; Fang, Yang

2015-06-01

To explore the effect of Bushen Huoxue Compound (BHC) on lactate dehydrogenase (LDH) leakage, expressions of vascular endothelial growth factor (VEGF) and VEGF mRNA in retinal Muller cells under high glucose condition or advanced glycosylation end products (AGEs) condition by using serum pharmacological method. The retinal Müller cells of 5-7 days post-natal Sprague Dawley (SD) rats were cultured with modified enzyme-digestion method. Purified retinal Muller cells were cultured in normal conditions, high glucose condition (50 mmol/L) or AGEs (50 mg/L and 100 mg/L) conditions, and BHC-containing serum was added to culture medium. The LDH leakage and VEGF expressions were measured by enzyme-linked immunosorbent assay (ELISA). In addition, the relative expression of VEGF mRNA was tested by reverse transcription polymerase chain reaction (RT-PCR). Compared with the normal control group, expressions of VEGF and VEGF mRNA were significantly increased in the high glucose group, the low dose AGEs group and the high dose AGEs group (all P < 0.01). The LDH leakage was obviously increased in the high dose AGEs group, when compared with the normal control group and the high glucose group (P < 0.01). The LDH leakage, expressions of VEGF and VEGF mRNA were obviously decreased by BHC-containing serum both in high glucose and AGEs conditions (P < 0.05, P < 0.01). BHC-containing serum had no significant effect on the LDH leakage and expressions of VEGF and VEGF mRNA in normal conditions (P > 0.05). AGEs intervention could obviously lower the stability of Müller cell membrane. Up-regulated expressions of VEGF and VEGF mRNA in cultured Müller cells could be induced by AGEs or high glucose. BHC-containing serum could stabilize the stability of Müller cell membrane, inhibit the transcription of VEGF mRNA and decrease the protein expression of VEGF, which might be one of important mechanisms for preventing and treating diabetic retinopathy.

Chemokine-like factor-like MARVEL transmembrane domain-containing 3 expression is associated with a favorable prognosis in esophageal squamous cell carcinoma.

PubMed

Han, Tianci; Shu, Tianci; Dong, Siyuan; Li, Peiwen; Li, Weinan; Liu, Dali; Qi, Ruiqun; Zhang, Shuguang; Zhang, Lin

2017-05-01

Decreased expression of human chemokine-like factor-like MARVEL transmembrane domain-containing 3 (CMTM3) has been identified in a number of human tumors and tumor cell lines, including gastric and testicular cancer, and PC3, CAL27 and Tca-83 cell lines. However, the association between CMTM3 expression and the clinicopathological features and prognosis of esophageal squamous cell carcinoma (ESCC) patients remains unclear. The aim of the present study was to investigate the correlation between CMTM3 expression and clinicopathological parameters and prognosis in ESCC. CMTM3 mRNA and protein expression was analyzed in ESCC and paired non-tumor tissues by quantitative real-time polymerase chain reaction, western blotting and immunohistochemical analysis. The Kaplan-Meier method was used to plot survival curves and the Cox proportional hazards regression model was also used for univariate and multivariate survival analysis. The results revealed that CMTM3 mRNA and protein expression levels were lower in 82.5% (30/40) and 75% (30/40) of ESCC tissues, respectively, when compared with matched non-tumor tissues. Statistical analysis demonstrated that CMTM3 expression was significantly correlated with lymph node metastasis (P=0.002) and clinical stage (P<0.001) in ESCC tissues. Furthermore, the survival time of ESCC patients exhibiting low CMTM3 expression was significantly shorter than that of ESCC patients exhibiting high CMTM3 expression (P=0.01). In addition, Kaplan-Meier survival analysis revealed that the overall survival time of patients exhibiting low CMTM3 expression was significantly decreased compared with patients exhibiting high CMTM3 expression (P=0.010). Cox multivariate analysis indicated that CMTM3 protein expression was an independent prognostic predictor for ESCC after resection. This study indicated that CMTM3 expression is significantly decreased in ESCC tissues and CMTM3 protein expression in resected tumors may present an effective prognostic biomarker.

The immunohistochemical expression and potential prognostic value of HDAC6 and AR in invasive breast cancer.

PubMed

Li, Congying; Cao, Lu; Xu, Cong; Liu, Fang; Xiang, Guomin; Liu, Xiaozhen; Jiao, Jiao; Niu, Yun

2018-05-01

Previous studies have investigated the role of histone deacetylase 6 (HDAC6) in the regulation of androgen receptor (AR) in prostate cancer; however, the role of HDAC6 has not yet been clearly identified in breast cancer. The aim of this study was to examine the expression of HDAC6 and AR, determine the correlation between HDAC6 and AR, and assess the prognostic value of HDAC6 and AR in breast cancer. A total of 228 cases of invasive breast cancer were randomly selected. The expression of HDAC6 and AR was analyzed by immunohistochemistry. χ 2 Tests were performed to determine the association between conventional clinicopathological factors and HDAC6, AR, and HDAC6/AR co-expression. Spearman correlation methods were performed to determine the correlation between HDAC6 and AR, and Kaplan-Meier analyses were performed to determine the prognostic impact of HDAC6, AR and HDAC6/AR co-expression; 58.8% (134/228) patients exhibited high expression of HDAC6. High HDAC6 expression was significantly associated with high histologic grade (G3) (P<.001) and p53 overexpression (P=.002). HDAC6 and AR expression levels were significantly associated (r=0.382, P<.01). In estrogen receptor (ER)-negative samples, high expression of HDAC6 was more common in the AR+ groups (P<.001) and correlated with high histologic grade (G3) (P=.009), as well as higher HER2 (P=.006) and p53 levels (P=.012). Higher expression of AR and HDAC6 and HDAC6/AR co-expression had a worse clinical prognosis. The expression levels of HDAC6 and AR are correlated in breast cancer; moreover, HDAC6 and AR have prognostic value in predicting the overall survival (OS) of ER-negative breast cancer patients. Copyright © 2017 Elsevier Inc. All rights reserved.

Cyclin D1 is significantly associated with stage of tumor and predicts poor survival in endometrial carcinoma patients.

PubMed

Khabaz, Mohamad Nidal; Abdelrahman, Amer Shafie; Butt, Nadeem Shafique; Al-Maghrabi, Basim; Al-Maghrabi, Jaudah

2017-10-01

Cyclin D1 overexpression has been described to have oncogenic role and association with diagnosis, prognosis and survival in various tumors. This study will describe the immunohistochemical phenotype of cyclin D1, and investigate the correlation between these patterns of expression and clinicopathological parameters of endometrial carcinomas, to conclude the clinical relevance of cyclin D1 expression in the evolution of endometrial neoplasms. This study employed 101 endometrial tissue samples which include 71 endometrial carcinomas and thirty normal and benign endometrium cases. All these tissue samples were used in the assembly of tissue microarrays which have been utilized afterward in immunohistochemistry staining to detect cyclin D1 expression. Forty (56.3%) cases of endometrial carcinomas showed brown nuclear expression of cyclin D1 including 36 (61%) cases of endometrioid carcinomas, and 3 (33.3%) cases of serous carcinomas. Twenty three (76.6%) cases of control group demonstrated nuclear expression. High score cyclin D1 immunohistochemical staining has been significantly linked with patient age (P=0.0001). Large proportion of high score cyclin D1 immunohistochemical staining was observed in females who are <40years of age while high proportions of negative staining were observed in older age groups. Histologic type of tissue was also significantly related to cyclin D1 immunohistochemical staining (P-value=0.0001), high staining is more common in normal proliferative and secretory endometrium while serous carcinoma is more prevalent with negative staining. Stage of tumor was significantly associated with cyclin D1 immunohistochemical staining (P-value=0.029), proportion of stage III and IV are higher in negative cyclin D1 immunostaining. Significantly higher proportion of high score cyclin D1 immunostaining is observed in controls while higher proportion of negative cyclin D1 immunostaining is observed among carcinoma cases (P-value=0.0001). No significant associations between cyclin D1 immunohistochemical staining and grade, recurrence and alive status were observed. Significant different survival distributions were observed (P-value=0.011) and poor survival behavior was correlated with negative cyclin D1 immunohistochemical staining. In conclusion, greater frequency of cyclin D1 expression was revealed in normal endometrial tissues in comparison with carcinomas. The distribution pattern of cyclin D1 immunoexpression suggests poor prognoses in endometrial carcinoma patients. Copyright © 2017 Elsevier Inc. All rights reserved.

[Effect of TUBB3, TS and ERCC1 mRNA expression on chemoresponse and clinical outcome of advanced gastric cancer by multiplex branched-DNA liquid chip technology].

PubMed

Huang, Jin; Hu, Huabin; Xie, Yangchun; Tang, Youhong; Liu, Wei; Zhong, Meizuo

2013-06-01

To analyze the impact of β-tubulin-III (TUBB3), thymidylate synthase (TS) and excision repair cross complementation group 1 (ERCC1) mRNA expression on chemoresponse and clinical outcome of patients with advanced gastric cancer treated with TXT/CDDP/FU (DCF) regimen chemotherapy. The study population consisted of 48 patients with advanced gastric cancer. All patients were treated with DCF regimen palliative chemotherapy. The mRNA expressions of TUBB3, TS and ERCC1 of primary tumors were examined by multiplex branched-DNA liquid chip technology. The patients with low TUBB3 mRNA expression had higher response rate to chemotherapy than patients with high TUBB3 expression (P=0.011). There were no significant differences between response rate and TS or ERCC1 expression pattern. Median overall survival (OS) and median time to progression (TTP) were significantly longer in patients with low TUBB3 mRNA expression (P=0.002, P<0.001). TS or ERCC1 expression was not correlated with TTP and OS. In the combined analysis including TUBB3, TS and ERCC1, the patients with 0 or 1 high expression gene had better response rate, TTP and OS than the remaining patients (all P<0.001). Multivariate analysis revealed that ECOG (Eastern Cooperative Oncology Group)≥2 (HR=2.42, P=0.009) and TUBB3 (HR=2.34, P=0.036) mRNA expression significantly impacted on OS. High TUBB3 mRNA expression is correlated with resistance to DCF regimen chemotherapy. TUBB3 might be a predictive and prognostic factor in patients with advanced gastric cancer treated with TXT-based chemotherapy. The combined evaluation of TUBB3, TS and ERCC1 expression can promote the individual treatment in advanced gastric cancer.

Connective tissue growth factor as a novel therapeutic target in high grade serous ovarian cancer.

PubMed

Moran-Jones, Kim; Gloss, Brian S; Murali, Rajmohan; Chang, David K; Colvin, Emily K; Jones, Marc D; Yuen, Samuel; Howell, Viive M; Brown, Laura M; Wong, Carol W; Spong, Suzanne M; Scarlett, Christopher J; Hacker, Neville F; Ghosh, Sue; Mok, Samuel C; Birrer, Michael J; Samimi, Goli

2015-12-29

Ovarian cancer is the most common cause of death among women with gynecologic cancer. We examined molecular profiles of fibroblasts from normal ovary and high-grade serous ovarian tumors to identify novel therapeutic targets involved in tumor progression. We identified 2,300 genes that are significantly differentially expressed in tumor-associated fibroblasts. Fibroblast expression of one of these genes, connective tissue growth factor (CTGF), was confirmed by immunohistochemistry. CTGF protein expression in ovarian tumor fibroblasts significantly correlated with gene expression levels. CTGF is a secreted component of the tumor microenvironment and is being pursued as a therapeutic target in pancreatic cancer. We examined its effect in in vitro and ex vivo ovarian cancer models, and examined associations between CTGF expression and clinico-pathologic characteristics in patients. CTGF promotes migration and peritoneal adhesion of ovarian cancer cells. These effects are abrogated by FG-3019, a human monoclonal antibody against CTGF, currently under clinical investigation as a therapeutic agent. Immunohistochemical analyses of high-grade serous ovarian tumors reveal that the highest level of tumor stromal CTGF expression was correlated with the poorest prognosis. Our findings identify CTGF as a promoter of peritoneal adhesion, likely to mediate metastasis, and a potential therapeutic target in high-grade serous ovarian cancer. These results warrant further studies into the therapeutic efficacy of FG-3019 in high-grade serous ovarian cancer.

Connective tissue growth factor as a novel therapeutic target in high grade serous ovarian cancer

PubMed Central

Moran-Jones, Kim; Gloss, Brian S.; Murali, Rajmohan; Chang, David K.; Colvin, Emily K.; Jones, Marc D.; Yuen, Samuel; Howell, Viive M.; Brown, Laura M.; Wong, Carol W.; Spong, Suzanne M.; Scarlett, Christopher J.; Hacker, Neville F.; Ghosh, Sue; Mok, Samuel C.; Birrer, Michael J.; Samimi, Goli

2015-01-01

Ovarian cancer is the most common cause of death among women with gynecologic cancer. We examined molecular profiles of fibroblasts from normal ovary and high-grade serous ovarian tumors to identify novel therapeutic targets involved in tumor progression. We identified 2,300 genes that are significantly differentially expressed in tumor-associated fibroblasts. Fibroblast expression of one of these genes, connective tissue growth factor (CTGF), was confirmed by immunohistochemistry. CTGF protein expression in ovarian tumor fibroblasts significantly correlated with gene expression levels. CTGF is a secreted component of the tumor microenvironment and is being pursued as a therapeutic target in pancreatic cancer. We examined its effect in in vitro and ex vivo ovarian cancer models, and examined associations between CTGF expression and clinico-pathologic characteristics in patients. CTGF promotes migration and peritoneal adhesion of ovarian cancer cells. These effects are abrogated by FG-3019, a human monoclonal antibody against CTGF, currently under clinical investigation as a therapeutic agent. Immunohistochemical analyses of high-grade serous ovarian tumors reveal that the highest level of tumor stromal CTGF expression was correlated with the poorest prognosis. Our findings identify CTGF as a promoter of peritoneal adhesion, likely to mediate metastasis, and a potential therapeutic target in high-grade serous ovarian cancer. These results warrant further studies into the therapeutic efficacy of FG-3019 in high-grade serous ovarian cancer. PMID:26575166

Inducible nitric oxide synthase, nitrotyrosine and apoptosis in gastric adenocarcinomas and their correlation with a poor survival

PubMed Central

Li, Long-Gang; Xu, Hui-Mian

2005-01-01

AIM: To detect the presence of inducible nitric oxide synthase (iNOS), nitrotyrosine (NT) and apoptosis in gastric adenocarcinomas and their possible correlations with the clinicopathological characteristics and prognosis of gastric adenocarcinoma. METHODS: Sixty-six specimens of gastric adenocarcinoma and corresponding adjacent normal gastric tissues were studied. Immunohistochemistry was employed to localize iNOS and NT protein and an immunohistochemical scoring system was used. The occurrence of apoptotic cell death (apoptotic index [AI]) was analyzed by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick-end labeling (TUNEL) method. RESULTS: Results showed that iNOS expression was detected at an intermediate or high level in 41 of 66 (62%) specimens of gastric adenocarcinoma. NT expression was 58%. Neither of them was found in the normal gastric tissues; there were significant positive correlations among iNOS expression, NT expression and AI. Many clinicopathologic characteristics of gastric adenocarcinoma, such as tumor size, depth of invasion, lymph node metastasis and TNM staging, were related to iNOS and NT expressions (P<0.05). In 66 surviving patients, the 5-year survival rate of 41 patients who had tumors with intermediate or high iNOS expressions and high AIs (4.09%; 19.96%) was significantly lower than that of 25 patients who had tumors with negative or low iNOS expressions and low AIs (0.79%; 47.14%) (P = 0.001). COX’s multivariate analysis revealed that the iNOS expression was identified as one of the significant independent prognostic factors predictive of a poor survival (relative risk [RR] = 2.69). CONCLUSION: NO produced by iNOS may play a stronger role in promoting gastric adenocarcinoma growth than in suppressing its growth. iNOS and NT expressions by gastric adenocarcinoma may correlate with a poor survival. PMID:15849807

Berberine enhances the AMPK activation and autophagy and mitigates high glucose-induced apoptosis of mouse podocytes.

PubMed

Jin, Yingli; Liu, Shuping; Ma, Qingshan; Xiao, Dong; Chen, Li

2017-01-05

High glucose concentration can induce injury of podocytes and berberine has a potent activity against diabetic nephropathy. However, whether and how berberine can inhibit high glucose-mediated injury of podocytes have not been clarified. This study tested the effect of berberine on high glucose-mediated apoptosis and the AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR) activation and autophagy in podocytes. The results indicated that berberine significantly mitigated high glucose-decreased cell viability, and nephrin and podocin expression as well as apoptosis in mouse podocytes. Berberine significantly increased the AMPK activation and mitigated high glucose and/or the AMPK inhibitor, compound C-mediated mTOR activation and apoptosis in podocytes. Berberine significantly enhanced the AMPK activation and protected from high glucose-induced apoptosis in the AMPK-silencing podocytes. Furthermore, berberine significantly increased the high glucose-elevated Unc-51-like autophagy-activating kinase 1 (ULK1) S317/S555 phosphorylation, Beclin-1 expression, the ratios of LC3II to LC3I expression and the numbers of autophagosomes, but reduced ULK1 S757 phosphorylation in podocytes. In addition, berberine significantly attenuated compound C-mediated inhibition of autophagy in podocytes. The protective effect of berberine on high glucose-induced podocyte apoptosis was significantly mitigated by pre-treatment with 3-methyladenine or bafilomycin A1. Collectively, berberine enhanced autophagy and protected from high glucose-induced injury in podocytes by promoting the AMPK activation. Our findings may provide new insights into the molecular mechanisms underlying the anti-diabetic nephropathy effect of berberine and may aid in design of new therapies for intervention of diabetic nephropathy. Copyright © 2016 Elsevier B.V. All rights reserved.

High expression of anti-apoptotic protein Bcl-2 is a good prognostic factor in colorectal cancer: Result of a meta-analysis.

PubMed

Huang, Qi; Li, Shu; Cheng, Pu; Deng, Mei; He, Xin; Wang, Zhen; Yang, Cheng-Hui; Zhao, Xiao-Ying; Huang, Jian

2017-07-21

To systematically evaluate the prognostic-predictive capability of Bcl-2 in colorectal cancer (CRC). A systematic literature search was conducted using PubMed, Web of Science and EMBASE databases. Any eligible study must meet the following criteria: (1) bcl-2 expression was evaluated in human CRC tissues by immunohistochemistry; (2) assessment of the relationships between bcl-2 expression and overall survival (OS), disease free survival (DFS), recurrent free survival (RFS) or clinic-pathological characteristics of CRC was included; (3) sufficient information was provided to estimate the hazard ratio (HR) or odds ratio and their 95% confidence intervals (CIs); and (4) the study was published in English. The impact of Bcl-2 expression on survival of CRC patients were evaluated through this meta-analysis. A total of 40 eligible articles involving 7658 patients were enrolled in our final analysis. We drew the conclusion that Bcl-2 high expression was significantly correlated with favorable OS (pooled HR = 0.69, 95%CI: 0.55-0.87, P = 0.002) and better DFS/RFS (pooled HR = 0.65, 95%CI: 0.50-0.85, P = 0.001). Additionally, the subgroup analysis suggested that Bcl-2 overexpression was significantly associated with prognosis (OS) especially in patients came from Europe and America but not Asian and patients who did not receive any adjuvant therapy before surgery. Finally, our present results indicated that expression of bcl-2 protein was associated with high differentiation grade and A/B Ducks' stage. Bcl-2 high expression was significantly correlated with favorable OS and better DFS/RFS. Hence, we propose that Bcl-2 may be a valuable prognostic-predictive marker in CRC.

High expression of anti-apoptotic protein Bcl-2 is a good prognostic factor in colorectal cancer: Result of a meta-analysis

PubMed Central

Huang, Qi; Li, Shu; Cheng, Pu; Deng, Mei; He, Xin; Wang, Zhen; Yang, Cheng-Hui; Zhao, Xiao-Ying; Huang, Jian

2017-01-01

AIM To systematically evaluate the prognostic-predictive capability of Bcl-2 in colorectal cancer (CRC). METHODS A systematic literature search was conducted using PubMed, Web of Science and EMBASE databases. Any eligible study must meet the following criteria: (1) bcl-2 expression was evaluated in human CRC tissues by immunohistochemistry; (2) assessment of the relationships between bcl-2 expression and overall survival (OS), disease free survival (DFS), recurrent free survival (RFS) or clinic-pathological characteristics of CRC was included; (3) sufficient information was provided to estimate the hazard ratio (HR) or odds ratio and their 95% confidence intervals (CIs); and (4) the study was published in English. The impact of Bcl-2 expression on survival of CRC patients were evaluated through this meta-analysis. RESULTS A total of 40 eligible articles involving 7658 patients were enrolled in our final analysis. We drew the conclusion that Bcl-2 high expression was significantly correlated with favorable OS (pooled HR = 0.69, 95%CI: 0.55-0.87, P = 0.002) and better DFS/RFS (pooled HR = 0.65, 95%CI: 0.50-0.85, P = 0.001). Additionally, the subgroup analysis suggested that Bcl-2 overexpression was significantly associated with prognosis (OS) especially in patients came from Europe and America but not Asian and patients who did not receive any adjuvant therapy before surgery. Finally, our present results indicated that expression of bcl-2 protein was associated with high differentiation grade and A/B Ducks’ stage. CONCLUSION Bcl-2 high expression was significantly correlated with favorable OS and better DFS/RFS. Hence, we propose that Bcl-2 may be a valuable prognostic-predictive marker in CRC. PMID:28785155

Relationship between microRNA-146a expression and plasma renalase levels in hemodialyzed patients

PubMed Central

Koch, Wojciech; Kukula-Koch, Wirginia; Gaweł, Kinga; Bednarek-Skublewska, Anna; Małecka-Massalska, Teresa; Milanowski, Janusz; Petkowicz, Beata; Solski, Janusz

2017-01-01

Background microRNA (miRNA) belongs to the non-coding RNAs family responsible for the regulation of gene expression. Renalase is a protein composed of 342 amino acids, secreted by the kidneys and possibly plays an important role in the regulation of sympathetic tone and blood pressure. The aim of the present study was to investigate plasma renalase concentration, and explore the relationship between miRNA-146a-5p expression and plasma renalase levels in hemodialyzed patients. Methods The study population comprised 55 subjects who succumbed to various cardiac events, 27 women and 28 men, aged 65–70 years. The total RNA including miRNA fraction was isolated using QiagenmiRNEasy Serum/Plasma kit according to the manufacturer’s protocol. The isolated miRNAs were analyzed using a quantitative polymerase chain reaction (qRT-PCR) technique. The plasma renalase levels were measured using a commercial ELISA kit. Results In the group of patients with high levels of renalase, higher miRNA-146a expression was found, compared with those with low concentration of renalase. Patients with simultaneous low miRNA-146a expression and high level of renalase were confirmed to deliver a significantly longer survival time compared with other patients. Conclusions miRNA-146a and plasma renalase levels were estimated as independent prognostic factors of hemodialyzed patients’ survival time. Patients with low miRNA-146a expression demonstrated a significantly longer survival time in contrast to the patients with a high expression level of miRNA-146a. Moreover, a significantly longer survival time was found in patients with high renalase activity compared with patients with low activity of the enzyme. PMID:28614373

Thymidylate Synthase Gene Polymorphism Affects the Response to Preoperative 5-Fluorouracil Chemoradiation Therapy in Patients With Rectal Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hur, Hyuk; Kang, Jeonghyun; Kim, Nam Kyu, E-mail: namkyuk@yuhs.ac

2011-11-01

Purpose: This study aims to correlate thymidylate synthase (TS) gene polymorphisms with the tumor response to preoperative 5-fluorouracil (5-FU)-based chemoradiation therapy (CRT) in patients with rectal cancer. Methods and Materials: Forty-four patients with rectal cancer treated with 5-FU-based preoperative CRT were prospectively enrolled in this study. Thymidylate synthase expression and TS gene polymorphisms were evaluated in tumor obtained before preoperative CRT and were correlated with the pathologic response, as assessed by histopathologic staging (pTNM) and tumor regression grade. Results: Patients exhibited 2R/3R and 3R/3R tandem repeat polymorphisms in the TS gene. With regard to TS expression in these genotypes, 2R/3RCmore » and 3RC/3RC were defined as the low-expression group and 2R/3RG, 3RC/3RG, and 3RG/3RG as the high-expression group. There was no significant correlation between TS expression and tumor response. There was no significant difference in the tumor response between patients homozygous for 3R/3R and patients heterozygous for 2R/3R. However, 13 of 14 patients in the low-expression group with a G>C single-nucleotide polymorphism (SNP) (2R/3RC [n = 5] or 3RC/3RC [n = 9]) exhibited a significantly greater tumor downstaging rate, as compared with only 12 of 30 patients in the high-expression group without the SNP (2R/3RG [n = 10], 3RC/3RG [n = 9], or 3RG/3RG [n = 11]) (p = 0.001). The nodal downstaging rate was also significantly greater in this low-expression group, as compared with the high-expression group (12 of 14 vs. 14 of 30, p = 0.014). However, there was no significant difference in the tumor regression grade between these groups. Conclusions: This study suggests that SNPs within the TS enhancer region affect the tumor response to preoperative 5-FU-based CRT in rectal cancer.« less

Diagnostic value of CD10 and Bcl2 expression in distinguishing cutaneous basal cell carcinoma from squamous cell carcinoma and seborrheic keratosis.

PubMed

Gaballah, Mohammad A; Ahmed, Rehab-Allah

2015-12-01

The distinction between cutaneous basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and seborrheic keratosis (SK), which are common entities in clinical practice, can be difficult clinically and histologically. CD10 and Bcl2 antigens are important factors in tumor growth, survival and spread. The aim of the present study is to define the frequency of CD10 and Bcl2 expression in such cutaneous tumors and its relation to the clinicopathological characteristics as well as their possible diagnostic utility. CD10 and Bcl2 immunohistochemistry was performed on 30 BCC, 20 SCC and 15 SK. 93.3% of SK cases and 53.3% of BCC cases showed significant expression of CD10 in tumor cells when compared either with each other or with SCC cases (100% negative). Stromal CD10 expression was positive in 50% of BCC cases and 75% of SCC cases. Stromal CD10 expression was significantly higher in high risk BCC and BCC with infiltrating deep margins; furthermore, it showed a significant positive correlation with grade of SCC. A significant inverse correlation between CD10 expression in stromal and tumor cells of BCC was present. Bcl2 was significantly expressed in 93.3% of SK cases and 80% of BCC cases when compared with SCC cases (100% negative). It was found that for distinguishing BCC from SK, only CD10 expression in tumor cells provided a high diagnostic value with positive likelihood ratio (PLR) was 7.00. In addition, CD10 and Bcl2 expression in tumor cells could give convincing diagnostic value to distinguish SCC from SK (PLR=15.00 for each marker). Moreover, for differentiating BCC from SCC, only Bcl2 in the tumor cells could provide a high diagnostic value (PLR=5.5). In conclusion, CD10 and Bcl2 can help in differentiating cutaneous BCC from SK and SCC. The overexpression of CD10 in the stromal cells of SCC and some variants of BCC suggests the invasive properties of such tumors. Copyright © 2015 Elsevier GmbH. All rights reserved.

RANK Expression and Osteoclastogenesis in Human Monocytes in Peripheral Blood from Rheumatoid Arthritis Patients.

PubMed

Nanke, Yuki; Kobashigawa, Tsuyoshi; Yago, Toru; Kawamoto, Manabu; Yamanaka, Hisashi; Kotake, Shigeru

2016-01-01

Rheumatoid arthritis (RA) appears as inflammation of synovial tissue and joint destruction. Receptor activator of NF- κ B (RANK) is a member of the TNF receptor superfamily and a receptor for the RANK ligand (RANKL). In this study, we examined the expression of RANK high and CCR6 on CD14 + monocytes from patients with RA and healthy volunteers. Peripheral blood samples were obtained from both the RA patients and the healthy volunteers. Osteoclastogenesis from monocytes was induced by RANKL and M-CSF in vitro . To study the expression of RANK high and CCR6 on CD14 + monocytes, two-color flow cytometry was performed. Levels of expression of RANK on monocytes were significantly correlated with the level of osteoclastogenesis in the healthy volunteers. The expression of RANK high on CD14 + monocyte in RA patients without treatment was elevated and that in those receiving treatment was decreased. In addition, the high-level expression of RANK on CD14 + monocytes was correlated with the high-level expression of CCR6 in healthy volunteers. Monocytes expressing both RANK and CCR6 differentiate into osteoclasts. The expression of CD14 + RANK high in untreated RA patients was elevated. RANK and CCR6 expressed on monocytes may be novel targets for the regulation of bone resorption in RA and osteoporosis.

Tumor 5-FU-related mRNA Expression and Efficacy of Oral Fluoropyrimidines in Adjuvant Chemotherapy of Colorectal Cancer.

PubMed

Koda, Keiji; Miyauchi, Hideaki; Kosugi, Chihiro; Kaiho, Takashi; Takiguchi, Nobuhiro; Kobayashi, Susumu; Maruyama, Takashi; Matsubara, Hisahiro

2016-10-01

It has not been elucidated whether the clinical efficacy of oral fluoropyrimidines for adjuvant chemotherapy of colorectal cancer varies with tumor biological characteristics. A multicenter randomized trial was performed comparing oral tegafur/gimeracil/oteracil (S-1) and uracil-tegafur/ leucovorin (UFT/LV) as adjuvant therapy for stage III colorectal cancer. Postoperative survival was compared based on the 5-FU-related mRNA levels in cancer tissues. Among patients with tumor expressing dihydropyrimidine dehydrogenase (DPD) mRNA within the 66.7th percentile (lower 2/3) of all cases, overall survival (OS) was significantly better in the S-1 than in the UFT/LV group. In the S-1 group, patients with low DPD-expressing tumors had significantly better OS than those with highly expressing tumors. Patients with low thymidine synthase (TS)-expressing tumors had significantly better OS than those with highly expressing tumors. The efficacy of oral fluoropyrimidines as adjuvant chemotherapy for colorectal cancer may be influenced by the level of 5-FU-related mRNA in cancer tissues. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Expression of PD-1 on peripheral blood Treg cells is related to the diagnosis, prognosis and treatment of T cell non-Hodgkin lymphoma.

PubMed

Zuo, Mengxuan; Shen, Haorui; Yin, Jingjing; Wang, Wei; Zhang, Yan; Zhou, Dao-Bin; Zhang, Wei

2018-05-24

The aim of study was to explore the PD-1 expression on Treg cells and its association with T-NHL. 137 patients newly diagnosed with T-NHL and 115 healthy controls were enrolled. The expression level of PD-1 was measured by flow cytometry at the time of diagnose and 3-8 course of treatment. Median fluorescence intensity (MFI) of PD-1 on Treg cells in T-NHL patients was significantly higher than that in healthy controls (P < 0.001). MFI of PD-1 in medium/high-risk T-NHL patients were higher than that in low-risk patients (P < 0.05). After treatment with Chidamide combined with chemotherapy, MFI of PD-1 significantly decreased (P < 0.05). In patients with high PD-1 expression (percentage>19.6% and MFI > 580), EFS was significantly lower than patients with low PD-1 expression (percentage<19.6% and MFI < 580). The PD-1expression on peripheral blood Treg cells of T-NHL patients is related to the diagnosis, prognosis and treatment of disease. Copyright © 2018. Published by Elsevier Ltd.

Gene expression analysis of a Helicobacter pylori-infected and high-salt diet-treated mouse gastric tumor model: identification of CD177 as a novel prognostic factor in patients with gastric cancer

PubMed Central

2013-01-01

Background Helicobacter pylori (H. pylori) infection and excessive salt intake are known as important risk factors for stomach cancer in humans. However, interactions of these two factors with gene expression profiles during gastric carcinogenesis remain unclear. In the present study, we investigated the global gene expression associated with stomach carcinogenesis and prognosis of human gastric cancer using a mouse model. Methods To find candidate genes involved in stomach carcinogenesis, we firstly constructed a carcinogen-induced mouse gastric tumor model combined with H. pylori infection and high-salt diet. C57BL/6J mice were given N-methyl-N-nitrosourea in their drinking water and sacrificed after 40 weeks. Animals of a combination group were inoculated with H. pylori and fed a high-salt diet. Gene expression profiles in glandular stomach of the mice were investigated by oligonucleotide microarray. Second, we examined an availability of the candidate gene as prognostic factor for human patients. Immunohistochemical analysis of CD177, one of the up-regulated genes, was performed in human advanced gastric cancer specimens to evaluate the association with prognosis. Results The multiplicity of gastric tumor in carcinogen-treated mice was significantly increased by combination of H. pylori infection and high-salt diet. In the microarray analysis, 35 and 31 more than two-fold up-regulated and down-regulated genes, respectively, were detected in the H. pylori-infection and high-salt diet combined group compared with the other groups. Quantitative RT-PCR confirmed significant over-expression of two candidate genes including Cd177 and Reg3g. On immunohistochemical analysis of CD177 in human advanced gastric cancer specimens, over-expression was evident in 33 (60.0%) of 55 cases, significantly correlating with a favorable prognosis (P = 0.0294). Multivariate analysis including clinicopathological factors as covariates revealed high expression of CD177 to be an independent prognostic factor for overall survival. Conclusions These results suggest that our mouse model combined with H. pylori infection and high-salt diet is useful for gene expression profiling in gastric carcinogenesis, providing evidence that CD177 is a novel prognostic factor for stomach cancer. This is the first report showing a prognostic correlation between CD177 expression and solid tumor behavior. PMID:23899160

Sexually Dimorphic Gene Expression Associated with Growth and Reproduction of Tongue Sole (Cynoglossus semilaevis) Revealed by Brain Transcriptome Analysis.

PubMed

Wang, Pingping; Zheng, Min; Liu, Jian; Liu, Yongzhuang; Lu, Jianguo; Sun, Xiaowen

2016-08-26

In this study, we performed a comprehensive analysis of the transcriptome of one- and two-year-old male and female brains of Cynoglossus semilaevis by high-throughput Illumina sequencing. A total of 77,066 transcripts, corresponding to 21,475 unigenes, were obtained with a N50 value of 4349 bp. Of these unigenes, 33 genes were found to have significant differential expression and potentially associated with growth, from which 18 genes were down-regulated and 12 genes were up-regulated in two-year-old males, most of these genes had no significant differences in expression among one-year-old males and females and two-year-old females. A similar analysis was conducted to look for genes associated with reproduction; 25 genes were identified, among them, five genes were found to be down regulated and 20 genes up regulated in two-year-old males, again, most of the genes had no significant expression differences among the other three. The performance of up regulated genes in Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was significantly different between two-year-old males and females. Males had a high gene expression in genetic information processing, while female's highly expressed genes were mainly enriched on organismal systems. Our work identified a set of sex-biased genes potentially associated with growth and reproduction that might be the candidate factors affecting sexual dimorphism of tongue sole, laying the foundation to understand the complex process of sex determination of this economic valuable species.

Comparative study of ROR2 and WNT5a expression in squamous/adenosquamous carcinoma and adenocarcinoma of the gallbladder

PubMed Central

Wu, Zheng-Chun; Xiong, Li; Wang, Ling-Xiang; Miao, Xiong-Ying; Liu, Zi-Ru; Li, Dai-Qiang; Zou, Qiong; Liu, Kui-Jie; Zhao, Hua; Yang, Zhu-Lin

2017-01-01

AIM To investigate the expression and clinical pathological significance of ROR2 and WNT5a in gallbladder squamous/adenosquamous carcinoma (SC/ASC) and adenocarcinoma (AC). METHODS EnVision immunohistochemistry was used to stain for ROR2 and WNT5a in 46 SC/ASC patients and 80 AC patients. RESULTS Poorly differentiated AC among AC patients aged > 45 years were significantly more frequent compared with SC/ASC patients, while tumors with a maximal diameter > 3 cm in the SC/ASC group were significantly more frequent compared with the AC group. Positive ROR2 and WNT5a expression was significantly lower in SC/ASC or AC with a maximal mass diameter ≤ 3 cm, a TNM stage of I + II, no lymph node metastasis, no surrounding invasion, and radical resection than in patients with a maximal mass diameter > 3 cm, TNM stage IV, lymph node metastasis, surrounding invasion, and no resection. Positive ROR2 expression in patients with highly differentiated SC/ASC was significantly lower than in patients with poorly differentiated SC/ASC. Positive ROR2 and WNT5a expression levels in highly differentiated AC were significantly lower than in poorly differentiated AC. Kaplan-Meier survival analysis showed that differentiation degree, maximal mass diameter, TNM stage, lymph node metastasis, surrounding invasion, surgical procedure and the ROR2 and WNT5a expression levels were closely related to average survival of SC/ASC or AC. The survival of SC/ASC or AC patients with positive expression of ROR2 and WNT5a was significantly shorter than that of patients with negative expression results. Cox multivariate analysis revealed that poor differentiation, a maximal diameter of the mass ≥ 3 cm, TNM stage III or IV, lymph node metastasis, surrounding invasion, unresected surgery and positive ROR2 or WNT5a expression in the SC/ASC or AC patients were negatively correlated with the postoperative survival rate and positively correlated with mortality, which are risk factors and independent prognostic predictors. CONCLUSION SC/ASC or AC patients with positive ROR2 or WNT5a expression generally have a poor prognosis. PMID:28465645

The effect of meaningfulness and integrative processing in expressive writing on positive and negative affect and life satisfaction.

PubMed

Schutte, Nicola S; Searle, Trudy; Meade, Stephen; Dark, Neill A

2012-01-01

Meaningfulness and integrative processing of expressive writing may influence the effect of expressive writing. Participants completed measures of positive affect, negative affect and life satisfaction before and after an expressive writing intervention. Participants were randomly assigned to one of four expressive writing instruction conditions, which combined higher and lower levels of meaning and integrative processing instructions. Meaningfulness and integrative processing instructions had significant effects in increasing positive affect and there was a significant interaction between meaningfulness instructions and integrative processing instructions; participants in the high meaningfulness and high integrative processing instruction condition showed the greatest increase in positive affect. Meaningfulness had a significant effect in decreasing negative affect. The intervention did not influence life satisfaction. Both meaningfulness and integrative processing instructions led to more self-reported personal meaningfulness of the writing and more cognitive, emotional, behavioural and situational changes. More self-reported meaningfulness of the writing and more cognitive, emotional, behavioural and situational changes made as a result of the writing were in turn associated with greater increases in positive affect. The results of the study affirm the importance of meaningfulness and processing in expressive writing and potentially provide information regarding how to increase the effectiveness of expressive writing.

Metallothionein expression in human breast cancer.

PubMed Central

Goulding, H.; Jasani, B.; Pereira, H.; Reid, A.; Galea, M.; Bell, J. A.; Elston, C. W.; Robertson, J. F.; Blamey, R. W.; Nicholson, R. A.

1995-01-01

Metallothioneins are ubiquitous low molecular weight proteins characterised by high cysteine content and affinity for binding heavy metals. Abnormal metallothionein function and expression have been implicated in various disease states, including neoplasia. The aim of this study was to investigate metallothionein expression in human breast carcinoma. Sections of routinely fixed and processed blocks of tumour from 100 consecutive cases of primary operable breast carcinoma were stained for metallothionein using a recently developed monoclonal antibody and a standard immunohistochemical technique. Expression was scored on the basis of microscopical assessment of percentage of tumour cells staining. One patient was lost to follow-up and excluded from the study. A significant association (P < 0.0001) was observed between metallothionein expression and tumour type, with low levels being observed in tumours of good prognostic type. There was also a significant association with local recurrence (P < 0.02) and a significant difference (P < 0.02) in both survival and disease-free interval between tumours showing low and high levels of expression, the latter indicating a poor prognosis. No relationship was observed with patient age, tumour size, lymph node stage, histological grade, vascular invasion, menopausal status or oestrogen receptor status. The assessment of metallothionein expression in human breast cancer appears to provide prognostic information and may have important implications for understanding its development. Images Figure 1 Figure 2 PMID:7547250

Effect of polysaccharide of dendrobium candidum on proliferation and apoptosis of human corneal epithelial cells in high glucose

PubMed Central

Li, Qiangxiang; Chen, Jing; Li, Yajia; Chen, Ting; Zou, Jing; Wang, Hua

2017-01-01

Abstract Background: The aim of the study was to observe the effect of polysaccharide of dendrobium candidum (PDC) and high glucose on proliferation, apoptosis of human corneal epithelial cells (HCEC). Methods: The MTT method was used to screen and take the optimal high-glucose concentration, treatment time, and PDC concentration using HCEC and divide it into 4 groups: control group (C), high glucose group (HG), PDC group, and HG + PDC group. We observed and compared the effect of the 4 groups on HCEC proliferation by MTT, apoptosis by Annexin V-FITC/PI double fluorescent staining and flow cytometry (FCM), and expression of bax mRNA and bcl-2 mRNA by RT-qPCR. Results: Compared with the control group, proliferative activity of HCEC cells was reduced; the cells apoptosis ratio was increased; the expression of bax mRNA was increased, and the expression of bcl-2 mRNA was reduced in the HG group. Proliferative activity of HCEC cells in the PDC group was increased, and the expression of bcl-2 mRNA was increased but that of bax mRNA was decreased. Proliferative activity of HCEC cells in the HG + PDC group was increased, but it could not restore to the normal level; the expression of bax mRNA was significantly decreased but the expression of bcl-2 mRNA was significantly increased. Conclusions: Our results demonstrate that high glucose can inhibit proliferative activity and induce apoptosis of HCEC. PDC can improve the proliferative activity of HCEC cells under the high glucose environment and reduce the apoptosis of cells by regulating the expression of bax and bcl-2. PDC play a very important role on protecting and repairing of corneal epithelial cells damage in high glucose. PMID:28796073

[Effects of blueberry on apoptosis and expression of Bcl-2 and Bax in HSC-T6].

PubMed

Lu, Shuang; Cheng, Mingliang; Yang, Demeng; Liu, Yang; Guan, Li; Wu, Jun

2015-08-18

To investigate the effects of blueberry on the apoptosis, expression of Bcl-2 and Bax in rat hepatic stellate cell (HSC-T6). 10% blueberry serum at low, middle and high dose, 10% Fu-Fang-Bie-Jia-Ruan-Gan tablet serum and 10% saline serum were prepared by method of serum pharmacology. Subcultured HSC-T6 was divided into saline serum control group, blueberry serum at low, middle, high dose and Fu-Fang-Bie-Jia-Ruan-Gan tablet serum group, and then was respectively incubated at different dose of 10% blueberry serum, 10% Fu-Fang-Bie-Jia-Ruan-Gan tablet serum and 10% saline serum for 72 hours.Apoptosis of HSC-T6 was detected using flow cytometry with annexin V FITC/PI double staining. The expression of Bcl-2 and Bax in HSC-T6 were examined using immunocytochemistry and Western blotting, respectively. There was no significant difference for HSC-T6 Bax protein expression in the low, middle and high dose blueberry serum groups, compared with saline serum control group, respectively.In the high-dose blueberry serum group HSC-T6 early and total apoptosis rate increased significantly compared with the saline serum control group (5.55% ± 0.98% vs 2.53% ± 0.46%, 7.01% ± 1.05% vs 2.96% ± 0.81%, both P<0.05); Bcl-2 protein expression was significantly decreased (A value, 82 ± 35 vs 51 ± 13, P<0.05); Bcl-2/Bax ratio was significantly decreased (0.26 ± 0.02 vs 0.46 ± 0.03, P<0.05); HSC-T6 early and total apoptosis rate, Bcl-2 expression and Bcl-2/Bax ratio in the low and the middle dose blueberry serum group showed no significant difference with the saline serum control group. Blueberry can induce HSC-T6 apoptosis by down-regulating Bcl-2 expression and decreasing the ratio of Bcl-2/Bax in HSC-T6 cells, so it may have potential interference effects on hepatic fibrosis.

Sex-specific hormone receptors in urothelial carcinomas of the human urinary bladder: a comparative analysis of clinicopathological features and survival outcomes according to receptor expression.

PubMed

Tuygun, Can; Kankaya, Duygu; Imamoglu, Abdurrahim; Sertcelik, Ayse; Zengin, Kursad; Oktay, Murat; Sertcelik, Nurettin

2011-01-01

To investigate the expression of sex-specific hormone receptors in normal bladder urothelium and urothelial carcinomas (UCs) of the bladder, and to analyze clinicopathological features and survival outcomes according to receptor expression. We evaluated the clinical data and tumor specimens of 139 patients with bladder cancer (BC). In addition, 72 samples of normal urothelium were included. Immunohistochemistry was performed using streptavidin-biotin peroxidase method, a monoclonal androgen receptor (AR), and an estrogen receptor-β (ERβ) antibody on paraffin-embedded tissue sections. Expression levels of each receptor were assessed by evaluating 500 tumor cells for each case and the percentage of positively-stained nuclei was recorded. None of the 58 male control cases showed any AR and ERβ expression. Five (35, 71%) of the 14 female control cases expressed ERβ. Of the 139 patients with UCs, 71 (51, 07%) expressed AR (62 male vs. 9 female; P = 0.413) and 44 (31, 65%) (39 male vs. 5 female; P = 0.402) showed ERβ expression (P < 0.001). No significant relationship was found between ERβ expression levels and tumor grades, and stages (P = 0.441; P = 0.247). AR expression was significantly lower in T2-tumors (21%) than in Ta-tumors (60%) and T1-tumors (60%) (P < 0.001). It was significantly higher in low-grade papillary UCs (64%) compared with high-grade papillary UCs (44%) and infiltrative high-grade UCs (17%) (P = 0.039; P < 0.001). Data of 79 patients with noninvasive BC were eligible to present, with a median 29 months follow-up. AR expression level did not influence recurrence-free survival (RFS) and progression-free survival (PFS) (P = 0.095; P = 0.110). No significant association was found between ERβ expression level and RFS (P = 0.293). PFS in patients with lower ERβ-expressing tumors was significantly better than that in patients with higher ERβ-expressing tumors (P = 0.035). Multivariate analysis confirmed this significant influence on PFS (P = 0.025). Although ERβ expression had no impact on histopathological tumor characteristics, decrease in its expression may be associated with better PFS rates in patients with noninvasive BC. Conversely, loss of AR expression was associated with higher grade UCs and invasive UCs, but had no prognostic effect on survival. Finally, sex-specific hormone receptors alone cannot be responsible for gender differences in BC rates because they were expressed in similar rates in both sexes. Copyright © 2011 Elsevier Inc. All rights reserved.

Prognostic significance of Fas and Fas ligand system-associated apoptosis in gastric cancer.

PubMed

Ohno, S; Tachibana, M; Shibakita, M; Dhar, D K; Yoshimura, H; Kinugasa, S; Kubota, H; Masunaga, R; Nagasue, N

2000-12-01

Previous studies indicate that gastric carcinomas express Fas ligand and down-regulate Fas to escape from the host immune attack; however, the prognostic importance of Fas/FasL expression in this tumor is yet to be evaluated. Specimens from 87 gastric carcinoma patients of different stages treated in a defined period with curative intent were evaluated for apoptosis, Fas, FasL, and CD8 expression using an immunohistochemical method. The percentage of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive apoptotic cells expressed as apoptotic index (AI) was higher in 43 patients when the cut-off value was set at the median value. There were no significant correlations between AI and clinicopathologic parameters. Thirty-nine patients showed a high number of CD8+ cells within cancer nests. Positive FasL and Fas expression was seen in 53 and 72 patients, respectively. CD8 and FasL expressions were related only to patients' age. Fas expression had significant correlations with tumor invasion and Lauren classification. There were significant direct correlations between AI and number of nest CD8+ cells and between AI and grade of Fas expression. Apoptotic index, pT stage, CD8 expression, and Fas expression were identified as independent prognostic factors. Spontaneous apoptosis in gastric carcinoma may be an independent prognosticator for survival and is significantly influenced by tumor Fas expression and number of nest CD8 + cells.

High expression of FOXP3 in primary melanoma is associated with tumour progression.

PubMed

Gerber, A L; Münst, A; Schlapbach, C; Shafighi, M; Kiermeir, D; Hüsler, R; Hunger, R E

2014-01-01

The antitumour immune response plays an important role in the prognosis of melanoma. High numbers of circulating regulatory T cells have been associated with rapid disease progression. To assess the influence of forkhead box protein (FOXP)3, CD1a and langerin expression on the prognosis of primary melanoma. We analysed 185 primary melanomas by immunohistochemical staining for expression of the regulatory T-cell marker FOXP3 and the dendritic cell markers langerin and CD1a, and correlated marker expression with clinical outcome. Disease-free survival and overall survival were significantly longer in patients expressing low levels of FOXP3 in the primary melanoma, whereas they were associated with high expression of CD1a. The negative prognostic value of FOXP3 expression was independent of the Breslow tumour thickness. Langerin expression did not correlate with the clinical outcome. High expression of FOXP3 in the primary melanoma may be used as an additional independent prognostic marker for early tumour progression in patients with melanoma. © 2013 British Association of Dermatologists.

High EphA2 protein expression in renal cell carcinoma is associated with a poor disease outcome.

PubMed

Xu, Jinsheng; Zhang, Junxia; Cui, Liwen; Zhang, Huiran; Zhang, Shenglei; Bai, Yaling

2014-08-01

The receptor tyrosine kinase, ephrin type-A receptor 2 (EphA2), is normally expressed at sites of cell-to-cell contact in adult epithelial tissues, however, recent studies have shown that it is also overexpressed in various types of epithelial carcinomas, with the greatest level of EphA2 expression observed in metastatic lesions. In the present study, the association between the expression of EphA2 and the outcome of RCC patients was assessed. The high expression level of EphA2 was identified by log-rank test for a statistically significant prediction of the RCC outcome. In an overall multivariate analysis, the high expression level of EphA2 was identified as an independent predictor of RCC outcome. The length of survival of the patients with high EphA2 expression was shorter than that of the patients with a low level of expression (relative risk, 2.304; 95% CI, 1.102-4.818; P=0.027). The analysis of the expression levels of EphA2 in tumor tissues may aid in the identification of the patient subgroup that are at a high risk of a poor disease outcome.

Maximizing capture of gene co-expression relationships through pre-clustering of input expression samples: an Arabidopsis case study.

PubMed

Feltus, F Alex; Ficklin, Stephen P; Gibson, Scott M; Smith, Melissa C

2013-06-05

In genomics, highly relevant gene interaction (co-expression) networks have been constructed by finding significant pair-wise correlations between genes in expression datasets. These networks are then mined to elucidate biological function at the polygenic level. In some cases networks may be constructed from input samples that measure gene expression under a variety of different conditions, such as for different genotypes, environments, disease states and tissues. When large sets of samples are obtained from public repositories it is often unmanageable to associate samples into condition-specific groups, and combining samples from various conditions has a negative effect on network size. A fixed significance threshold is often applied also limiting the size of the final network. Therefore, we propose pre-clustering of input expression samples to approximate condition-specific grouping of samples and individual network construction of each group as a means for dynamic significance thresholding. The net effect is increase sensitivity thus maximizing the total co-expression relationships in the final co-expression network compendium. A total of 86 Arabidopsis thaliana co-expression networks were constructed after k-means partitioning of 7,105 publicly available ATH1 Affymetrix microarray samples. We term each pre-sorted network a Gene Interaction Layer (GIL). Random Matrix Theory (RMT), an un-supervised thresholding method, was used to threshold each of the 86 networks independently, effectively providing a dynamic (non-global) threshold for the network. The overall gene count across all GILs reached 19,588 genes (94.7% measured gene coverage) and 558,022 unique co-expression relationships. In comparison, network construction without pre-sorting of input samples yielded only 3,297 genes (15.9%) and 129,134 relationships. in the global network. Here we show that pre-clustering of microarray samples helps approximate condition-specific networks and allows for dynamic thresholding using un-supervised methods. Because RMT ensures only highly significant interactions are kept, the GIL compendium consists of 558,022 unique high quality A. thaliana co-expression relationships across almost all of the measurable genes on the ATH1 array. For A. thaliana, these networks represent the largest compendium to date of significant gene co-expression relationships, and are a means to explore complex pathway, polygenic, and pleiotropic relationships for this focal model plant. The networks can be explored at sysbio.genome.clemson.edu. Finally, this method is applicable to any large expression profile collection for any organism and is best suited where a knowledge-independent network construction method is desired.

Maximizing capture of gene co-expression relationships through pre-clustering of input expression samples: an Arabidopsis case study

PubMed Central

2013-01-01

Background In genomics, highly relevant gene interaction (co-expression) networks have been constructed by finding significant pair-wise correlations between genes in expression datasets. These networks are then mined to elucidate biological function at the polygenic level. In some cases networks may be constructed from input samples that measure gene expression under a variety of different conditions, such as for different genotypes, environments, disease states and tissues. When large sets of samples are obtained from public repositories it is often unmanageable to associate samples into condition-specific groups, and combining samples from various conditions has a negative effect on network size. A fixed significance threshold is often applied also limiting the size of the final network. Therefore, we propose pre-clustering of input expression samples to approximate condition-specific grouping of samples and individual network construction of each group as a means for dynamic significance thresholding. The net effect is increase sensitivity thus maximizing the total co-expression relationships in the final co-expression network compendium. Results A total of 86 Arabidopsis thaliana co-expression networks were constructed after k-means partitioning of 7,105 publicly available ATH1 Affymetrix microarray samples. We term each pre-sorted network a Gene Interaction Layer (GIL). Random Matrix Theory (RMT), an un-supervised thresholding method, was used to threshold each of the 86 networks independently, effectively providing a dynamic (non-global) threshold for the network. The overall gene count across all GILs reached 19,588 genes (94.7% measured gene coverage) and 558,022 unique co-expression relationships. In comparison, network construction without pre-sorting of input samples yielded only 3,297 genes (15.9%) and 129,134 relationships. in the global network. Conclusions Here we show that pre-clustering of microarray samples helps approximate condition-specific networks and allows for dynamic thresholding using un-supervised methods. Because RMT ensures only highly significant interactions are kept, the GIL compendium consists of 558,022 unique high quality A. thaliana co-expression relationships across almost all of the measurable genes on the ATH1 array. For A. thaliana, these networks represent the largest compendium to date of significant gene co-expression relationships, and are a means to explore complex pathway, polygenic, and pleiotropic relationships for this focal model plant. The networks can be explored at sysbio.genome.clemson.edu. Finally, this method is applicable to any large expression profile collection for any organism and is best suited where a knowledge-independent network construction method is desired. PMID:23738693

Inhibiting effects of rhynchophylline on methamphetamine-dependent zebrafish are related with the expression of tyrosine hydroxylase (TH).

PubMed

Zhu, Chen; Liu, Wei; Luo, Chaohua; Liu, Yi; Li, Chan; Fang, Miao; Lin, Yingbo; Ou, Jinying; Chen, Minting; Zhu, Daoqi; Yung, Ken Kin-Lam; Mo, Zhixian

2017-03-01

In this study, to study the effect of rhynchophylline on TH in midbrain of methamphetamine-induced conditioned place preference (CPP) adult zebrafish, place preference adult zebrafish models were established by methamphetamine (40μg/g) and the expression of TH was observed by immunohistochemistry technique and Western blot. Ketamine (150μg/g), high dose of rhynchophylline (100μg/g) group can significantly reduce the place preference; immunohistochemistry results showed that the number of TH-positive neurons in midbrain was increased in the methamphetamine model group, whereas less TH-positive neurons were found in the ketamine group and high dosage rhynchophylline group. Western blot results showed that the expression of TH protein was significantly increased in the model group, whereas less expression was found in the ketamine group, high dosage rhynchophylline group. Our data pointed out that TH plays an important role in the formation of methamphetamine-induced place preference in adult zebrafish. Rhynchophylline reversed the expression of TH in the midbrain demonstrates the potential effect of mediates methamphetamine induced rewarding effect. Copyright © 2017 Elsevier B.V. All rights reserved.

EMMPRIN expression in oral squamous cell carcinomas: correlation with tumor proliferation and patient survival.

PubMed

Monteiro, Luís Silva; Delgado, Maria Leonor; Ricardo, Sara; Garcez, Fernanda; do Amaral, Barbas; Pacheco, José Júlio; Lopes, Carlos; Bousbaa, Hassan

2014-01-01

The aim of our study was to explore the clinicopathological and prognostic significance of extracellular matrix metalloproteinase inducer (EMMPRIN) expression in oral squamous cell carcinomas (OSCC), and its relation with the proliferative tumor status of OSCC. We examined EMMPRIN and Ki-67 proteins expression by immunohistochemistry in 74 cases with OSCC. Statistical analysis was conducted to examine their clinicopathological and prognostic significance in OSCC. EMMPRIN membrane expression was observed in all cases, with both membrane and cytoplasmic tumor expression in 61 cases (82.4%). EMMPRIN overexpression was observed in 56 cases (75.7%). Moderately or poorly differentiated tumors showed EMMPRIN overexpression more frequently than well-differentiated tumors (P = 0.002). Overexpression of EMMPRIN was correlated with high Ki-67 expression (P = 0.004). In the multivariate analysis, EMMPRIN overexpression reveals an adverse independent prognostic value for cancer-specific survival (CSS) (P = 0.034). Our results reveal that EMMPRIN protein is overexpressed in more than two-thirds of OSCC cases, especially in high proliferative and less differentiated tumors. The independent value of EMMPRIN overexpression in CSS suggests that this protein could be used as an important biological prognostic marker for patients with OSCC. Moreover, the high expression of EMMPRIN makes it a possible therapeutic target in OSCC patients.

Clinical Significance of SASH1 Expression in Glioma

PubMed Central

Yang, Liu; Zhang, Haitao; Yao, Qi; Yan, Yingying; Wu, Ronghua; Liu, Mei

2015-01-01

Objective. SAM and SH3 domain containing 1 (SASH1) is a recently discovered tumor suppressor gene. The role of SASH1 in glioma has not yet been described. We investigated SASH1 expression in glioma cases to determine its clinical significance on glioma pathogenesis and prognosis. Methods. We produced tissue microarrays using 121 patient-derived glioma samples and 30 patient-derived nontumor cerebral samples. Immunohistochemistry and Western blotting were used to evaluate SASH1 expression. We used Fisher's exact tests to determine relationships between SASH1 expression and clinicopathological characteristics; Cox regression analysis to evaluate the independency of different SASH1 expression; Kaplan-Meier analysis to determine any correlation of SASH1 expression with survival rate. Results. SASH1 expression was closely correlated with the WHO glioma grade. Of the 121 cases, 66.9% with low SASH1 expression were mostly grade III-IV cases, whereas 33.1% with high SASH1 expression were mostly grades I-II. Kaplan-Meier analysis revealed a significant positive correlation between SASH1 expression and postoperative survival. Conclusions. SASH1 was widely expressed in normal and low-grade glioma tissues. SASH1 expression strongly correlated with glioma grades, showing higher expression at a lower grade, which decreased significantly as grade increased. Furthermore, SASH1 expression was positively correlated with better postoperative survival in patients with glioma. PMID:26424902

Elevated expression of Thoc1 is associated with aggressive phenotype and poor prognosis in colorectal cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Chenchen; Yue, Ben; Yuan, Chenwei

The THO complex 1 (Thoc1) is a nuclear matrix protein playing vital roles in transcription elongation and mRNA export. Recently, aberrant expression of Thoc1 has been reported in an increasing array of tumor types. However, the clinical significance of Thoc1 expression in colorectal cancer (CRC) is still unknown. The present study aimed to characterize the expression of Thoc1 in human CRC and evaluate its clinical significance. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting analyses showed that the mRNA and protein expression of Thoc1 in CRC specimens was significantly higher than that in adjacent normal colon mucosae. Immunohistochemistry (IHC)more » was conducted to characterize the expression pattern of Thoc1 in 185 archived paraffin-embedded CRC specimens. Statistical analyses revealed that high levels of Thoc1 expression were associated with the clinical stages and tumor differentiation. CRC patients with high levels of Thoc1 expression had poorer overall-survival and disease-free survival, whereas those with lower levels of Thoc1 expression survived longer. Furthermore, multivariate Cox regression analyses demonstrated that Thoc1 expression remained an independent prognostic factor for increased disease recurrence and decreased survival. Our results suggest for the first time that Thoc1 is involved in the development and progression of CRC, and elevated expression of Thoc1 is associated with aggressive phenotype and poor prognosis in CRC. These findings may prove to be clinically useful for developing a new therapeutic target of CRC treatment.« less

High Expression of P38α and Preoperative Carbohydrate Antigen 19-9 Indicate Poor Prognosis in Patients with Pancreatic Ductal Adenocarcinoma.

PubMed

Chen, Jionghuang; Zhao, Ting; Jia, Shengnan; Zhou, Senhao; Zhou, Liangjing; Wang, Shaowen; Ding, Guoping; Jiang, Guixing; Cao, Liping

2018-01-01

Background: P38α is a ubiquitous protein kinase, which plays diverse roles in cancers. Surprisingly, P38α functions vary markedly in different cancers (e.g., cancer suppressor vs cancer promoter). However, there is no report on the expression of P38α, the family's most important member, in pancreatic ductal adenocarcinoma (PDAC) and its association with clinicoathological parameters and patients' prognosis. Materials and methods: We retrospectively analyzed 152 patients who underwent surgery and were pathologically diagnosed with PDAC from September 2013 to September 2015. We used immunohistochemistry to detect P38α expression in tumor and adjacent normal tissues. The significance of the association between P38α and clinicopathological parameters was evaluated using the χ² test and t tests. The Kaplan-Meier method was used to assess the association between P38α expression and preoperative carbohydrate antigen 19-9 (CA19-9) levels and patients' overall survival. The Cox regression model was used to analyze the association between clinicopathological parameters, P38α and preoperative CA19-9 levels, and prognosis. Statistical significance was defined as P < 0.05. Results: P38α was expressed in 63.16% tumor tissues of PDAC, which was significantly higher compared with the adjacent normal tissues (26.32%, P < 0.001). High expression of P38α was associated with patients' histological grade ( P = 0.013), lymphatic metastasis ( P = 0.025) and TNM stage ( P = 0.048). The median survival time of the P38α-high group was 9.2 months, which was shorter compared with that of the P38α-low group (17.3 months, P = 0.011). The median survival time of the CA19-9 > 43.63 group was 11.1 months shorter than that of the CA19-9 < 43.63 group (24.8 months, P < 0.001). The Cox regression model revealed that age ( P = 0.003), lymphatic invasion ( P = 0.015), TNM stage ( P = 0.003), histological grade ( P < 0.001), preoperative CA19-9 ( P = 0.049), and P38α expression ( P = 0.008) were statistically significant independent risk factors affecting prognosis. Specifically, overall survival was 28.4 months in the P38α-low and CA19-9 < 43.63 groups, 16.3 months in the P38α-high or CA19-9 > 43.63 groups, and 9.7 months in the P38α-high and CA19-9 > 43.63 groups ( P < 0.001). Conclusions: High expression of P38α was significantly associated with histological grade, lymphatic metastasis, TNM stage and prognosis in patients with PDAC. P38α and preoperative CA19-9 levels were independent risk factors affecting the prognosis of PDAC patients. High expression of p38α and preoperative carbohydrate antigen 19-9 indicate poor prognosis in patients with PDAC.

Inverse expression of somatostatin and CXCR4 chemokine receptors in gastroenteropancreatic neuroendocrine neoplasms of different malignancy

PubMed Central

Kaemmerer, Daniel; Träger, Tina; Hoffmeister, Maike; Sipos, Bence; Hommann, Merten; Sänger, Järg; Schulz, Stefan; Lupp, Amelie

2015-01-01

Introduction Somatostatin receptors (SSTR) are widely distributed in well-differentiated neuroendocrine neoplasms (NEN) and serve as primary targets for diagnostics and treatment. An overexpression of the chemokine receptor CXCR4, in contrast, is considered to be present mainly in highly proliferative and advanced tumors. Comparative data are still lacking, however, for neuroendocrine carcinomas (NEC). Methods SSTR subtype (1, 2A, 3, 5) and CXCR4 expression was evaluated in G1 (n = 31), G2 (n = 47), and low (G3a; Ki-67: 21–49%; n = 21) and highly proliferative (G3b; Ki-67: >50%, n = 22) G3 (total n = 43) gastroenteropancreatic NEN samples by performing immunohistochemistry with monoclonal rabbit anti-human anti-SSTR and anti-CXCR4 antibodies, respectively, and was correlated with clinical data. Results Both CXCR4 and SSTR were widely expressed in all tumors investigated. CXCR4 expression differed significantly between the G1 and G3 specimens and within the G3 group (G3a to G3b), and was positively correlated with Ki-67 expression. SSTR2A, in contrast, exhibited an inverse association with Ki-67. SSTR2A was highly expressed in G1 and G2 tumors, but was significantly less abundant in G3 carcinomas. Additionally, SSTR1 expression was higher in G3a than in G3b tumors. Conclusion We observed an elevation in CXCR4 and a decrease in SSTR2A expression with increasing malignancy. Interestingly, 23% of the G3 specimens had strong SSTR2A expression. Because CXCR4 was strongly expressed in highly proliferative G3 carcinomas, it is an interesting new target and needs to be validated in larger studies. PMID:26259237

Progranulin expression in breast cancer with different intrinsic subtypes.

PubMed

Li, Li Qin; Min, Li Shan; Jiang, Qun; Ping, Jin Liang; Li, Jing; Dai, Li Cheng

2012-04-15

Progranulin is a newly discovered 88-kDa glycoprotein originally purified from the highly tumorigenic mouse teratoma-derived cell line PC. We found that high progranulin expression was associated with higher breast carcinoma angiogenesis, reflected by increased vascular endothelial growth factor expression and higher microvessel density. However, no immunohistochemical evidence currently exists to correlate progranulin expression with clinicopathological features in different intrinsic subtypes of breast carcinoma biopsies. The aim of this study was to investigate the progranulin expression profiles in the intrinsic subtypes of breast carcinomas and their relevance to histopathological and clinicopathological features. Tissue blocks containing 264 cases of breast carcinomas from 2006 to 2009 were classified as different intrinsic subtypes. Tissues of four intrinsic subtypes were immunostained for progranulin, vascular endothelial growth factor and CD105. Their relevance to histopathological and clinicopathological features was also analyzed. Twenty tissue samples from breast fibroadenomas were included in this study. Progranulin expression showed no significant differences in different intrinsic subtypes, although an increasing tendency could be found in the triple-negative breast cancer (TNBC) subgroup (χ(2)=5.00, df=3, p=0.17). However, differences were significant when pathologically node metastasis-positive (pN(+)) TNBC were excluded (χ(2)=17.84, df=3, p<0.01). Some clinicopathological parameters, including CK5/6 (χ(2)=0.08, df=3, p=0.78), E-cadherin (χ(2)=0.71, df=3, p=0.40) and P53 (χ(2)=0.05, df=3, p=0.83), displayed no correlation with activity of progranulin in pathologically node metastasis-negative (pN(-)) TNBC. It was noted that the EGFR expression level of the pN(-) TNBC subtype was significantly higher in cases with strong progranulin expression than in cases with weak progranulin expression (χ(2)=11.26, df=1, p<0.01). A significantly higher expression level of progranulin in pN(-) TNBC suggests that progranulin is a promising new target for pN(-) TNBC treatment. Strong expression of progranulin correlates with positive EGFR expression in the pN(-) TNBC subtype. The close relationship between EGFR and progranulin/VEGF/CD105 expression may partly play a role in high angiogenesis levels in the pN(-) TNBC subtype. Copyright © 2012 Elsevier GmbH. All rights reserved.

Expression of Spindle and Kinetochore-Associated Protein 1 Is Associated with Poor Prognosis in Papillary Thyroid Carcinoma

PubMed Central

Dong, Chao; Wang, Xiao-li; Ma, Bin-lin

2015-01-01

Aim. Spindle and kinetochore-associated protein 1 (SKA1) is one subtype of SKA, whose protein can make spindle microtubules attach steadily to the kinetochore in the middle of mitosis. At present, there are fewer researches on the relationship between SKA1 expression and tumor development. Methods. In this study, immunohistochemical analysis was used to determine the expression of SKA1 in papillary thyroid carcinoma (PTC) and adjacent tissues. We used quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis to further verify the results. Results. We found that SKA1 expression was significantly higher in PTC tissues than normal adjacent tissues (P < 0.05). There existed a significant correlation among a higher SKA1 expression, including lymphoid node (P = 0.005), clinical stage (P = 0.015), and extrathyroid invasion (P = 0.004). Survival analysis showed high SKA1 expression in PTC patients more likely to relapse after surgery. Conclusion. High SKA1 expression is predictive of poor prognosis of PTC, implying that SKA1 may be a promising new target for targeted therapies for PTC. PMID:26063960

The diagnostic and prognostic value of SALL4 in hepatoblastoma.

PubMed

Zhou, Shengmei; Venkatramani, Rajkumar; Gomulia, Ellen; Shillingford, Nick; Wang, Larry

2016-11-01

To investigate the expression of spalt-like transcription factor 4 (SALL4), a regulator of embryonal development, in three epithelial components of hepatoblastoma (HB) and the relationship between SALL4 expression levels and patients' clinicopathological features. A total of 115 specimens from 79 patients with HB were selected for immunostaining of SALL4. Nuclear staining was semi-quantified using the immunoreactive score (IS; range: 0-12). SALL4 expression was seen in all embryonal components (mean IS = 8.58) and in 41% of fetal components (mean IS = 0.78). No SALL4 expression was seen in either small cell undifferentiated or mesenchymal components of HB. Neither chemotherapy nor metastasis altered SALL4 expression significantly. High SALL4 expression levels were associated significantly with decreased overall survival (OS) (P = 0.004), event-free survival (EFS) (P = 0.003) and the presence of metastasis (P = 0.049) on univariate analysis. Multivariate analysis identified SALL4 as an independent prognostic predictor for OS (P = 0.029). SALL4 is useful for subtyping HB, and high SALL4 expression is associated with decreased survival in HB. © 2016 John Wiley & Sons Ltd.

Annexin A1: A new immunohistological marker of cholangiocarcinoma

PubMed Central

Hongsrichan, Nuttanan; Rucksaken, Rucksak; Chamgramol, Yaovalux; Pinlaor, Porntip; Techasen, Anchalee; Yongvanit, Puangrat; Khuntikeo, Narong; Pairojkul, Chawalit; Pinlaor, Somchai

2013-01-01

AIM: To evaluate a new immunohistological marker, annexin A1 (ANXA1), in cholangiocarcinoma (CCA) and hepatocellular carcinoma (HCC). METHODS: Expression of ANXA1 protein was investigated in liver tissues from patients with CCA and HCC by immunohistochemistry. Its expression on differences stages of tumor development was investigated in hamster CCA tissues induced by Opisthorchis viverrini and N-nitrosodimethylamine. Moreover, mRNA expression of ANXA1 was assessed in CCA cell lines by quantitative real-time polymerase chain reaction and silencing of ANXA1 gene expression using small interfering RNA. RESULTS: In human CCA tissue arrays, immunohistochemical analysis revealed that the positive expression of ANXA1 was 94.1% (64/68 cases) consisting of a high expression (66.2%, 45/68 cases) and a low expression (33.8%, 23/68 cases). However, expression of ANXA1 protein was negative in all histologic patterns for HCC (46/46 cases) and healthy individuals (6/6 cases). In hamster with opisthorchiasis-associated CCA, the expression of ANXA1 was observed in the cytoplasm of inflammatory cells, bile duct epithelia and tumor cells. Grading scores of ANXA1 expression were significantly increased with tumor progression. In addition, mRNA expression of ANXA1 significantly increased in all of the various CCA cell lines tested compared to an immortalized human cholangiocyte cell line (MMNK1). Suppressing the ANXA1 gene significantly reduced the matrix metalloproteinase (MMP) 2 and MMP9, and transforming growth factor-β genes, but increased nuclear factor-κB gene expression. CONCLUSION: ANXA1 is highly expressed in CCA, but low in HCC, suggesting it may serve as a new immunohistochemical marker of CCA. ANXA1 may play a role in opisthorchiasis-associated cholangiocarcinogenesis. PMID:23674846

Pro-inflammatory and anti-inflammatory cytokine expression in post-treatment apical periodontitis

PubMed Central

Porpino, Mariana Teixeira Maneschy; Antunes, Henrique dos Santos; Rodrigues, Renata Costa Val; Perez, Alejandro Ron; Pires, Fábio Ramôa; Siqueira, José Freitas; Armada, Luciana

2018-01-01

Abstract Objective: This study evaluated the expression of pro-inflammatory (IL-1β, IL-6, IFN-γ and TNF-α) and anti-inflammatory (IL-4 and TGF-β) cytokines in apical periodontitis lesions. Correlations between these cytokines and clinical and cone-beam computed tomographic (CBCT) data were also assessed. Material and Methods: Apical periodontitis lesions’ data were obtained from 27 patients subjected to periradicular surgery. Specimens were processed for histopathologic and immunohistochemical analysis. Sections were evaluated according to the amount of positive staining for each antibody. Expression levels of the target mediators were compared with clinical and CBCT data. Results: Twenty lesions were diagnosed as granuloma and 7 as cyst. In granulomas, IL-4 expression was significantly higher than IL-6 (p=0.001) and TNF-α (p=0.001). There was a significant relationship between high levels of TNF-α and lesions <5 mm (p=0.017). In cysts, IL-6 expression was significant lower than IL-4 (p=0.001) and IFN-γ (p=0.004). There was a significant relationship between high levels of TGF-β and endodontic treatment performed ≤4 years before (p=0.045). In general, IL-4 was the most expressed mediator in both cysts and granulomas. Conclusions: There was a balance between the expression of pro-inflammatory and anti-inflammatory cytokines associated with the chronic periradicular inflammatory process. TNF-α and TGF-β were related to some clinical and CBCT data. PMID:29898177

Clinicopathological significance of SLP-2 overexpression in human gallbladder cancer.

PubMed

Wang, Wei-Xin; Lin, Qing-Feng; Shen, Dong; Liu, Shao-Ping; Mao, Wei-Dong; Ma, Gui; Qi, Wei-Dong

2014-01-01

Several studies have indicated that overexpression of stomatin-like protein 2 (SLP-2) has been identified in several types of cancer. However, its role and clinical relevance in gallbladder cancer (GBC) is unknown. The purpose of this study was to reveal the prognostic significance of SLP-2 in GBC. The SLP-2 expression was examined at mRNA and protein levels by real-time quantitative polymerase chain reaction (qRT-PCR), and immunohistochemistry in GBC tissues and adjacent noncancerous tissues. Statistical analyses were applied to test the associations between SLP-2 expression, clinicopathologic factors, and prognosis. Immunohistochemistry and qRT-PCR showed that the protein and mRNA expression levels of SLP-2 were both significantly higher in GBC tissues than in adjacent noncancerous tissues. In addition, immunohistochemistry analysis showed that SLP-2 expression was significantly correlated with histological grade (P <0.001), pathologic T stage (P = 0.019), clinical stage (P = 0.001), and lymph node metastasis (P = 0.026). The Kaplan-Meier survival curves indicated that patients with high expression of SLP-2 had shorter overall survival than those with low expression (P <0.001). Meanwhile, the Cox multivariate analysis indicated that high expressions of SLP-2 were an independent prognostic factor for patients with GBC. These data showed that SLP-2 may play an important role in human GBC tumorigenesis, and SLP-2 might serve as a novel prognostic marker in human GBC.

Increased expression of Rab coupling protein in squamous cell carcinoma of the head and neck and its clinical significance

PubMed Central

DAI, YAOZHANG; LIU, YONG; HUANG, DONGHAI; YU, CHANGYUN; CAI, GENGMING; PI, LEIMING; REN, CAIPING; CHEN, GEORGIA Z.; TIAN, YONGQUAN; ZHANG, XIN

2012-01-01

The role of Rab coupling protein (RCP) has not been previously investigated in squamous cell carcinoma of the head and neck (SCCHN). The aim of this study was to explore RCP protein expression and its clinicopathological significance in SCCHN. RCP protein expression in 95 SCCHN samples, 18 vocal nodule epithelia and 16 leukoplakia epithelia samples was analyzed by immunohistochemistry and correlated with clinicopathological parameters and patient outcome. Our data indicated that vocal nodule epithelia, leukoplakia epithelia and SCCHN showed a gradual increase in the expression of RCP protein. RCP overexpression was significantly associated with T classification, clinical staging, lymph node metastasis and recurrence. Survival analysis revealed that a high RCP expression was significantly correlated with shorter overall survival and disease-free survival. In conclusion, RCP protein may contribute to the malignant progression of SCCHN, and serves as a novel prognostic marker in patients with SCCHN. PMID:22783424

Increased expression of Rab coupling protein in squamous cell carcinoma of the head and neck and its clinical significance.

PubMed

Dai, Yaozhang; Liu, Yong; Huang, Donghai; Yu, Changyun; Cai, Gengming; Pi, Leiming; Ren, Caiping; Chen, Georgia Z; Tian, Yongquan; Zhang, Xin

2012-06-01

The role of Rab coupling protein (RCP) has not been previously investigated in squamous cell carcinoma of the head and neck (SCCHN). The aim of this study was to explore RCP protein expression and its clinicopathological significance in SCCHN. RCP protein expression in 95 SCCHN samples, 18 vocal nodule epithelia and 16 leukoplakia epithelia samples was analyzed by immunohistochemistry and correlated with clinicopathological parameters and patient outcome. Our data indicated that vocal nodule epithelia, leukoplakia epithelia and SCCHN showed a gradual increase in the expression of RCP protein. RCP overexpression was significantly associated with T classification, clinical staging, lymph node metastasis and recurrence. Survival analysis revealed that a high RCP expression was significantly correlated with shorter overall survival and disease-free survival. In conclusion, RCP protein may contribute to the malignant progression of SCCHN, and serves as a novel prognostic marker in patients with SCCHN.

Cell-cycle and suppressor proteins expression in uterine cervix in HIV/HPV co-infection: comparative study by tissue micro-array (TMA).

PubMed

Nicol, Alcina F; Pires, Andréa Rodrigues Cordovil; de Souza, Simone R; Nuovo, Gerard J; Grinsztejn, Beatriz; Tristão, Aparecida; Russomano, Fabio B; Velasque, Luciane; Lapa e Silva, José R; Pirmez, Claude

2008-10-07

The oncoproteins of human papillomavirus (HPVs) directly effect cell-cycle control. We hypothesize that regulatory and cell cycle protein expression might be additionally modified in the cervix of HIV/HPV co-infected women. We analyzed the expression of Rb, p27, VEGF and Elf-1 transcriptor factor by immunohistochemistry in 163 paraffin-embeded cervical samples using Tissue Micro-Array (TMA) and correlated this to HIV-1 and HPV infection. HIV/HPV co-infection was associated with a significant increase in expression (p < 0.001) of VEGF and p27 in both low and high grade CIN when compared to the cervices of women infected by HPV alone. Decreased Rb expression was evident with increased CIN grade in the cervices of women infected with HPV alone (p = 0.003 average of cells/mm2 in CIN I: 17.9, CIN II/III: 4.8, and tumor 3.9). Rb expression increased 3-fold for both low and high grade CIN with HPV/HIV-1 co-infection compared to HPV infection alone but did not reach statistical significance. There was a significant increase in Elf-1 expression in HPV+/HIV- women with CIN II/III and tumor (average of cells/mm2 in CIN I: 63.8; CIN II/III: 115.7 and tumor: 112.0, p = 0.005), in comparison to controls. Co-infection of HPV and HIV leads to significant increase in the VEGF and p27 expression when compared to HPV+/HIV-negative infection that could facilitate viral persistence and invasive tumor development.

Expression and clinical significance of connective tissue growth factor in thyroid carcinomas.

PubMed

Wang, Guimin; Zhang, Wei; Meng, Wei; Liu, Jia; Wang, Peisong; Lin, Shan; Xu, Liyan; Li, Enmin; Chen, Guang

2013-08-01

To examine expression of the connective tissue growth factor (CTGF) gene in human thyroid cancer and establish whether a correlation exists between the presence of CTGF protein and clinicopathological parameters of the disease. CTGF protein expression was investigated retrospectively by immunohistochemical analysis of CTGF protein levels in thyroid tumour tissue. Associations between immunohistochemical score and several clinicopathological parameters were examined. In total, 131 thyroid tissue specimens were included. High levels of CTGF protein were observed in papillary thyroid carcinoma tissue; benign thyroid tumour tissue scored negatively for CTGF protein. In papillary thyroid carcinoma, there was a significant relationship between high CTGF protein levels and Union for International Cancer Control disease stage III-IV, and presence of lymph node metastasis. In papillary thyroid carcinomas, CTGF protein levels were not significantly associated with sex or age. These findings suggest that the CTGF protein level is increased in papillary thyroid carcinoma cells compared with benign thyroid tumours. CTGF expression might play a role in the development of malignant tumours in the thyroid.

Overexpressing of OsAMT1-3, a High Affinity Ammonium Transporter Gene, Modifies Rice Growth and Carbon-Nitrogen Metabolic Status

PubMed Central

Bao, Aili; Liang, Zhijun; Zhao, Zhuqing; Cai, Hongmei

2015-01-01

AMT1-3 encodes the high affinity NH4+ transporter in rice roots and is predominantly expressed under nitrogen starvation. In order to evaluate the effect of AMT1-3 gene on rice growth, nitrogen absorption and metabolism, we generated AMT1-3-overexpressing plants and analyzed the growth phenotype, yield, carbon and nitrogen metabolic status, and gene expression profiles. Although AMT1-3 mRNA accumulated in transgenic plants, these plants displayed significant decreases in growth when compared to the wild-type plants. The nitrogen uptake assay using a 15N tracer revealed poor nitrogen uptake ability in AMT1-3-overexpressing plants. We found significant decreases in AMT1-3-overexpressing plant leaf carbon and nitrogen content accompanied with a higher leaf C/N ratio. Significant changes in soluble proteins and carbohydrates were also observed in AMT1-3-overexpressing plants. In addition, metabolite profile analysis demonstrated significant changes in individual sugars, organic acids and free amino acids. Gene expression analysis revealed distinct expression patterns of genes that participate in carbon and nitrogen metabolism. Additionally, the correlation between the metabolites and gene expression patterns was consistent in AMT1-3-overexpressing plants under both low and high nitrogen growth conditions. Therefore, we hypothesized that the carbon and nitrogen metabolic imbalance caused by AMT1-3 overexpressing attributed to the poor growth and yield of transgenic plants. PMID:25915023

[Joint effects of water temperature and salinity on the expression of gill Hsp70 gene in Pinctada martensii (Dunker)].

PubMed

Wang, Ya-Nan; Wang, Hui; Zhu, Xiao-Wen; Luo, Ming-Ming; Liu, Zhi-Gang; Du, Xiao-Dong

2012-12-01

By using central composite experimental design and response surface method, the joint effects of water temperature (16-40 degrees C) and salinity (10-50) on the expression of gill Hsp70 gene in Pinctada martensii (Dunker) were studied under laboratory conditions. The results showed that the linear and quadratic effects of temperature on the expression of gill Hsp70 gene were significant, the linear effect of salinity was not significant, while the quadratic effect of salinity was significant. The interactive effect of temperature and salinity was not significant, and the effect of temperature was greater than that of salinity. The model equation of the gill Hsp70 gene expression was established, with the R2, Adj. R2, and Pred. R2 as high as 98.7%, 97.4%, and 89.2%, respectively, suggesting that the overarching predictive capability of the model was very satisfactory, and could be practicably applied for prediction. Through the optimization of the model, the expression of the gill Hsp70 gene reached its minimum (0.5276) when the temperature was 26.78 degrees C and the salinity was 29.33, with the desirability value being 98%. These experimental results could offer theoretical reference for the high expression of gill Hsp70 gene in P. martensii, the maintenance of cell internal environment stability, and the enhancement of P. martensii stress resistance.

The Relationship between RUNX3 Expression, Nursing Strategies and Nutritional Status in Elderly Patients with Advanced Gastric Cancer.

PubMed

Song, Wen; Teng, Wenhui; Shi, Xinyan; Liu, Xiaozhen; Cui, Zheng; Tian, Zibin

2017-06-01

The aim of this study was to explore the relationship between nutritional status and expression of RUNX3 in gastric cancer cells and to investigate the effects of nursing strategies on the nutritional status of elderly patients with advanced gastric cancer. Forty-eight elderly patients admitted at Affiliated Hospital of Qingdao University with advanced gastric cancer and 30 healthy controls were selected as subjects from 2014-15. The correlation between RNX3 gene expression and nutritional status of the gastric cancer patients was investigated. The patients with advanced gastric cancer who had low expression of RUNX3 gene were treated with holistic nursing while routine nursing was taken for those patients who had normal or high expression of RUNX3 gene. The nutritional statuses of these patients were evaluated after 3 months of nursing. After a follow-up of 1 year, the influence of different nursing methods on the survival time was evaluated. Compared with normal gastric tissue, the expression of RUNX3 gene and protein in tissues of advanced gastric cancer were significantly decreased ( P <0.01). Compared with patients with normal or high expressions of RUNX3, the nutritional statuses of advanced gastric cancer patients with low expressions of RUNX3 were lower ( P <0.01). The nutritional statuses of patients with low expressions of RUNX3 were notably improved after holistic nursing, becoming equivalent to those with normal or high expression of RUNX3 who received routine nursing ( P >0.05). The survival time of patients with low expression of RUNX3 who received holistic nursing were similar to patients with normal or high expression of RUNX3 who received routine nursing ( P >0.05). RUNX3 is correlated with the occurrence and development of advanced gastric cancer. The low nutritional status of elderly advanced gastric cancer patients with low expressions of RUNX3 can be significantly enhanced by holistic nursing, thereby prolonging survival time.

Glutathione-s-transferase-pi expression in early breast cancer: association with outcome and response to chemotherapy.

PubMed

Arun, Banu K; Granville, Laura A; Yin, Guosheng; Middleton, Lavinia P; Dawood, Shaheenah; Kau, Shu-Wan; Kamal, Arif; Hsu, Limin; Hortobagyi, Gabriel N; Sahin, Aysegul A

2010-06-01

Glutathione-S-transferase-pi (GST-pi) is a detoxification enzyme expressed in breast cancer; however its involvement in chemotherapy sensitivity and prognosis is not well understood. We evaluated the expression of GSTpi and its predictive role of chemotherapy response. Breast tumor samples from 166 patients at stage I/II of the disease were immunostained for GST-pi, and the expression was 96 %. There was a trend toward improved disease-free survival with high GST-pi expression (p =.09). There was a statistically non-significant association between high GST-pi expression and improved outcome with adjuvant chemotherapy (p =.055). Further studies should evaluate the role of GST-pi expression in relation to response to different chemotherapies.

Targeted taste cell-specific overexpression of brain-derived neurotrophic factor in adult taste buds elevates phosphorylated TrkB protein levels in taste cells, increases taste bud size, and promotes gustatory innervation.

PubMed

Nosrat, Irina V; Margolskee, Robert F; Nosrat, Christopher A

2012-05-11

Brain-derived neurotrophic factor (BDNF) is the most potent neurotrophic factor in the peripheral taste system during embryonic development. It is also expressed in adult taste buds. There is a lack of understanding of the role of BDNF in the adult taste system. To address this, we generated novel transgenic mice in which transgene expression was driven by an α-gustducin promoter coupling BDNF expression to the postnatal expression of gustducin in taste cells. Immunohistochemistry revealed significantly stronger BDNF labeling in taste cells of high BDNF-expressing mouse lines compared with controls. We show that taste buds in these mice are significantly larger and have a larger number of taste cells compared with controls. To examine whether innervation was affected in Gust-BDNF mice, we used antibodies to neural cell adhesion molecule (NCAM) and ATP receptor P2X3. The total density of general innervation and specifically the gustatory innervation was markedly increased in high BDNF-expressing mice compared with controls. TrkB and NCAM gene expression in laser capture microdissected taste epithelia were significantly up-regulated in these mice. Up-regulation of TrkB transcripts in taste buds and elevated taste cell-specific TrkB phosphorylation in response to increased BDNF levels indicate that BDNF controls the expression and activation of its high affinity receptor in taste cells. This demonstrates a direct taste cell function for BDNF. BDNF also orchestrates and maintains taste bud innervation. We propose that the Gust-BDNF transgenic mouse models can be employed to further dissect the specific roles of BDNF in the adult taste system.

Targeted Taste Cell-specific Overexpression of Brain-derived Neurotrophic Factor in Adult Taste Buds Elevates Phosphorylated TrkB Protein Levels in Taste Cells, Increases Taste Bud Size, and Promotes Gustatory Innervation*

PubMed Central

Nosrat, Irina V.; Margolskee, Robert F.; Nosrat, Christopher A.

2012-01-01

Brain-derived neurotrophic factor (BDNF) is the most potent neurotrophic factor in the peripheral taste system during embryonic development. It is also expressed in adult taste buds. There is a lack of understanding of the role of BDNF in the adult taste system. To address this, we generated novel transgenic mice in which transgene expression was driven by an α-gustducin promoter coupling BDNF expression to the postnatal expression of gustducin in taste cells. Immunohistochemistry revealed significantly stronger BDNF labeling in taste cells of high BDNF-expressing mouse lines compared with controls. We show that taste buds in these mice are significantly larger and have a larger number of taste cells compared with controls. To examine whether innervation was affected in Gust-BDNF mice, we used antibodies to neural cell adhesion molecule (NCAM) and ATP receptor P2X3. The total density of general innervation and specifically the gustatory innervation was markedly increased in high BDNF-expressing mice compared with controls. TrkB and NCAM gene expression in laser capture microdissected taste epithelia were significantly up-regulated in these mice. Up-regulation of TrkB transcripts in taste buds and elevated taste cell-specific TrkB phosphorylation in response to increased BDNF levels indicate that BDNF controls the expression and activation of its high affinity receptor in taste cells. This demonstrates a direct taste cell function for BDNF. BDNF also orchestrates and maintains taste bud innervation. We propose that the Gust-BDNF transgenic mouse models can be employed to further dissect the specific roles of BDNF in the adult taste system. PMID:22442142

GRP78 Protein Expression as Prognostic Values in Neoadjuvant Chemoradiotherapy and Laparoscopic Surgery for Locally Advanced Rectal Cancer.

PubMed

Lee, Hee Yeon; Jung, Ji-Han; Cho, Hyun-Min; Kim, Sung Hwan; Lee, Kang-Moon; Kim, Hyung-Jin; Lee, Jong Hoon; Shim, Byoung Yong

2015-10-01

We investigated the relationships between biomarkers related to endoplasmic reticulum stress proteins (glucose-regulated protein of molecular mass 78 [GRP78] and Cripto-1 [teratocarcinoma-derived growth factor 1 protein]), pathologic response, and prognosis in locally advanced rectal cancer. All clinical stage II and III rectal cancer patients received 50.4 Gy over 5.5 weeks, plus 5-fluorouracil (400 mg/m(2)/day) and leucovorin (20 mg/m(2)/day) bolus on days 1 to 5 and 29 to 33, and surgery was performed at 7 to 10 weeks after completion of all therapies. Expression of GRP78 and Cripto-1 proteins was determined by immunohistochemistry and was assessed in 101 patients with rectal cancer treated with neoadjuvant chemoradiotherapy (CRT). High expression of GRP78 and Cripto-1 proteins was observed in 86 patients (85.1%) and 49 patients (48.5%), respectively. Low expression of GRP78 protein was associated with a significantly high rate of down staging (80.0% vs. 52.3%, respectively; p=0.046) and a significantly low rate of recurrence (0% vs. 33.7%, respectively; p=0.008) compared with high expression of GRP78 protein. Mean recurrence-free survival according to GRP78 expression could not be estimated because the low expression group did not develop recurrence events but showed a significant correlation with time to recurrence, based on the log rank method (p=0.007). GRP78 also showed correlation with overall survival, based on the log rank method (p=0.045). GRP78 expression is a predictive and prognostic factor for down staging, recurrence, and survival in rectal cancer patients treated with 5-fluorouracil and leucovorin neoadjuvant CRT.

The prognostic significance of Smad3, Smad4, Smad3 phosphoisoform expression in esophageal squamous cell carcinoma.

PubMed

Cho, Soo Youn; Ha, Sang Yun; Huang, Song-Mei; Kim, Jeong Hoon; Kang, Myung Soo; Yoo, Hae-Yong; Kim, Hyeon-ho; Park, Cheol-Keun; Um, Sung-Hee; Kim, Kyung-Hee; Kim, Seok-Hyung

2014-11-01

Smad3 functions as an integrator of diverse signaling, including transforming growth factor β signaling and the function of Smad3 is complexly regulated by differential phosphorylation at various sites of Smad3. Despite the importance of Smad3 and its various phosphoisoforms, their prognostic significance has rarely been studied. In this study, we demonstrated the prognostic significance of Smad3, its phosphoisoforms, and Smad4 expression by immunohistochemistry in 126 esophageal squamous cell carcinomas. The phosphoisoforms of Smad3 studied in this article included phosphorylation at C-terminal (pSmad3C)(Ser(423/425)) and phosphorylation at the linker region (pSmad3L)(Ser(213)). High expression of Smad3 was associated with shorter overall survival. Co-existence of high expression of pSmad3L(S213) and low expression of pSmad3C(S423/425) were associated with advanced N stage and an independent prognostic factor for overall [hazard ratio (HR) 2.03, 95 % confidence interval (CI) (1.10-3.75), p = 0.023] and disease-free survival [HR 2.41, 95 % CI (1.32-4.39), p = 0.004]. In conclusion, co-existence of high pSmad3L(Ser(213)) expression and low pSmad3C(Ser(423/425)) expression can be considered as immunohistochemical biomarkers for predicting prognosis as well as future therapeutic targets. In addition, our results of combinatory effect of differential phosphorylation of Smad3 on prognosis suggest the mode of action of Smad3 might be logically determined by its phosphorylation pattern.

PAI-1 expression and its regulation by promoter 4G/5G polymorphism in clear cell renal cell carcinoma.

PubMed

Choi, Jung-Woo; Lee, Ju-Han; Park, Hong Seok; Kim, Young-Sik

2011-10-01

To characterise patients with high plasminogen activator inhibitor-1 (PAI-1) expression as oral PAI-1 antagonists are currently in preclinical trials, and to determine whether the PAI-1 promoter 4G/5G polymorphism regulates PAI-1 expression in clear cell renal cell carcinoma (CCRCC). PAI-1 expression was examined by immunohistochemistry in 69 CCRCC specimens. In addition, the promoter 4G/5G polymorphism was investigated by both allele-specific PCR and direct DNA sequencing. PAI-1 was overexpressed in 25/69 (36.2%) patients with CCRCC. PAI-1 staining was intense in tumour cells with a high Fuhrman nuclear grade and in spindle-shaped tumour cells. PAI-1 expression was significantly associated with older age at diagnosis (p=0.027), high nuclear grade (p<0.001), advanced clinical stage (p=0.030) and distant metastasis (p=0.009). In survival analyses, PAI-1 expression was correlated with disease-free survival in Kaplan-Meier curves (p=0.015) but was not significant in the Cox hazards model (p=0.527). The frequencies of the promoter polymorphism were 24.6% (17/69) 4G/4G, 43.5% (30/69) 4G/5G and 31.9% (22/69) 5G/5G. The homozygous 4G/4G or 5G/5G group showed a tendency for a high nuclear grade (p=0.05) but the 4G/5G polymorphism was not related to other prognostic parameters. PAI-1 expression was poorly correlated with its promoter 4G/5G polymorphism (Spearman ρ=0.088). CCRCC with high PAI-1 expression is characterised by older age, high nuclear grade, advanced stage, distant metastasis and/or shortened disease-free survival. PAI-1 expression is not affected by the promoter 4G/5G polymorphism.

Effect of Opuntia humifusa Supplementation and Acute Exercise on Insulin Sensitivity and Associations with PPAR-γ and PGC-1α Protein Expression in Skeletal Muscle of Rats

PubMed Central

Kang, Junyong; Lee, Junghun; Kwon, Daekeun; Song, Youngju

2013-01-01

This study examined whether Opuntia humifusa (O. humifusa), which is a member of the Cactaceae family, supplementation and acute swimming exercise affect insulin sensitivity and associations with PPAR-γ and PGC-1α protein expression in rats. Thirty-two rats were randomly divided into four groups (HS: high fat diet sedentary group, n = 8; HE: high fat diet acute exercise group, n = 8; OS: 5% O. humifusa supplemented high fat diet sedentary group, n = 8; OE: 5% O. humifusa supplemented high fat diet acute exercise group, n = 8). Rats in the HE and OE swam for 120 min. before being sacrificed. Our results indicated that serum glucose level, fasting insulin level and homeostasis model assessment of insulin resistance (HOMA-IR) in OS were significantly lower compared to those of the HS (p < 0.01, p < 0.05, p < 0.05). In addition, PPAR-γ protein expression in the OS and OE was significantly higher than that of the HS and HE, respectively (p < 0.05, p < 0.01). PGC-1α and GLUT-4 protein expressions in the OS were significantly higher compared to those of the HS (p < 0.05, p < 0.05). From these results, O. humifusa supplementation might play an important role for improving insulin sensitivity through elevation of PPAR-γ, PGC-1α, and GLUT-4 protein expression in rat skeletal muscle. PMID:23538842

Clinical significance of erythropoietin receptor expression in oral squamous cell carcinoma

PubMed Central

2012-01-01

Background Hypoxic tumors are refractory to radiation and chemotherapy. High expression of biomarkers related to hypoxia in head and neck cancer is associated with a poorer prognosis. The present study aimed to evaluate the clinicopathological significance of erythropoietin receptor (EPOR) expression in oral squamous cell carcinoma (OSCC). Methods The study included 256 patients who underwent primary surgical resection between October 1996 and August 2005 for treatment of OSCC without previous radiotherapy and/or chemotherapy. Clinicopathological information including gender, age, T classification, N classification, and TNM stage was obtained from clinical records and pathology reports. The mRNA and protein expression levels of EPOR in OSCC specimens were evaluated by Q-RT-PCR, Western blotting and immunohistochemistry assays. Results We found that EPOR were overexpressed in OSCC tissues. The study included 17 women and 239 men with an average age of 50.9 years (range, 26–87 years). The mean follow-up period was 67 months (range, 2–171 months). High EPOR expression was significantly correlated with advanced T classification (p < 0.001), advanced TNM stage (p < 0.001), and positive N classification (p = 0.001). Furthermore, the univariate analysis revealed that patients with high tumor EPOR expression had a lower 5-year overall survival rate (p = 0.0011) and 5-year disease-specific survival rate (p = 0.0017) than patients who had low tumor levels of EPOR. However, the multivariate analysis using Cox’s regression model revealed that only the T and N classifications were independent prognostic factors for the 5-year overall survival and 5-year disease-specific survival rates. Conclusions High EPOR expression in OSCC is associated with an aggressive tumor behavior and poorer prognosis in the univariate analysis among patients with OSCC. Thus, EPOR expression may serve as a treatment target for OSCC in the future. PMID:22639817

A Qualitative Case Study Exploring Best Practices for Accommodating Students with Written Expressive Disorders

ERIC Educational Resources Information Center

Samuels, Cecelia

2013-01-01

A qualitative case study was conducted to explore best practices for accommodating elementary, middle, and high school students with written expressive disorders. Students with disorders of written expression experience significant impairments in writing for their age, intelligence, and educational experience. Accommodations are crucial…

Chemopreventive glucosinolate accumulation in various broccoli and collard tissues: Microfluidic-based targeted transcriptomics for by-product valorization

PubMed Central

Becker, Talon M.; Juvik, John A.

2017-01-01

Floret, leaf, and root tissues were harvested from broccoli and collard cultivars and extracted to determine their glucosinolate and hydrolysis product profiles using high performance liquid chromatography and gas chromotography. Quinone reductase inducing bioactivity, an estimate of anti-cancer chemopreventive potential, of the extracts was measured using a hepa1c1c7 murine cell line. Extracts from root tissues were significantly different from other tissues and contained high levels of gluconasturtiin and glucoerucin. Targeted gene expression analysis on glucosinolate biosynthesis revealed that broccoli root tissue has elevated gene expression of AOP2 and low expression of FMOGS-OX homologs, essentially the opposite of what was observed in broccoli florets, which accumulated high levels of glucoraphanin. Broccoli floret tissue has significantly higher nitrile formation (%) and epithionitrile specifier protein gene expression than other tissues. This study provides basic information of the glucosinolate metabolome and transcriptome for various tissues of Brassica oleracea that maybe utilized as potential byproducts for the nutraceutical market. PMID:28945821

Chemopreventive glucosinolate accumulation in various broccoli and collard tissues: Microfluidic-based targeted transcriptomics for by-product valorization.

PubMed

Lee, Young-Sang; Ku, Kang-Mo; Becker, Talon M; Juvik, John A

2017-01-01

Floret, leaf, and root tissues were harvested from broccoli and collard cultivars and extracted to determine their glucosinolate and hydrolysis product profiles using high performance liquid chromatography and gas chromotography. Quinone reductase inducing bioactivity, an estimate of anti-cancer chemopreventive potential, of the extracts was measured using a hepa1c1c7 murine cell line. Extracts from root tissues were significantly different from other tissues and contained high levels of gluconasturtiin and glucoerucin. Targeted gene expression analysis on glucosinolate biosynthesis revealed that broccoli root tissue has elevated gene expression of AOP2 and low expression of FMOGS-OX homologs, essentially the opposite of what was observed in broccoli florets, which accumulated high levels of glucoraphanin. Broccoli floret tissue has significantly higher nitrile formation (%) and epithionitrile specifier protein gene expression than other tissues. This study provides basic information of the glucosinolate metabolome and transcriptome for various tissues of Brassica oleracea that maybe utilized as potential byproducts for the nutraceutical market.

Energy balance and hypothalamic effects of a high-protein/low-carbohydrate diet.

PubMed

Kinzig, Kimberly P; Hargrave, Sara L; Hyun, Jayson; Moran, Timothy H

2007-10-22

Diets high in fat or protein and extremely low in carbohydrate are frequently reported to result in weight loss in humans. We previously reported that rats maintained on a low-carbohydrate-high fat diet (LC-HF) consumed similar kcals/day as chow (CH)-fed rats and did not differ in body weight after 7 weeks. LC-HF rats had a 45% decrease in POMC expression in the ARC, decreased plasma insulin, and increased plasma leptin and ghrelin. In the present study we assessed the effects of a low-carbohydrate-high-protein diet (HP: 30% fat, 65% protein, and 5% CHO) on body weight, caloric intake, plasma hormone levels and hypothalamic gene expression. Male rats (n=16) were maintained on CH or HP for 4 weeks. HP rats gained significantly less weight than CH rats (73.4+/-9.4 and 125.0+/-8.2 g) and consumed significantly less kcals/day (94.8+/-1.5 and 123.6+/-1.1). Insulin was significantly reduced in HP rats (HP: 1.8+/-0.6 vs. CH: 4.12+/-0.8 ng/ml), there were no differences between groups in plasma leptin and plasma ghrelin was significantly elevated in HP rats (HP: 127.5+/-45 vs. CH: 76.9+/-8 pg/ml). Maintenance on HP resulted in significantly increased ARC POMC (HP: 121+/-10.0 vs. 100+/-5.9) and DMH NPY (HP: 297+/-82.1 vs. CH: 100+/-37.7) expression compared to CH controls. These data suggest that the macronutrient content of diets differentially influences hypothalamic gene expression in ways that can affect overall intake.

Emotional intelligence, trauma severity, and emotional expression.

PubMed

Kao, Min C; Chen, Yung Y

2016-07-01

This study investigated Emotional Intelligence (EI) as a moderator for the association between emotional expression and adaptive trauma processing, as measured by depressive symptoms. Using Pennebaker's written emotional expression paradigm, 105 participants were assigned to either a conventional trauma-writing or religious trauma-writing condition. Depressive symptoms were assessed at baseline and again at one-month post writing. No significant association between EI and religiousness was found at baseline. Results indicated a three-way interaction among EI, trauma severity, and writing condition on depressive symptoms at follow-up. For the religious trauma-writing condition only, there was a significant difference between high- versus low-EI participants who experienced more severe trauma in depressive symptoms at follow-up, such that low-EI participants registered less depressive symptoms than high-EI participants; while there was no significant difference between low versus high EI for participants with less severe trauma. These findings encourage further investigation of the conditions under which religion may be a beneficial factor in trauma adaptation.

Properties and Expression of Na+/K+-ATPase α-Subunit Isoforms in the Brain of the Swamp Eel, Monopterus albus, Which Has Unusually High Brain Ammonia Tolerance

PubMed Central

Chen, Xiu L.; Wee, Nicklaus L. J. E.; Hiong, Kum C.; Ong, Jasmine L. Y.; Chng, You R.; Ching, Biyun; Wong, Wai P.; Chew, Shit F.; Ip, Yuen K.

2013-01-01

The swamp eel, Monopterus albus, can survive in high concentrations of ammonia (>75 mmol l−1) and accumulate ammonia to high concentrations in its brain (∼4.5 µmol g−1). Na+/K+-ATPase (Nka) is an essential transporter in brain cells, and since NH4 + can substitute for K+ to activate Nka, we hypothesized that the brain of M. albus expressed multiple forms of Nka α-subunits, some of which might have high K+ specificity. Thus, this study aimed to clone and sequence the nka α-subunits from the brain of M. albus, and to determine the effects of ammonia exposure on their mRNA expression and overall protein abundance. The effectiveness of NH4 + to activate brain Nka from M. albus and Mus musculus was also examined by comparing their Na+/K+-ATPase and Na+/NH4 +-ATPase activities over a range of K+/NH4 + concentrations. The full length cDNA coding sequences of three nkaα (nkaα1, nkaα3a and nkaα3b) were identified in the brain of M. albus, but nkaα2 expression was undetectable. Exposure to 50 mmol l−1 NH4Cl for 1 day or 6 days resulted in significant decreases in the mRNA expression of nkaα1, nkaα3a and nkaα3b. The overall Nka protein abundance also decreased significantly after 6 days of ammonia exposure. For M. albus, brain Na+/NH4 +-ATPase activities were significantly lower than the Na+/K+-ATPase activities assayed at various NH4 +/K+ concentrations. Furthermore, the effectiveness of NH4 + to activate Nka from the brain of M. albus was significantly lower than that from the brain of M. musculus, which is ammonia-sensitive. Hence, the (1) lack of nkaα2 expression, (2) high K+ specificity of K+ binding sites of Nkaα1, Nkaα3a and Nkaα3b, and (3) down-regulation of mRNA expression of all three nkaα isoforms and the overall Nka protein abundance in response to ammonia exposure might be some of the contributing factors to the high brain ammonia tolerance in M. albus. PMID:24391932

FOXP3, CBLB and ITCH gene expression and cytotoxic T lymphocyte antigen 4 expression on CD4+CD25high T cells in multiple sclerosis

PubMed Central

Sellebjerg, F; Krakauer, M; Khademi, M; Olsson, T; Sørensen, P S

2012-01-01

Expression of the forkhead box protein 3 (FoxP3) transcription factor is regulated by the E3 ubiquitin ligases Itch and Cbl-b and induces regulatory activity CD4+CD25high T cells. Treatment with interferon (IFN)-β enhances regulatory T cell activity in multiple sclerosis (MS). We studied the phenotype of CD4+CD25high T cells in MS by flow cytometry and its relationship with expression of the FOXP3, ITCH and CBLB genes. We found that untreated MS patients had lower cell surface expression of cytotoxic T lymphocyte antigen 4 (CTLA-4) on CD4+CD25high T cells and higher intracellular CTLA-4 expression than healthy controls. Cell surface expression of CTLA-4 on CD4+CD25high T cells correlated with expression of FOXP3 mRNA in untreated patients and increased significantly with time from most recent injection in patients treated with IFN-β. FOXP3 mRNA expression correlated with CBLB and ITCH and T helper type 2 cytokine mRNA expression in MS patients. These data link expression of FOXP3, CBLB and ITCH mRNA and CTLA-4 expression on the surface of CD4+CD25high T cell in MS. We hypothesize that this may reflect alterations in the inhibitory effect of CTLA-4 or in regulatory T cell function. PMID:23039885

High expression of DNA methyltransferases in primary human medulloblastoma.

PubMed

Pócza, T; Krenács, T; Turányi, E; Csáthy, J; Jakab, Z; Hauser, P

2016-01-01

Epigenetic alterations have been implicated in cancer development. DNA methylation modulates gene expression, which is catalyzed by DNA methyltransferases (DNMTs). The objective of our study was to evaluate expression of DNMTs in medulloblastoma and analyze its correlation with clinical features. Nuclear expression of DNMT1, DNMT3A and DNMT3B was analyzed in human primary medulloblastoma of 44 patients using immunohistochemistry. Correlation of expression of DNMT levels with classical histological subtypes, novel molecular subgroups and survival of patients was analyzed. Elevated expression of DNMT1, DNMT3A and DNMT3B was observed in 63.64%, 68.18% and 72.73% of all cases, respectively. None of them showed a correlation with classical histology or survival. Concerning molecular subtypes, significantly higher expression of DNMT1 was observed in the SHH group compared to non-SHH samples (p = 0.02), but without significant difference in DNMT3A or DNMT3B levels between any subtypes. In conclusion, DNMT1, DNMT3A and DNMT3B are highly expressed in human medulloblastoma samples, suggesting that promoter hypermethylation may play a role in medulloblastoma development. Demethylation of tumor suppressor gene promoters may be considered as a possible future target in therapy of medulloblastoma.

[Expression of SRD5A1 and its prognostic role in prostate cancer: Analysis based on the data-mining of ONCOMINE].

PubMed

Xu, Bin; Liu, Ning; Chen, Shu-Qiu; Jiang, Hua; Zhang, Li-Jie; Zhang, Xiao-Wen; Yang, Yu; Sha, Guo-Zhu; Liu, Jing; Zhu, Wei-Dong; Chen, Ming

2016-09-01

To explore the expression of I-5α-reductase (SRD5A1)and its prognostic role in prostate cancer . Data about SRD5A1 were retrieved from the ONCOMINE database and the role of SRD5A1 in prostate cancer was analyzed. Totally, 992 studies of different types relevant to the expression of SRD5A1 were identified in the ONCOMINE database. The SRD5A1 expression was statistically significant in 239 of the studies, overexpressed in 157 (11 in prostate cancer) and underexpressed in the other 82 (3 in prostate cancer). Eighteen of the studies, with 1 068 samples, addressed the expression of SRD5A1 in prostate cancer and normal tissues, which was significantly higher in the former than in the latter tissue (P<0.05). In 3 of the studies, the SRD5A1 expression was high in primary prostate cancer and increased with its metastasis (P<0.0 5). Two of the studies with prognostic data showed a higher rate of postoperative biochemical recurrence and a higher total mortality rate in the patients with a high than in those with a low expression of SRD5A1 (P<0.05). SRD5A1 is highly expressed in prostate cancer, especially in metastatic and castration-resistant prostate cancer and its expression is associated with the prognosis of prostate cancer, which may be an important target of medication for prostate cancer.

Methyl-methanesulfonate sensitivity 19 expression is associated with metastasis and chemoradiotherapy response in esophageal cancer

PubMed Central

Zhang, Jin-Liang; Wang, Hui-Yun; Yang, Qing; Lin, Shi-Yong; Luo, Guang-Yu; Zhang, Rong; Xu, Guo-Liang

2015-01-01

AIM: To investigate the clinical significance of methyl-methanesulfonate sensitivity 19 (MMS19) expression in esophageal squamous cell carcinoma (ESCC). METHODS: Between June 2008 and May 2013, specimens from 103 patients who underwent endoscopic biopsy for the diagnosis of ESCC at the endoscopy center of Sun Yat-Sen University Cancer Center were collected; 52 matched-normal esophageal squamous epithelium samples were biopsied as controls. MMS19 protein expression was measured by immunohistochemistry. Of the 103 cases of ESCC, 49 received radical surgery following neoadjuvant chemoradiotherapy consisting of concurrent radiation in a total dose of 40 Gy and two cycles of chemotherapy with vinorelbine and cisplatin. Relationships between MMS19 expression, clinicopathologic characteristics and chemoradiotherapy response were analyzed. RESULTS: The MMS19 protein could be detected in both the cytoplasm and nucleus of most specimens. High cytoplasmic expression of MMS19 was detected in 63.1% of ESCC samples, whereas high nuclear expression of MMS19 was found in 35.0%. High cytoplasmic MMS19 expression was associated with regional lymph node metastases (OR = 11.3, 95%CI: 2.3-54.7; P < 0.001) and distant metastases (OR = 13.1, 95%CI: 1.7-103.0; P = 0.002). Furthermore, high cytoplasmic MMS19 expression was associated with a response of ESCC to chemoradiotherapy (OR = 11.5, 95%CI: 3.0-44.5; P < 0.001), with a high cytoplasmic MMS19 expression rates in 79.3% and 25.0% of patients from the good chemoradiotherapy response group and poor response group, respectively. Nuclear MMS19 expression did not show any significant association with clinicopathologic characteristics or chemoradiotherapy response in ESCC. CONCLUSION: The results of our preliminary study suggest that MMS19 may be a potential new predictor of metastasis and chemoradiotherapy response in ESCC. PMID:25892874

High-Risk HPV, Biomarkers, and Outcome in Matched Cohorts of Head and Neck Cancer Patients Positive and Negative for HIV.

PubMed

Walline, Heather M; Carey, Thomas E; Goudsmit, Christine M; Bellile, Emily L; D'Souza, Gypsyamber; Peterson, Lisa A; McHugh, Jonathan B; Pai, Sara I; Lee, J Jack; Shin, Dong M; Ferris, Robert L

2017-02-01

In this study, high-risk HPV (hrHPV) incidence, prognostic biomarkers, and outcome were assessed in HIV-positive (case) and HIV-negative (control) patients with head and neck squamous cell cancer (HNSCC). HIV-positive cases were matched to controls by tumor site, sex, and age at cancer diagnosis. A tissue microarray (TMA) was constructed and DNA isolated from tumor tissue. MultiPlex-PCR MassArray, L1-PCR, and in situ hybridization were used to assess hrHPV. TMA sections were stained for p16ink4a, TP53, RB, CCND1, EGFR, and scored for intensity and proportion of positive tumor cells. The HNSCC cohort included 41 HIV-positive cases and 41 HIV-negative controls. Tumors from 11 of 40 (28%) cases, and 10 of 41 (24%) controls contained hrHPV. p16 expression, indicative of E7 oncogene activity, was present in 10 of 11 HPV-positive cases and 7 of 10 HPV-positive controls. Low p16 and high TP53 expression in some HPV-positive tumors suggested HPV-independent tumorigenesis. Survival did not differ in cases and controls. RB expression was significantly associated with poor survival (P = 0.01). High TP53 expression exhibited a trend for poorer survival (P = 0.12), but among cases, association with poor survival reached statistical significance (P = 0.04). The proportion of HPV-positive tumors was similar, but the heterogeneity of HPV types was higher in the HIV-positive cases than in HIV-negative controls. High RB expression predicted poor survival, and high TP53 expression was associated with poorer survival in the HIV-positive cases but not HIV-negative controls. HIV infection did not increase risk of death from HNSCC, and HPV-positive tumors continued to be associated with a significantly improved survival, independent of HIV status. Mol Cancer Res; 15(2); 179-88. ©2016 AACR. ©2016 American Association for Cancer Research.

Genome-wide DNA methylation profiling integrated with gene expression profiling identifies PAX9 as a novel prognostic marker in chronic lymphocytic leukemia.

PubMed

Rani, Lata; Mathur, Nitin; Gupta, Ritu; Gogia, Ajay; Kaur, Gurvinder; Dhanjal, Jaspreet Kaur; Sundar, Durai; Kumar, Lalit; Sharma, Atul

2017-01-01

In chronic lymphocytic leukemia (CLL), epigenomic and genomic studies have expanded the existing knowledge about the disease biology and led to the identification of potential biomarkers relevant for implementation of personalized medicine. In this study, an attempt has been made to examine and integrate the global DNA methylation changes with gene expression profile and their impact on clinical outcome in early stage CLL patients. The integration of DNA methylation profile ( n  = 14) with the gene expression profile ( n  = 21) revealed 142 genes as hypermethylated-downregulated and; 62 genes as hypomethylated-upregulated in early stage CLL patients compared to CD19+ B-cells from healthy individuals. The mRNA expression levels of 17 genes identified to be differentially methylated and/or differentially expressed was further examined in early stage CLL patients ( n  = 93) by quantitative real time PCR (RQ-PCR). Significant differences were observed in the mRNA expression of MEIS1 , PMEPA1 , SOX7 , SPRY1 , CDK6 , TBX2 , and SPRY2 genes in CLL cells as compared to B-cells from healthy individuals. The analysis in the IGHV mutation based categories (Unmutated = 39, Mutated = 54) revealed significantly higher mRNA expression of CRY1 and PAX9 genes in the IGHV unmutated subgroup ( p  < 0.001). The relative risk of treatment initiation was significantly higher among patients with high expression of CRY1 (RR = 1.91, p  = 0.005) or PAX9 (RR = 1.87, p  = 0.001). High expression of CRY1 (HR: 3.53, p  < 0.001) or PAX9 (HR: 3.14, p  < 0.001) gene was significantly associated with shorter time to first treatment. The high expression of PAX9 gene (HR: 3.29, 95% CI 1.172-9.272, p  = 0.016) was also predictive of shorter overall survival in CLL. The DNA methylation changes associated with mRNA expression of CRY1 and PAX9 genes allow risk stratification of early stage CLL patients. This comprehensive analysis supports the concept that the epigenetic changes along with the altered expression of genes have the potential to predict clinical outcome in early stage CLL patients.

[Expression of ATAD2 in different liver lesions and its clinical significance].

PubMed

Liu, F; Zhou, X; Ji, H H; Li, H; Xiang, F G

2017-05-20

Objective: To examine the expression of ATAD2 in different liver lesions and its clinical significance. Methods: ATAD2 expression in 60 hepatocellular carcinoma (HCC) surgical specimens (49 of which have concurrent liver cirrhosis), 43 HCC biopsy specimens, 2 high-grade liver dysplastic nodule specimens, 3 low-grade liver dysplastic nodule specimens, 50 liver cirrhosis tissue samples, and 20 normal liver tissue samples were measured using immunohistochemistry. The F-test, q-test, t-test, and chi-square test were used for statistical analysis of data. Results: ATAD2 was expressed in 56 HCC surgical specimens (93.33%), 35 HCC biopsy specimens (81.40%), and 2 high-grade liver dysplastic nodule specimens (2/2), but not in the low-grade liver dysplastic nodule, liver cirrhosis tissue, and normal liver tissue samples. The mean expression of ATAD2 was significantly higher in HCC tissues than in high-grade and low-grade liver dysplastic nodule tissues, liver cirrhosis tissue, and normal liver tissue ( F = 22.96, q = 3.138, 3.972, 12.272, and 9.101, respectively, all P < 0.01). There were no significant differences in the mean expression and positive expression rate of ATAD2 between HCC surgical and biopsy specimens ( t = 1.40, P > 0.05; χ ² = 3.47, P >0.05). Of the 35 HCC biopsy specimens that expressed ATAD2, the mean ATAD2 expression was ≥1% in 35 specimens (100%), ≥3% in 27 specimens (77.14%), and ≥5 % in 23 specimens (65.71%). In addition, among the pathological grade I-II HCC biopsy specimens, the mean ATAD2 expression was ≥1% in 28 specimens (100%), ≥3% in 22 specimens (62.86%), and ≥5% in 19 specimens (54.29%). Moreover, ATAD2 expression in HCC was associated with serum alpha-fetoprotein level, presence of hepatitis B virus surface antigen (HBsAg), and presence of concurrent liver cirrhosis ( t = 2.09, 2.30, and 2.18, respectively, all P < 0.05). Conclusion: ATAD2 may play an important role in HCC tumorigenesis, and may be involved in malignant transformation of cells. ATAD2 expression can be a valuable marker for differentiating the nature of lesions in liver biopsy tissues during clinical practice.

[Effect of repeated fasting/refeeding on body weight control and energy balance regulation in rats].

PubMed

Wu, Bo; Du, Youai; Liu, Chongbin; Du, Zhou; Xiao, Min; Lu, Bo

2010-09-01

To investigate the changes of expression on leptin, a series of neuroendocrine factors and hormones associated with body weight control and energy balance regulation of rats, which were treated with repeated fasting/refeeding and followed by fed with high fat diet. Designing a repeated fasting/refeeding rats model (RFR) fed with basic stock diet on repeated cycles of 1 d fasting and 1 d refeeding for 6 weeks. The rats in RFR-LF/ HF group were switched to a high fat diet and fed the diet every day for another 6 weeks. The control rats were randomly divided into 3 groups, control group, high-fat diet (HF) group and common fat diet (CF) group. The rats in HF and CF group were killed by the end of the 12th week. The body weight, Lee's index, body fat content and serum lipid, GH, T4, leptin, insulin, and plasma ACTH levels were measured. The expression of NPY and POMC mRNA in hypothalamus were detected by reverse transcription chain reaction (RT-PCR). The Lee's index, body fat content, serum TC, TG, LDL, leptin and insulin levels of RFR-LF/HF group were lower significantly than those of HF group whereas higher significantly than those of CF group. The expression of NPY mRNA of RFR-LF/HF group were higher significantly than those of HF and CF groups, while the expression of POMC mRNA was lower significantly than that of HF and CF groups. The feeding pattern of repeated fasting/refeeding can decrease the degree of obesity induced by high fat diet, and also reduce the leptin and insulin resistance, but cause serious disturbance of the expression of neuroendocrine peptides in the central nervous system of rat.

Increased expression of interleukin-23 associated with progression of colorectal cancer.

PubMed

Hu, Wan-Hsiang; Chen, Hong-Hwa; Yen, Shao-Lun; Huang, Hsuan-Ying; Hsiao, Chang-Chun; Chuang, Jiin-Haur

2017-02-01

The prognostic significance of interleukin-23 in colorectal cancer remains unclear. We designed this study to investigate the association between colorectal cancer and interleukin-23 (IL-23) or interleukin-23 receptor (IL-23R) expression and the resulting clinical features and survival. Immunohistochemical staining was performed for IL-23 and IL-23R in colorectal cancer samples. H-score was calculated to compare the expression of IL-23 and IL-23R. The median of H-score was used as the cut-off value to separate patients into high or low expression groups. The differences in clinicopathological features were evaluated. Cox regression hazard ratios were used for survival analysis. A total of 129 colorectal cancer patients were enrolled. H-score for the late TNM stage patients was higher than that for the early TNM stage patients (P = 0.002). Patients with high IL-23 expression were associated with advanced pathological T category (P < 0.001) and late TNM stage (P = 0.003). High IL-23 expression was associated with poor 5-year disease-free survival and overall survival in patients (P = 0.048 and P = 0.028, respectively). Multivariate adjustment demonstrated a significant association between high IL-23 expression and overall survival (hazard ratio = 1.865, P = 0.041). Elevated IL-23 expression was associated with poor outcome and can be used as a prognostic biomarker for colorectal cancer. J. Surg. Oncol. 2017;115:208-212. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

RUNX1 and RUNX3 protect against YAP-mediated EMT, stem-ness and shorter survival outcomes in breast cancer

PubMed Central

Kulkarni, Madhura; Tan, Tuan Zea; Syed Sulaiman, Nurfarhanah Bte; Lamar, John M.; Bansal, Prashali; Cui, Jianzhou; Qiao, Yiting; Ito, Yoshiaki

2018-01-01

Hippo pathway target, YAP has emerged as an important player in solid tumor progression. Here, we identify RUNX1 and RUNX3 as novel negative regulators of oncogenic function of YAP in the context of breast cancer. RUNX proteins are one of the first transcription factors identified to interact with YAP. RUNX1 or RUNX3 expression abrogates YAP-mediated pro-tumorigenic properties of mammary epithelial cell lines in an interaction dependent manner. RUNX1 and RUNX3 inhibit YAP-mediated migration and stem-ness properties of mammary epithelial cell lines by co-regulating YAP-mediated gene expression. Analysis of whole genome expression profiles of breast cancer samples revealed significant co-relation between YAP–RUNX1/RUNX3 expression levels and survival outcomes of breast cancer patients. High RUNX1/RUNX3 expression proved protective towards YAP-dependent patient survival outcomes. High YAP in breast cancer patients’ expression profiles co-related with EMT and stem-ness gene signature enrichment. High RUNX1/RUNX3 expression along with high YAP reflected lower enrichment of EMT and stem-ness signatures. This antagonistic activity of RUNX1 and RUNX3 towards oncogenic function of YAP identified in mammary epithelial cells as well as in breast cancer expression profiles gives a novel mechanistic insight into oncogene–tumor suppressor interplay in the context of breast cancer progression. The novel interplay between YAP, RUNX1 and RUNX3 and its significance in breast cancer progression can serve as a prognostic tool to predict cancer recurrence. PMID:29581836

Surface Expression of Hsp25 and Hsp72 Differentially Regulates Tumor Growth and Metastasis

PubMed Central

Bausero, María A.; Page, Diana T.; Osinaga, Eduardo; Asea, Alexzander

2006-01-01

The expression of unique surface structures on tumors that allow for recognition and activation of host immunocompetent cells plays an important role in determining tumor growth and/or metastasis. Recent studies have identified an important role for heat shock proteins (Hsp) in antitumor surveillance; however, the exact role of Hsp expressed on the surface of tumors has not been fully addressed. In this study, we show that 4T1 mammary adenocarcinoma cells sorted for high Hsp25 surface expression (Hsp25high) grow significantly faster than cells sorted for intermediate Hsp25 surface expression (Hsp25intermediate) or wild-type 4T1 cells implanted into the abdominal breast gland of female BALB/c mice (p < 0.05). In addition, histological examination of lung tissues revealed that Hsp25high 4T1 cells metastasized to the lungs more aggressively than either Hsp25intermediate or wild-type 4T1 cells (p < 0.05). Exposure of 4T1 cells to nonlethal heat shock (43°C, 30 min) induced the surface expression of Hsp72 and a concomitant reduction in Hsp25 surface expression. The growth and metastastic potential of Hsp72+ 4T1 cells was significantly less than that of Hsp25high, Hsp25intermediate or wild-type 4T1 cells (p < 0.05). Taken together, these studies identify an important role for expression of Hsp25 and Hsp72 during tumor growth and metastatic spread which might be helpful in the design of antimetastatic therapies. PMID:15627887

Surface expression of Hsp25 and Hsp72 differentially regulates tumor growth and metastasis.

PubMed

Bausero, María A; Page, Diana T; Osinaga, Eduardo; Asea, Alexzander

2004-01-01

The expression of unique surface structures on tumors that allow for recognition and activation of host immunocompetent cells plays an important role in determining tumor growth and/or metastasis. Recent studies have identified an important role for heat shock proteins (Hsp) in antitumor surveillance; however, the exact role of Hsp expressed on the surface of tumors has not been fully addressed. In this study, we show that 4T1 mammary adenocarcinoma cells sorted for high Hsp25 surface expression (Hsp25(high)) grow significantly faster than cells sorted for intermediate Hsp25 surface expression (Hsp25(intermediate)) or wild-type 4T1 cells implanted into the abdominal breast gland of female BALB/c mice (p < 0.05). In addition, histological examination of lung tissues revealed that Hsp25(high) 4T1 cells metastasized to the lungs more aggressively than either Hsp25(intermediate) or wild-type 4T1 cells (p < 0.05). Exposure of 4T1 cells to nonlethal heat shock (43 degrees C, 30 min) induced the surface expression of Hsp72 and a concomitant reduction in Hsp25 surface expression. The growth and metastastic potential of Hsp72(+) 4T1 cells was significantly less than that of Hsp25(high), Hsp25(intermediate) or wild-type 4T1 cells (p < 0.05). Taken together, these studies identify an important role for expression of Hsp25 and Hsp72 during tumor growth and metastatic spread which might be helpful in the design of antimetastatic therapies. Copyright 2004 S. Karger AG, Basel.

Expression of Zinc Finger and BTB Domain-containing 7A in Colorectal Carcinoma.

PubMed

Joo, Jin Woo; Kim, Hyun-Soo; Do, Sung-Im; Sung, Ji-Youn

2018-05-01

Previous studies have revealed that zinc finger and BTB domain-containing 7A (ZBTB7A), an important proto-oncogene, plays multiple roles in carcinogenesis and is up-regulated in several human malignancies. However, the expression of ZBTB7A in colorectal carcinoma (CRC) has seldom been documented. In this study, we investigated the differential expression of ZBTB7A in CRC cell lines and tissues. Expression levels of ZBTB7A mRNA and protein were examined in CRC cell lines. ZBTB7A protein expression was also evaluated in tissue samples of normal colonic mucosa, high-grade dysplasia, and CRC using immunohistochemical staining. All CRC cell lines exhibited significantly higher ZBTB7A mRNA expression levels than did normal colonic epithelial cells. The ZBTB7A protein expression levels were clearly higher in the CRC cell lines than in the normal colonic epithelial cells. Consistent with the cell line data, immunostaining revealed that there were significant differences in ZBTB7A protein expression between tissue samples of CRC and normal colonic mucosa (p=0.048) and high-grade dysplasia (p=0.015). In addition, metastatic CRC exhibited significantly higher ZBTB7A protein expression levels than primary CRC (p=0.027). We demonstrated that ZBTB7A expression is up-regulated in CRC cell lines and tissues. Our data suggest that ZBTB7A is involved in the development and progression of CRC. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Immunohistochemical detection of HIF-1alpha and CAIX in advanced head-and-neck cancer. Prognostic role and correlation with tumor markers and tumor oxygenation parameters.

PubMed

Kappler, Matthias; Taubert, Helge; Holzhausen, Hans-Jürgen; Reddemann, Rolf; Rot, Swetlann; Becker, Axel; Kuhnt, Thomas; Dellas, Kathrin; Dunst, Jürgen; Vordermark, Dirk; Hänsgen, Gabriele; Bache, Matthias

2008-08-01

Tumor hypoxia has an impact on the outcome of cancer patients treated with radiotherapy. The validity of endogenous markers such as hypoxia-inducible factor-1alpha (HIF-1alpha) and carbonic anhydrase isozyme IX (CAIX) to detect therapeutically relevant Levels of hypoxia within tumors is controversially discussed. Furthermore, the association of these hypoxia markers with tumor markers or tumor oxygenation parameters is of importance for understanding the relationship between the different factors. Tumortissue sections of 34 patients with advanced head-and-neck cancertreated with radio(chemo)therapy were assessed by immunohistochemistry for the expression of HIF-1alpha and CAIX. The relationships of both markers with tumor oxygenation parameters, molecular factors like P53, OPN, VEGF, VHL, survivin, and Ki67 levels, and clinical parameters were studied. Bivariate analysis showed a significant correlation of HIF-1alpha expression with high P53 and high OPN expression, high serum VEGF Levels, and low VHL and low Ki67 expression. The CAIX expression was inversely correlated with pH value and directly correlated with T-stage. However, no correlation was found between HIF-1alpha and CAIX expression. Neither in a univariate Cox proportional hazard regression nor in a Kaplan-Meier analysis did expression of HIF-1alpha or CAIX have a significant impact on clinical outcome. However, in a Kaplan-Meier analysis, the combination of both factors showed that patients with intratumoral overexpression of either HIF-1alpha or CAIX or both markers died on average 2 years earlier than patients whose tumors had low expression of both factors (p < 0.05). Expression of HIF-1alpha and CAIX was correlated with different tumor parameters. Only combined HIF-1alpha and CAIX expression was significantly predictive of patients' overall survival.

[Expression of c-kit in North African nasopharyngeal carcinomas: correlation with age and LMP1].

PubMed

Charfi, S; Khabir, A; Ayadi, L; Mseddi, M; Makni, H; Gorbel, A; Daoud, J; Frikha, M; Jlidi, R; Busson, P; Boudawara, T S

2007-09-01

To determine the level and prognostic significance of c-kit expression in the two age groups of North African nasopharyngeal carcinomas. A retrospective study of 99 NPC specimens from Tunisian patients was investigated by immunohistochemistry. Immunohistochemical data were correlated with Epstein-Barr virus LMP1 expression and pathological, clinical and survival parameters. c-kit was detected in 79% of the cases for patients under 30 years of age (juvenile form) but in only 56% of specimens in patients over 30 years (P=0.039) and was significantly over-expressed for patients with lymph node involvement (P=0.015). LMP1 score was 5.78 (+/-1.84) for c-kit negative tumors compared to 8,23 (+/-2.39) for c-kit positive tumors (P=0.002). Multivariate analysis including age, lymph nodes involvement and LMP1 expression as co-variables, showed that only age (P=0.027) and LMP1 expression (P=0.005) were significantly correlated to the c-kit expression. c-kit is highly expressed in the juvenile form of North African nasopharyngeal carcinomas. There is a significant association between LMP1 and c-kit expression. The contrasted levels of C-kit expression in the two age groups strengthen the hypothesis that these clinical forms result from distinct oncogenic mechanisms.

High glucose increases Cdk5 activity in podocytes via transforming growth factor-β1 signaling pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Yue; Li, Hongbo; Hao, Jun

Podocytes are highly specialized and terminally differentiated glomerular cells that play a vital role in the development and progression of diabetic nephropathy (DN). Cyclin-dependent kinase 5 (Cdk5), who is an atypical but essential member of the Cdk family of proline-directed serine/threonine kinases, has been shown as a key regulator of podocyte differentiation, proliferation and morphology. Our previous studies demonstrated that the expression of Cdk5 was significantly increased in podocytes of diabetic rats, and was closely related with podocyte injury of DN. However, the mechanisms of how expression and activity of Cdk5 are regulated under the high glucose environment have notmore » yet been fully elucidated. In this study, we showed that high glucose up-regulated the expression of Cdk5 and its co-activator p35 with a concomitant increase in Cdk5 kinase activity in conditionally immortalized mouse podocytes in vitro. When exposed to 30 mM glucose, transforming growth factor-β1 (TGF-β1) was activated. Most importantly, we found that SB431542, the Tgfbr1 inhibitor, significantly decreased the expression of Cdk5 and p35 and Cdk5 kinase activity in high glucose-treated podocytes. Moreover, high glucose increased the expression of early growth response-1 (Egr-1) via TGF-β1-ERK1/2 pathway in podocytes and inhibition of Egr-1 by siRNA decreased p35 expression and Cdk5 kinase activity. Furthermore, inhibition of Cdk5 kinase activity effectively alleviated podocyte apoptosis induced by high glucose or TGF-β1. Thus, the TGF-β1-ERK1/2-Egr-1 signaling pathway may regulate the p35 expression and Cdk5 kinase activity in high glucose-treated podocytes, which contributes to podocyte injury of DN. - Highlights: • HG up-regulated the expression of Cdk5 and p35, and Cdk5 activity in podocytes. • HG activated TGF-β1 pathway and SB431542 inhibited Cdk5 expression and activity. • HG increased the expression of Egr-1 via TGF-β1-ERK1/2 pathway. • Inhibition of Egr-1 decreased p35 expression in HG-cultured podocytes. • Inhibition of Cdk5 activity alleviated podocyte apoptosis induced by HG or TGF-β1.« less

Effect of patchouli alcohol on the regulation of heat shock-induced oxidative stress in IEC-6 cells.

PubMed

Liu, Xiaoxi; Jiang, Linshu; Liu, Fenghua; Chen, Yuping; Xu, Lei; Li, Deyin; Ma, Yunfei; Li, Huanrong; Xu, Jianqin

2016-08-01

Purpose Patchouli alcohol (PA) is used to treat gastrointestinal dysfunction. The purpose of this study was to ascertain the function of PA in the regulated process of oxidative stress in rat intestinal epithelial cells (IEC-6). Materials and methods Oxidative stress was stimulated by exposing IEC-6 cells to heat shock (42 °C for 3 h). IEC-6 cells in treatment groups were pretreated with various concentrations of PA (10, 40, and 80 ng/mL) for 3 h before heat shock. Results Heat shock caused damage to the morphology of IEC-6 cells, and increased reactive oxygen species (ROS) level and malondialdehyde (MDA) content. Moreover, mRNA and protein expression by target genes related to oxidative stress in heat shock were also altered. Specifically, the mRNA expression by HSP70, HSP90, GSH-px, NRF2 nd HO-1were all increased, and Nrf2 and Keap1 protein expression were increased after heat shock. However, pretreatment with PA weakened the level of damage to the cellular morphology, and decreased the MDA content caused by heat shock, indicating PA had cytoprotective activities. Pretreatment with PA at high dose significantly increased generation of intracellular ROS. Compared with the heat shock group alone, PA pretreatment significantly decreased the mRNA expression by HSP70, HSP90, SOD, CAT, GSH-px, KEAP1 and HO-1. Furthermore, the high dose of PA significantly increased Nrf2 protein expression, while both the intermediate and high dose of PA significantly increased HO-1 protein expression. Conclusion Heat-shock-induced oxidative stress in IEC-6 cells, and PA could alleviate the Nrf2-Keap1 cellular oxidative stress responses.

Lower and reduced expression of EphA4 is associated with advanced TNM stage, lymph node metastasis, and poor survival in breast carcinoma.

PubMed

Sun, Yuejun; Qian, Jianzhong; Lu, Min; Xu, Hongming

2016-09-01

The expression of EphA4 has been well documented in the development of nerve and in certain types of human cancer. Few studies of EphA4, however, have focused on breast carcinoma. In this study, a set of breast carcinomas was subjected to immunohistochemical staining. In normal luminal cells, EphA4 was weakly detected in 11 (14.3 %), moderately detected in 15 (19.5 %) and highly detected in 51 out of 77 (66.2 %) samples, while in breast carcinoma cells, EphA4 was weakly detected in 42 (54.5 %), moderately detected in 19 (24.7 %) and highly detected in 16 out of 77 (20.8 %) samples (P < 0.001). The expression of EphA4 protein was significantly reduced in 68.8 % of breast carcinoma samples comparing with normal cells. The expression of EphA4 was significantly associated with tumor grade (P = 0.003), TNM stage (P = 0.034), lymph node metastasis (P = 0.034) and Ki-67 (P < 0.001). No significant relationship was found between the expression of EphA4 and age, molecular subtypes, and HER2 status. Survival analysis showed that significant association of low expression of EphA4 in tumor cells with short overall survival (P = 0.048) and disease-free survival (P = 0.051). Our data show that EphA4 was reduced in breast carcinoma, which is associated with high grade, advanced TNM stage, lymph node metastasis, and poor outcome of patients. © 2016 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.

[Effect of high-fat diet on expression of transient receptor potential vanilloid 1 in respiratory tract and dorsal root ganglion of mice].

PubMed

Zhu, Lian; Xu, Zhi-Liang

2017-07-01

To investigate the effect of high-fat diet on the expression of transient receptor potential vanilloid 1 (TRPV1) in the respiratory system and the dorsal root ganglion (DRG) of mice, as well as its effect on the excitability of sensory neurons. A total of 20 C57BL/6 mice were randomly divided into normal-diet (ND) group and high-fat diet (HFD) group, with 10 mice in each group. The mice were given corresponding diets and body weights were monitored. After 7 weeks of feeding, lung tissue, bronchial tissue, and DRG at thoracic segments 3-4 were collected and immunohistochemical staining was performed. A patch clamp was used to measure the number of action potentials and TRPV1 current intensity in the DRG. After 7 weeks of feeding, the HFD group had significantly greater mean weight gain than the ND group (6.4±2.6 g vs 2.3±0.5 g; P<0.001). The HFD group had significantly higher expression of TRPV1 in the bronchus, pulmonary alveoli, and DRG than the ND group (P<0.05). Compared with the ND group, the HFD group had significant increases in the TRPV1 current intensity and number of action potentials in the DRG (P<0.05). High-fat diet induces a significant increase in body weight and leads to high expression of TRPV1 and high excitability in the respiratory system and the peripheral sensory neurons. This suggests that TRPV1 may be an important factor in the physiopathological mechanisms of bronchial hyperresponsiveness.

Galectin-9 Expression Predicts Favorable Clinical Outcome in Solid Tumors: A Systematic Review and Meta-Analysis

PubMed Central

Zhou, Xiaoxiang; Sun, Lejia; Jing, Dan; Xu, Gang; Zhang, Jinmei; Lin, Li; Zhao, Jingjing; Yao, Zhuoran; Lin, Hongfeng

2018-01-01

Background and Objective: Galectin-9 (Gal-9) is one of the galectin family members which are known as proteins with β-galactoside-binding affinity. Accumulative evidence suggest that Gal-9 plays multifaceted roles in tumor biology. However, the prognostic significance of Gal-9 in solid cancer patients remains controversial. The objective of the study was to clarify the prognostic significance of Gal-9 in solid tumors via meta-analysis. Methods: We searched PubMed, Embase and the Cochrane library for studies that report the correlation between Gal-9 expression and prognosis or clinicopathological parameters in solid cancer patients from inception to October 2017, with no language restriction. We calculated pooled hazard ratio (HR) and 95% confidence interval (CI) to investigate the prognostic significance of Gal-9 expression in solid tumors. We also calculated Odds ratio (OR) to explore the association between Gal-9 expression and clinicopathological features. Results: We included Fourteen studies with 2326 patients in our meta-analysis. The synthetic results revealed that high Gal-9 expression indicated improved overall survival (OS; HR = 0.70, 95% CI = 0.51–0.71, P = 0.006) but had no correlation with disease-free survival (DFS)/recurrence-free survival (RFS) (HR = 0.85, 95% CI = 0.51–1.41, P = 0.527) in solid tumors. In stratified analyses, high Gal-9 expression was significantly correlated with improved OS in hepatocellular carcinoma and colon cancer and with improved DFS/RFS in gastric cancer and non-small cell lung cancer. In addition, ethnicity and the method of data extraction didn’t affect the positive prognostic values of high Gal-9 expression. Moreover, high Gal-9 expression was significantly correlated with a smaller depth of invasion (TI/TII vs. TIII/TIV, OR = 2.80, 95% CI = 1.97–3.96, P < 0.001), an earlier histopathological stage (I/II vs. III/IV, OR = 3.00, 95% CI = 2.04–4.42, P < 0.001), negative lymph node metastasis (Presence vs. Absence, OR = 0.47, 95% CI = 0.25–0.89, P = 0.020) and negative distal tumor metastasis (Presence vs. Absence, OR = 13.85, 95% CI = 3.50–54.76, P < 0.001). Conclusion: Gal-9 expression indicates beneficial outcome in patients with solid tumors and is correlated with the pathogenesis of solid tumors. Gal-9 may serve as a prognostic biomarker and an emerging therapeutic target against solid tumors. PMID:29765332

Galectin-9 Expression Predicts Favorable Clinical Outcome in Solid Tumors: A Systematic Review and Meta-Analysis.

PubMed

Zhou, Xiaoxiang; Sun, Lejia; Jing, Dan; Xu, Gang; Zhang, Jinmei; Lin, Li; Zhao, Jingjing; Yao, Zhuoran; Lin, Hongfeng

2018-01-01

Background and Objective: Galectin-9 (Gal-9) is one of the galectin family members which are known as proteins with β-galactoside-binding affinity. Accumulative evidence suggest that Gal-9 plays multifaceted roles in tumor biology. However, the prognostic significance of Gal-9 in solid cancer patients remains controversial. The objective of the study was to clarify the prognostic significance of Gal-9 in solid tumors via meta-analysis. Methods: We searched PubMed, Embase and the Cochrane library for studies that report the correlation between Gal-9 expression and prognosis or clinicopathological parameters in solid cancer patients from inception to October 2017, with no language restriction. We calculated pooled hazard ratio (HR) and 95% confidence interval (CI) to investigate the prognostic significance of Gal-9 expression in solid tumors. We also calculated Odds ratio (OR) to explore the association between Gal-9 expression and clinicopathological features. Results: We included Fourteen studies with 2326 patients in our meta-analysis. The synthetic results revealed that high Gal-9 expression indicated improved overall survival (OS; HR = 0.70, 95% CI = 0.51-0.71, P = 0.006) but had no correlation with disease-free survival (DFS)/recurrence-free survival (RFS) (HR = 0.85, 95% CI = 0.51-1.41, P = 0.527) in solid tumors. In stratified analyses, high Gal-9 expression was significantly correlated with improved OS in hepatocellular carcinoma and colon cancer and with improved DFS/RFS in gastric cancer and non-small cell lung cancer. In addition, ethnicity and the method of data extraction didn't affect the positive prognostic values of high Gal-9 expression. Moreover, high Gal-9 expression was significantly correlated with a smaller depth of invasion (TI/TII vs. TIII/TIV, OR = 2.80, 95% CI = 1.97-3.96, P < 0.001), an earlier histopathological stage (I/II vs. III/IV, OR = 3.00, 95% CI = 2.04-4.42, P < 0.001), negative lymph node metastasis (Presence vs. Absence, OR = 0.47, 95% CI = 0.25-0.89, P = 0.020) and negative distal tumor metastasis (Presence vs. Absence, OR = 13.85, 95% CI = 3.50-54.76, P < 0.001). Conclusion: Gal-9 expression indicates beneficial outcome in patients with solid tumors and is correlated with the pathogenesis of solid tumors. Gal-9 may serve as a prognostic biomarker and an emerging therapeutic target against solid tumors.

High expression of GPER1, EGFR and CXCR1 is associated with lymph node metastasis in papillary thyroid carcinoma.

PubMed

Tang, Cui; Yang, Lei; Wang, Ni; Li, Li; Xu, Man; Chen, George G; Liu, Zhi-Min

2014-01-01

Clinical and epidemiological studies have shown that estrogen may be involved in the development and progression of papillary thyroid carcinoma (PTC). G protein-coupled estrogen receptor 1 (GPER1) is a novel seven-transmembrane estrogen receptor that functions alongside traditional nuclear estrogen receptors (ERs) to regulate the cellular responses to estrogen. The purpose of this study was to examine GPER1, EGFR and CXCR1 expression in PTC and to assess the association of their expression with clinicopathological indicators. GPER1, EGFR and CXCR1 protein expression in 129 PTCs, 61 nodular hyperplasia and 118 normal thyroid tissue specimens were analyzed using immunohistochemistry. The protein expression levels of these three molecules were up-regulated in PTCs. High protein expression of GPER1, EGFR and CXCR1 was significantly correlated with lymph node metastasis (LNM) (P ≤ 0.001). Furthermore, GPER1, EGFR and CXCR1 protein expression were correlated with one another. Concomitant high expression of these molecules had stronger correlation with LNM than did each alone (P = 0.002 for GPER1/EGFR, P = 0.013 for GPER1/CXCR1, P = 0.018 for EGFR/CXCR1 and P < 0.001 for GPER1/EGFR/CXCR1). Additionally, GPER1, EGFR and CXCR1 mRNA expression was assessed in 30 PTCs, 10 nodular hyperplasia and 10 normal thyroid tissue specimens using real-time RT-PCR. GPER1, EGFR and CXCR1 mRNA expression levels were up-regulated in PTCs, and high mRNA expression of GPER1, EGFR and CXCR1 was significantly correlated with LNM (P < 0.001 for all these three molecules). These results demonstrated that the evaluation of GPER1, EGFR and CXCR1 expression in PTC may be useful in predicting the risk of LNM.

Secretory Leukocyte Protease Inhibitor Expression and High-Risk HPV Infection in Anal Lesions of HIV-Positive Patients.

PubMed

Nicol, Alcina F; Brunette, Laurie L; Nuovo, Gerard J; Grinsztejn, Beatriz; Friedman, Ruth K; Veloso, Valdiléa G; Cunha, Cynthia B; Coutinho, José R; Vianna-Andrade, Cecilia; Oliveira, Nathalia S; Woodham, Andrew W; DA Silva, Diane M; Kast, W Martin

2016-09-01

The aim of this study was to evaluate secretory leukocyte protease inhibitor (SLPI) expression in anal biopsies from HIV-positive (HIV+) individuals, and compare that to anal intraepithelial neoplasia (AIN) diagnoses and human papillomavirus (HPV) status. This is a cross-sectional study of a cohort of 54 HIV+ (31 males and 23 females) from an AIDS clinic in Rio de Janeiro, Brazil. The study material consisted of anorectal tissue biopsies obtained from HIV+ subjects, which were used to construct tissue microarray paraffin blocks for immunohistochemical analysis of SLPI expression. Biopsies were evaluated by an expert pathologist and classified as low-grade AIN1, high-grade AIN2/3, or normal squamous epithelium. In addition, DNA from the biopsies was extracted and analyzed for the presence of low- or high-risk HPV DNA. Histologically, normal squamous epithelium from the anorectal region showed strong positive SLPI staining in 17/20 (85%) samples. In comparison, 9/17 (53%) dysplastic squamous epithelial samples from AIN1 patients showed strong SLPI staining, and only 5/17 (29%) samples from AIN2/3 patients exhibited strong SPLI staining, which both were significantly fewer than those from normal tissue (P = 0.005). Furthermore, there was a significantly higher proportion of samples in which oncogenic high-risk HPV genotypes were detected in low SLPI-expressing tissues than that in tissues with high SLPI expression (P = 0.040). Taken together these results suggest that low SLPI expression is associated with high-risk HPV infections in the development of AIN.

The effect of a high protein diet on leucine and alanine turnover in acid maltase deficiency.

PubMed Central

Umpleby, A M; Trend, P S; Chubb, D; Conaglen, J V; Williams, C D; Hesp, R; Scobie, I N; Wiles, C M; Spencer, G; Sönksen, P H

1989-01-01

Leucine and alanine production rate was measured in 5 patients with acid maltase deficiency in the postabsorptive state, following 6 months on a normal diet with placebo and 6 months on an isocaloric high protein diet (16-22% protein). Whole body leucine production rate, a measure of protein degradation, expressed in terms of lean body mass was significantly greater than in five control subjects. Following the high protein diet, leucine production rate was decreased in four of the five patients but this was not statistically significant. Alanine production rate expressed in terms of lean body mass was significantly greater than in control subjects. After the high protein diet, alanine production rate and concentration were significantly decreased (p less than 0.05). There were no significant improvements in any of the clinically relevant variables measured in these patients. It is possible that a larger increase in protein intake over a longer time period may have a clinical effect. PMID:2507747

Transcriptome Analysis Reveals Signature of Adaptation to Landscape Fragmentation

PubMed Central

Ikonen, Suvi; Auvinen, Petri; Paulin, Lars; Koskinen, Patrik; Holm, Liisa; Taipale, Minna; Duplouy, Anne; Ruokolainen, Annukka; Saarnio, Suvi; Sirén, Jukka; Kohonen, Jukka; Corander, Jukka; Frilander, Mikko J.; Ahola, Virpi; Hanski, Ilkka

2014-01-01

We characterize allelic and gene expression variation between populations of the Glanville fritillary butterfly (Melitaea cinxia) from two fragmented and two continuous landscapes in northern Europe. The populations exhibit significant differences in their life history traits, e.g. butterflies from fragmented landscapes have higher flight metabolic rate and dispersal rate in the field, and higher larval growth rate, than butterflies from continuous landscapes. In fragmented landscapes, local populations are small and have a high risk of local extinction, and hence the long-term persistence at the landscape level is based on frequent re-colonization of vacant habitat patches, which is predicted to select for increased dispersal rate. Using RNA-seq data and a common garden experiment, we found that a large number of genes (1,841) were differentially expressed between the landscape types. Hexamerin genes, the expression of which has previously been shown to have high heritability and which correlate strongly with larval development time in the Glanville fritillary, had higher expression in fragmented than continuous landscapes. Genes that were more highly expressed in butterflies from newly-established than old local populations within a fragmented landscape were also more highly expressed, at the landscape level, in fragmented than continuous landscapes. This result suggests that recurrent extinctions and re-colonizations in fragmented landscapes select a for specific expression profile. Genes that were significantly up-regulated following an experimental flight treatment had higher basal expression in fragmented landscapes, indicating that these butterflies are genetically primed for frequent flight. Active flight causes oxidative stress, but butterflies from fragmented landscapes were more tolerant of hypoxia. We conclude that differences in gene expression between the landscape types reflect genomic adaptations to landscape fragmentation. PMID:24988207

Transcriptome analysis reveals signature of adaptation to landscape fragmentation.

PubMed

Somervuo, Panu; Kvist, Jouni; Ikonen, Suvi; Auvinen, Petri; Paulin, Lars; Koskinen, Patrik; Holm, Liisa; Taipale, Minna; Duplouy, Anne; Ruokolainen, Annukka; Saarnio, Suvi; Sirén, Jukka; Kohonen, Jukka; Corander, Jukka; Frilander, Mikko J; Ahola, Virpi; Hanski, Ilkka

2014-01-01

We characterize allelic and gene expression variation between populations of the Glanville fritillary butterfly (Melitaea cinxia) from two fragmented and two continuous landscapes in northern Europe. The populations exhibit significant differences in their life history traits, e.g. butterflies from fragmented landscapes have higher flight metabolic rate and dispersal rate in the field, and higher larval growth rate, than butterflies from continuous landscapes. In fragmented landscapes, local populations are small and have a high risk of local extinction, and hence the long-term persistence at the landscape level is based on frequent re-colonization of vacant habitat patches, which is predicted to select for increased dispersal rate. Using RNA-seq data and a common garden experiment, we found that a large number of genes (1,841) were differentially expressed between the landscape types. Hexamerin genes, the expression of which has previously been shown to have high heritability and which correlate strongly with larval development time in the Glanville fritillary, had higher expression in fragmented than continuous landscapes. Genes that were more highly expressed in butterflies from newly-established than old local populations within a fragmented landscape were also more highly expressed, at the landscape level, in fragmented than continuous landscapes. This result suggests that recurrent extinctions and re-colonizations in fragmented landscapes select a for specific expression profile. Genes that were significantly up-regulated following an experimental flight treatment had higher basal expression in fragmented landscapes, indicating that these butterflies are genetically primed for frequent flight. Active flight causes oxidative stress, but butterflies from fragmented landscapes were more tolerant of hypoxia. We conclude that differences in gene expression between the landscape types reflect genomic adaptations to landscape fragmentation.

High Expression of KCa3.1 in Patients with Clear Cell Renal Carcinoma Predicts High Metastatic Risk and Poor Survival

PubMed Central

Rabjerg, Maj; Oliván-Viguera, Aida; Hansen, Lars Koch; Jensen, Line; Sevelsted-Møller, Linda; Walter, Steen; Jensen, Boye L.; Marcussen, Niels; Köhler, Ralf

2015-01-01

Background Ca2+-activated K+ channels have been implicated in cancer cell growth, metastasis, and tumor angiogenesis. Here we hypothesized that high mRNA and protein expression of the intermediate-conductance Ca2+-activated K+ channel, KCa3.1, is a molecular marker of clear cell Renal Cell Carcinoma (ccRCC) and metastatic potential and survival. Methodology/Principal Findings We analyzed channel expression by qRT-PCR, immunohistochemistry, and patch-clamp in ccRCC and benign oncocytoma specimens, in primary ccRCC and oncocytoma cell lines, as well as in two ccRCC cell lines (Caki-1 and Caki-2). CcRCC specimens contained 12-fold higher mRNA levels of KCa3.1 than oncocytoma specimens. The large-conductance channel, KCa1.1, was 3-fold more highly expressed in ccRCC than in oncocytoma. KCa3.1 mRNA expression in ccRCC was 2-fold higher than in the healthy cortex of the same kidney. Disease specific survival trended towards reduction in the subgroup of high-KCa3.1-expressing tumors (p<0.08 vs. low-KCa3.1-expressing tumors). Progression-free survival (time to metastasis/recurrence) was reduced significantly in the subgroup of high-KCa3.1-expressing tumors (p<0.02, vs. low-KCa3.1-expressing tumors). Immunohistochemistry revealed high protein expression of KCa3.1 in tumor vessels of ccRCC and oncocytoma and in a subset of ccRCC cells. Oncocytoma cells were devoid of KCa3.1 protein. In a primary ccRCC cell line and Caki-1/2-ccRCC cells, we found KCa3.1-protein as well as TRAM-34-sensitive KCa3.1-currents in a subset of cells. Furthermore, Caki-1/2-ccRCC cells displayed functional Paxilline-sensitive KCa1.1 currents. Neither KCa3.1 nor KCa1.1 were found in a primary oncocytoma cell line. Yet KCa-blockers, like TRAM-34 (KCa3.1) and Paxilline (KCa1.1), had no appreciable effects on Caki-1 proliferation in-vitro. Conclusions/Significance Our study demonstrated expression of KCa3.1 in ccRCC but not in benign oncocytoma. Moreover, high KCa3.1-mRNA expression levels were indicative of low disease specific survival of ccRCC patients, short progression-free survival, and a high metastatic potential. Therefore, KCa3.1 is of prognostic value in ccRCC. PMID:25848765

Mast cells and matrix metalloproteinase 9 expression in actinic cheilitis and lip squamous cell carcinoma.

PubMed

Souza Freitas, Valéria; de Andrade Santos, Pedro Paulo; de Almeida Freitas, Roseana; Pereira Pinto, Leão; de Souza, Lélia Batista

2011-09-01

The aim of this study was to evaluate mast cell (MC) density and migration and their association with matrix metalloproteinase (MMP) 9 expression in squamous cell carcinoma (SCC) and actinic cheilitis (AC). Tryptase, c-Kit, and MMP-9 expression was evaluated in 20 cases of SCC, 20 cases of AC, and 7 cases of normal lip (control samples) by immunohistochemistry techniques. Tryptase(+) and c-Kit(+) MC densities were significantly higher in SCCs than in ACs and control samples (P < .001). However, no significant difference was found when comparing tryptase(+) and c-Kit(+) MC densities between ACs and control samples (P values .185 and .516, respectively). MMP-9 was strongly expressed in SCCs and moderately expressed in ACs and control samples. A highly significant association was found between tryptase(+) MC density and the expression of MMP-9 (P < .001). The increase in MC density associated with the strong expression of MMP-9 may favor SCC progression. Copyright © 2011 Mosby, Inc. All rights reserved.

Diagnostic and Prognostic Significance of Serum and Tissue Galectin 3 Expression in Patients with Carcinoma of the Bladder

PubMed Central

Gendy, Hoda El; Madkour, Bothina; Abdelaty, Sara; Essawy, Fayza; Khattab, Dina; Hammam, Olfat; Nour, Hani H.

2014-01-01

Background Galectins are group of proteins found in the cytoplasm, nucleus, cell surface and extracellular matrix. Galectin 3 (Gal-3) displays pathological expression in a variety of processes such as tumorigenesis. Patients and Method 70 patients classified into the control group, cystitis group, transitional cell carcinoma group, and squamous cell carcinoma group were enrolled in this study which aimed to detect the serum level and the intensity of tissue expression of Gal-3. Results Both serum level and tissue expression of Gal-3 were statistically higher in bladder cancer patients compared to the other groups. Gal-3 level expression increased from low to high grade urothelial tumors, with a statistically significant increase of its level and expression between muscle invasive and non-muscle invasive Ta urothelial tumors. Conclusion The serum Gal-3 level is sensitive and specific for the diagnosis of bladder cancer. The prognostic significance of tissue expression is to be confirmed. PMID:26195948

Chronic effects of aerobic exercise on gene expression of LOX-1 receptor in the heart of rats fed with high fat diet

PubMed Central

Riahi, Simin; Mohammadi, Mohammad Taghi; Sobhani, Vahid; Soleimany, Mansureh

2015-01-01

Objective(s): Lectin-like low density lipoprotein receptor (LOX-1) has pivot role in vascular complications, which is upregulated in numerous pathological conditions. Since exercise has beneficial effects in prevention of hyperlipidemic complications, present study examined protective effects of aerobic exercise through reduction of LOX-1 expression in heart during dyslipidemia. Materials and Methods: Four groups of rats were used (N=25): Normal, Normal and exercise, High fat and High fat and exercise. High fat diet (HFD) was made by adding 10% animal oil, 2% cholesterol and 0.5% colic acid to standard rodent chow. Exercise protocol consisted of swimming 1 hr/day, and 5 days/week for 8 weeks. Plasma lipids were evaluated at the end of experiment, 48 hr after final session of exercise. At the end, rats were sacrificed and heart was removed for determination of malondialdehyde (MDA) content, and LOX-1 expression. Results: HFD meaningfully changed lipid profile (>50%), but chronic exercise had no significant effects on lipid profile. LOX-1 expression was significantly increased in heart of rats fed with HFD, while swimming exercise considerably reduced gene expression of LOX-1. MDA content was significantly enhanced in rats fed with HFD (4.37±0.6 nmol/mg, P<0.01) compared to normal group (1.56±0.48 nmol/mg), whereas swimming exercise decreased MDA level of heart in rats fed with HFD (2.28±0.32, P<0.01). Conclusion: Findings indicated that swimming exercise is able to diminish heart expression of LOX-1 receptor concomitant reduction of oxidative stress. Since these parameters are involved in generation of dyslipidemic complications, swimming exercise is a good candidate to reduce these complications. PMID:26557970

Schizothorax prenanti corticotropin-releasing hormone (CRH): molecular cloning, tissue expression, and the function of feeding regulation.

PubMed

Wang, Tao; Zhou, Chaowei; Yuan, Dengyue; Lin, Fangjun; Chen, Hu; Wu, Hongwei; Wei, Rongbin; Xin, Zhiming; Liu, Ju; Gao, Yundi; Li, Zhiqiong

2014-10-01

Corticotropin-releasing hormone (CRH) is a potent mediator of endocrine, autonomic, behavioral, and immune responses to stress. For a better understanding of the structure and function of the CRH gene and to study its effect on feeding regulation in cyprinid fish, the cDNA of the CRH gene from the brain of Schizothorax prenanti was cloned and sequenced. The full-length CRH cDNA consisted of 1,046 bp with an open reading frame of 489 bp encoding a protein of 162 amino acids. Real-time quantitative PCR analyses revealed that CRH was widely expressed in central and peripheral tissues. In particular, high expression level of CRH was detected in brain. Furthermore, CRH mRNA expression was examined in different brain regions, especially high in hypothalamus. In addition, there was no significant change in CRH mRNA expression in fed group compared with the fasted group in the S. prenanti hypothalamus during short-term fasting. However, CRH gene expression presented significant decrease in the hypothalamus in fasted group compared with the fed group (P < 0.05) on day 7; thereafter, re-feeding could lead to a significant increase in CRH mRNA expression in fasted group on day 9. The results suggest that the CRH may play a critical role in feeding regulation in S. prenanti.

Diet-induced non-alcoholic fatty liver disease affects expression of major cytochrome P450 genes in a mouse model.

PubMed

Chiba, Tsuyoshi; Noji, Keiko; Shinozaki, Shohei; Suzuki, Sachina; Umegaki, Keizo; Shimokado, Kentaro

2016-12-01

Non-alcoholic fatty liver disease (NAFLD) is associated with impaired liver function, and resveratrol could suppress NAFLD progression. This study examined the effects of NAFLD on the expression of major cytochrome P450 (CYP) subtypes in the liver and whether the expression could be attenuated by resveratrol. C57BL/6 mice (male, 10 weeks of age) were fed a high-fat and high-sucrose (HFHS) diet to induce NAFLD. Major Cyp subtype mRNA expression in the liver was measured by real-time RT-PCR. Body and liver weights at 4 and 12 weeks were significantly higher in mice fed the HFHS diet compared with control. The HFHS diet significantly increased the accumulation of cholesterol and triglycerides at 12 weeks. Under this condition, the HFHS diet increased the expression of Cyp1a2 and decreased that of Cyp3a11 at 1 week and thereafter. On the other hand, Cyp1a1, 2b10 and 2c29 mRNA expression levels in the liver were significantly increased at 12 weeks only. Resveratrol (0.05% (w/w) in diet) slightly suppressed lipid accumulation in the liver, but failed to recover impaired Cyp gene expression levels in NAFLD. Drug metabolism may be impaired in NAFLD, and each Cyp subtype is regulated in a different manner. © 2016 Royal Pharmaceutical Society.

Differential expression and prognostic value of the chemokine receptor CXCR4 in bronchopulmonary neuroendocrine neoplasms.

PubMed

Kaemmerer, Daniel; Reimann, Christiane; Specht, Elisa; Wirtz, Ralph M; Sayeg, Manal; Baum, Richard P; Schulz, Stefan; Lupp, Amelie

2015-02-20

For many tumors, the overexpression of the chemokine receptor CXCR4 is associated with increased malignancy and poor patient outcomes. However, comprehensive data for neuroendocrine neoplasms of the lung are still lacking. CXCR4 expression was evaluated in a panel of bronchopulmonary neuroendocrine neoplasms (BP-NEN) comprising typical carcinoids (n = 26), atypical carcinoids (n = 30), and small cell lung cancers (SCLC, n = 34). Samples were analyzed by immunohistochemistry using the novel monoclonal rabbit anti-human CXCR4 antibody UMB-2 and by qRT-PCR. The expression was correlated with clinical data and overall patient survival. CXCR4 was predominantly localized at the plasma membrane of the tumor cells. CXCR4 was expressed with a high intensity in almost all of the 30 SCLC samples. In contrast, it was detected infrequently and with low intensity in the typical carcinoid and atypical carcinoid samples. There was a significant correlation between the immunohistochemistry and qRT-PCR data. Additionally, there was a significant negative relationship between CXCR4 expression and overall survival. With increasing malignancy, BP-NEN clearly differ in the extent of CXCR4 expression. As in other tumor entities, CXCR4 overexpression significantly correlates with negative patient outcome. Due to its particular high expression rate in SCLC, CXCR4 may serve as a promising new target for diagnostic and pharmacological intervention as well as for peptide receptor-based radionuclide therapy.

Parallel Gene Expression Differences between Low and High Latitude Populations of Drosophila melanogaster and D. simulans

PubMed Central

Zhao, Li; Wit, Janneke; Svetec, Nicolas; Begun, David J.

2015-01-01

Gene expression variation within species is relatively common, however, the role of natural selection in the maintenance of this variation is poorly understood. Here we investigate low and high latitude populations of Drosophila melanogaster and its sister species, D. simulans, to determine whether the two species show similar patterns of population differentiation, consistent with a role for spatially varying selection in maintaining gene expression variation. We compared at two temperatures the whole male transcriptome of D. melanogaster and D. simulans sampled from Panama City (Panama) and Maine (USA). We observed a significant excess of genes exhibiting differential expression in both species, consistent with parallel adaptation to heterogeneous environments. Moreover, the majority of genes showing parallel expression differentiation showed the same direction of differential expression in the two species and the magnitudes of expression differences between high and low latitude populations were correlated across species, further bolstering the conclusion that parallelism for expression phenotypes results from spatially varying selection. However, the species also exhibited important differences in expression phenotypes. For example, the genomic extent of genotype × environment interaction was much more common in D. melanogaster. Highly differentiated SNPs between low and high latitudes were enriched in the 3’ UTRs and CDS of the geographically differently expressed genes in both species, consistent with an important role for cis-acting variants in driving local adaptation for expression-related phenotypes. PMID:25950438

Parallel Gene Expression Differences between Low and High Latitude Populations of Drosophila melanogaster and D. simulans.

PubMed

Zhao, Li; Wit, Janneke; Svetec, Nicolas; Begun, David J

2015-05-01

Gene expression variation within species is relatively common, however, the role of natural selection in the maintenance of this variation is poorly understood. Here we investigate low and high latitude populations of Drosophila melanogaster and its sister species, D. simulans, to determine whether the two species show similar patterns of population differentiation, consistent with a role for spatially varying selection in maintaining gene expression variation. We compared at two temperatures the whole male transcriptome of D. melanogaster and D. simulans sampled from Panama City (Panama) and Maine (USA). We observed a significant excess of genes exhibiting differential expression in both species, consistent with parallel adaptation to heterogeneous environments. Moreover, the majority of genes showing parallel expression differentiation showed the same direction of differential expression in the two species and the magnitudes of expression differences between high and low latitude populations were correlated across species, further bolstering the conclusion that parallelism for expression phenotypes results from spatially varying selection. However, the species also exhibited important differences in expression phenotypes. For example, the genomic extent of genotype × environment interaction was much more common in D. melanogaster. Highly differentiated SNPs between low and high latitudes were enriched in the 3' UTRs and CDS of the geographically differently expressed genes in both species, consistent with an important role for cis-acting variants in driving local adaptation for expression-related phenotypes.

[Correlation of Rab coupling protein expression with clinicopathological characteristics and prognosis in laryngeal squamous cell carcinoma].

PubMed

Dai, Yaozhang; Liu, Yong; Tian, Xiufen; Zhang, Xin

2015-02-01

To explore the RCP protein expression and its clinicopathological significance in laryngeal squamous cell carcinoma (LSCC). RCP protein expression in human head and neck squamous cell carcinoma cell lines (NP-69, Tu686, Tu212, M2 and M4) was analyzed by Western blotting. Besides, its expression in 87 cases of LSCC, 18 cases of adjacent epithelial mucosa and 16 cases of vocal cord leukoplakia was detected by immunohistochemistry, and their correlation with clinicopathological parameters and patients' outcome was analyzed. The NP-69, Tu212 Tu686, M2 and M4 cells showed a gradual increase in the expression of RCP protein. The average relative expression levels of RCP protein in the NP-69, Tu212, Tu686, M2 and M4 cells were 0.05±0.01, 0.38±0.05, 0.63±0.02, 0.84±0.06 and 0.96±0.04, respectively. The same situation occurred in the adjacent mucosa, vocal cord leukoplakia and LSCC. Specifically, only 3 of 18 adjacent mucosa showed a low RCP expression (scored 0-2). Although the 16 cases of vocal cord leukoplakia had a low RCP expression, all their scores ranged from 0 to 3. While in the LSCC specimens, 59 (67.8%) cases demonstrated a high RCP expression (scored 8-15), 18 cases showed a lower RCP expression (scored 4-7), and only 10 cases were scored 2-3. Among the 87 LSCC cases, there were 28 cases (32.2%) of low RCP expression and 59 cases of high RCP expression. All the 18 cases of cancer-adjacent tissues and 16 cases of vocal cord leukoplakia were of low RCP expression. RCP overexpression was significantly associated with T classification, clinical staging, lymph node metastasis and recurrence (P<0.05 for all). Survival analysis revealed that the 5-year survival rate was 40.0% in the patients with high RCP expression and 75.0% in the patients with low RCP expression, the tumor-free 5-year survival rate was 30.7% and 64.0%, respectively, both showing a significant difference between the two subgroups (P<0.05). Univariate analysis revealed that alcohol history; smoking, T classification, clinical staging, lymph node metastasis and RCP expression were significantly associated with a poor prognosis (P<0.05 for all). The multivariate analysis showed that only recurrence and RCP expression were independent prognostic factors affecting the prognosis for patients with LSCC (P<0.05 for both). Expression of RCP protein may contribute to the malignant progression of LSCC, and may become a novel marker predicting tumor recurrence, cervical lymph node metastasis and prognosis for patients with laryngeal squamous cell carcinoma.

Maternal High-Fat and High-Salt Diets Have Differential Programming Effects on Metabolism in Adult Male Rat Offspring.

PubMed

Segovia, Stephanie A; Vickers, Mark H; Harrison, Claudia J; Patel, Rachna; Gray, Clint; Reynolds, Clare M

2018-01-01

Maternal high-fat or high-salt diets can independently program adverse cardiometabolic outcomes in offspring. However, there is a paucity of evidence examining their effects in combination on metabolic function in adult offspring. Female Sprague Dawley rats were randomly assigned to either: control (CD; 10% kcal from fat, 1% NaCl), high-salt (SD; 10% kcal from fat, 4% NaCl), high-fat (HF; 45% kcal from fat, 1% NaCl) or high-fat and salt (HFSD; 45% kcal from fat, 4% NaCl) diets 21 days prior to mating and throughout pregnancy and lactation. Male offspring were weaned onto a standard chow diet and were culled on postnatal day 130 for plasma and tissue collection. Adipocyte histology and adipose tissue, liver, and gut gene expression were examined in adult male offspring. HF offspring had significantly greater body weight, impaired insulin sensitivity and hyperleptinemia compared to CD offspring, but these increases were blunted in HFSD offspring. HF offspring had moderate adipocyte hypertrophy and increased expression of the pre-adipocyte marker Dlk1 . There was a significant effect of maternal salt with increased hepatic expression of Dgat1 and Igfb2 . Gut expression of inflammatory ( Il1r1, Tnfα, Il6 , and Il6r ) and renin-angiotensin system ( Agtr1a, Agtr1b ) markers was significantly reduced in HFSD offspring compared to HF offspring. Therefore, salt mitigates some adverse offspring outcomes associated with a maternal HF diet, which may be mediated by altered adipose tissue morphology and gut inflammatory and renin-angiotensin regulation.

Expression of the CXCL12/CXCR4 and CXCL16/CXCR6 axes in cervical intraepithelial neoplasia and cervical cancer

PubMed Central

Huang, Yu; Zhang, Jia; Cui, Zhu-Mei; Zhao, Jing; Zheng, Ye

2013-01-01

The chemokine CXCL12 is highly expressed in gynecologic tumors and is widely known to play a biologically relevant role in tumor growth and spread. Recent evidence suggests that CXCL16, a novel chemokine, is overexpressed in inflammation-associated tumors and mediates pro-tumorigenic effects of inflammation in prostate cancer. We therefore analyzed the expression of CXCL12 and CXCL16 and their respective receptors CXCR4 and CXCR6 in cervical intraepithelial neoplasia (CIN) and cervical cancer and further assessed their association with clinicopathologic features and outcomes. Tissue chip technology and immunohistochemistry were used to analyze the expression of CXCL12, CXCR4, CXCL16, and CXCR6 in healthy cervical tissue (21 cases), CIN (65 cases), and cervical carcinoma (60 cases). The association of protein expression with clinicopathologic features and overall survival was analyzed. These four proteins were clearly detected in membrane and cytoplasm of neoplastic epithelial cells, and their distribution and intensity of expression increased as neoplastic lesions progressed through CIN1, CIN2, and CIN3 to invasive cancer. Furthermore, the expression of CXCR4 was associated significantly with the histologic grade of cervical carcinoma, whereas the expression of CXCR6 was associated significantly with lymph node metastasis. In Kaplan-Meier analysis, patients with high CXCR6 expression had significantly shorter overall survival than did those with low CXCR6 expression. The elevated co-expression levels of CXCL12/CXCR4 and CXCL16/CXCR6 in CIN and cervical carcinoma suggest a durative process in cervical carcinoma development. Moreover, CXCR6 may be useful as a biomarker and a valuable prognostic factor for cervical cancer. PMID:22958742

Expression of the CXCL12/CXCR4 and CXCL16/CXCR6 axes in cervical intraepithelial neoplasia and cervical cancer.

PubMed

Huang, Yu; Zhang, Jia; Cui, Zhu-Mei; Zhao, Jing; Zheng, Ye

2013-05-01

The chemokine CXCL12 is highly expressed in gynecologic tumors and is widely known to play a biologically relevant role in tumor growth and spread. Recent evidence suggests that CXCL16, a novel chemokine, is overexpressed in inflammation-associated tumors and mediates pro-tumorigenic effects of inflammation in prostate cancer. We therefore analyzed the expression of CXCL12 and CXCL16 and their respective receptors CXCR4 and CXCR6 in cervical intraepithelial neoplasia (CIN) and cervical cancer and further assessed their association with clinicopathologic features and outcomes. Tissue chip technology and immunohistochemistry were used to analyze the expression of CXCL12, CXCR4, CXCL16, and CXCR6 in healthy cervical tissue (21 cases), CIN (65 cases), and cervical carcinoma (60 cases). The association of protein expression with clinicopathologic features and overall survival was analyzed. These four proteins were clearly detected in membrane and cytoplasm of neoplastic epithelial cells, and their distribution and intensity of expression increased as neoplastic lesions progressed through CIN1, CIN2, and CIN3 to invasive cancer. Furthermore, the expression of CXCR4 was associated significantly with the histologic grade of cervical carcinoma, whereas the expression of CXCR6 was associated significantly with lymph node metastasis. In Kaplan-Meier analysis, patients with high CXCR6 expression had significantly shorter overall survival than did those with low CXCR6 expression. The elevated co-expression levels of CXCL12/CXCR4 and CXCL16/CXCR6 in CIN and cervical carcinoma suggest a durative process in cervical carcinoma development. Moreover, CXCR6 may be useful as a biomarker and a valuable prognostic factor for cervical cancer.

The role of uric acid in the pathogenesis of diabetic retinopathy based on notch pathway.

PubMed

Zhu, Dan-Dan; Wang, Yun-Zhi; Zou, Chen; She, Xin-Ping; Zheng, Zhi

2018-06-19

Uric acid has been proposed as an independent risk factor of diabetic retinopathy. Although Notch signaling was reported to be affected in the presence of high concentrations of uric acid or glucose, the underlying mechanisms of hyperuricemia through the Notch signaling pathway to promote the development of diabetic retinopathy remain unknown. We incubated human retinal endothelial cells (HRECs) with high glucose, high uric acid and high glucose plus high glucose respectively and evaluated the apoptosis rate in different treated cells by Tunel staining. We induced diabetic model by intraperitoneally streptozotocin. Then healthy rats and diabetic rats were given with adenine and oteracil potassium by gavage. Using automatic biochemical analyzer to detect blood glucose, uric acid, urea nitrogen, creatinine levels, to verify the success of modeling. The expression and mRNA levels of ICAM-1, IL-6, MCP-1, TNF-a, receptors Notch 1, ligands Dll 1, Dll 4, Jagged 1, Jagged 2 were detected by RT-PCR and Western-Blot. Notch1 siRNA was used to interfere Notch signaling pathway, the expression and mRNA levels of ICAM-1, IL-6, MCP-1 and TNF-α was detected by RT-PCR and Western blot respectively. In vitro models, the apoptosis of HRECs cells in high uric acid plus high glucose group was the most significant. In vitro and vivo models, detection of inflammatory cytokines revealed that the expression of inflammatory cytokines increased most significantly in high uric acid plus high glucose group. Notch signaling pathway activity was also increased most significantly in high uric acid plus high glucose group. After Notch 1 siRNA transfection in high glucose and high glucose plus uric acid group, the activity of Notch signaling pathway was successfully down-regulated. We found that the apoptosis of HRECs was significantly decreased in cells transfected with Notch 1 siRNA compared to the blank vector group, and the expression of inflammatory cytokines in cells was also significantly decreased. Our study reported that high uric acid can promote the inflammation of the retina and increase the activity of Notch signaling pathway on the basis of high glucose. Hyperuricemia promotes the development of diabetic retinopathy by increasing the activity of Notch signaling pathway. Notch signaling pathway is a potential therapeutic target for diabetic retinopathy. Copyright © 2018. Published by Elsevier Inc.

Expression of WNT5A in Idiopathic Pulmonary Fibrosis and Its Control by TGF-β and WNT7B in Human Lung Fibroblasts.

PubMed

Newman, Donna R; Sills, W Shane; Hanrahan, Katherine; Ziegler, Amanda; Tidd, Kathleen McGinnis; Cook, Elizabeth; Sannes, Philip L

2016-02-01

The wingless (Wnt) family of signaling ligands contributes significantly to lung development and is highly expressed in patients with usual interstitial pneumonia (UIP). We sought to define the cellular distribution of Wnt5A in the lung tissue of patients with idiopathic pulmonary fibrosis (IPF) and the signaling ligands that control its expression in human lung fibroblasts and IPF myofibroblasts. Tissue sections from 40 patients diagnosed with IPF or UIP were probed for the immunolocalization of Wnt5A. Further, isolated lung fibroblasts from normal or IPF human lungs, adenovirally transduced for the overexpression or silencing of Wnt7B or treated with TGF-β1 or its inhibitor, were analyzed for Wnt5A protein expression. Wnt5A was expressed in IPF lungs by airway and alveolar epithelium, smooth muscle cells, endothelium, and myofibroblasts of fibroblastic foci and throughout the interstitium. Forced overexpression of Wnt7B with or without TGF-β1 treatment significantly increased Wnt5A protein expression in normal human smooth muscle cells and fibroblasts but not in IPF myofibroblasts where Wnt5A was already highly expressed. The results demonstrate a wide distribution of Wnt5A expression in cells of the IPF lung and reveal that it is significantly increased by Wnt7B and TGF-β1, which, in combination, could represent key signaling pathways that modulate the pathogenesis of IPF. © 2016 The Histochemical Society.

Expression of the pol gene of human endogenous retroviruses HERV-K and -W in leukemia patients.

PubMed

Bergallo, Massimiliano; Montanari, Paola; Mareschi, Katia; Merlino, Chiara; Berger, Massimo; Bini, Ilaria; Daprà, Valentina; Galliano, Ilaria; Fagioli, Franca

2017-12-01

The human endogenous retroviruses (HERVs) are a family of endogenous retroviruses that integrated into the germ cell DNA of primates over 30 million years ago. HERV expression seems impaired in several diseases, ranging from autoimmune to neoplastic disorders. The purpose of this study was to evaluate the overall endogenous retroviral transcription profile in bone marrow (BM) samples. A total of 30 paediatric high-risk leukaemia patients (lymphoid and myeloid malignancies) were tested for HERVs virus gene expression. Our findings show that HERV-K expression was significantly higher in leukaemia patients when compared to healthy donors of a similar median age. We observed a significantly high expression of HERV-K in acute lymphoblastic leukemia (ALL) patients. In this study, we also found a relative overexpression of the endogenous retrovirus HERV-K in BM cells from the majority of leukemia samples analyzed, in particular in ALL. This overexpression might be related to lymphatic leukemogenesis and it warrants further investigations.

Comparison of myofibroblasts expression in oral squamous cell carcinoma, verrucous carcinoma, high risk epithelial dysplasia, low risk epithelial dysplasia and normal oral mucosa.

PubMed

Chaudhary, Minal; Gadbail, Amol Ramchandra; Vidhale, Gaurav; Mankar Gadbail, Mugdha P; Gondivkar, Shailesh M; Gawande, Madhuri; Patil, Swati

2012-09-01

The aim was to evaluate and compare the presence of myofibroblasts in oral squamous cell carcinoma (OSCC), verrucous carcinoma (VC), high-risk epithelial dysplasia (HRED), low-risk epithelial dysplasia (LRED), and normal oral mucosa (NOM). The study consisted of 37 OSCC, 15 VC, 15 HRED, 15 LRED and 15 NOM. α-smooth muscle actin (α-SMA) antibody was used to identify myofibroblasts. The α-SMA expression was not observed in NOM and LRED. The α-SMA was expressed in 97.29% of OSCC, 86.66% of VC, 46.66 % of HRED. The α-SMA expression was significantly higher in OSCC than VC (p = 0.023) and HRED (p < 0.000). The α-SMA expression was significantly higher in VC than HRED (p = 0.043). Myofibroblastic expression, as highlighted by α-SMA, is undetectable in NOM and LRED but increases as the disease progresses from potentially malignant disorders, as HRED to VC to invasive OSCC. Thus, proliferation of myofibroblasts may be used as a stromal marker of oral premalignancy and malignancy.

Prognostic value of proliferating cell nuclear antigen in parotid gland cancer.

PubMed

Stenner, Markus; Demgensky, Ariane; Molls, Christoph; Hardt, Aline; Luers, Jan C; Grosheva, Maria; Huebbers, Christian U; Klussmann, Jens P

2012-04-01

Although cell proliferation is related to tumour aggressiveness and prognosis, there are few studies describing the expression of proliferative markers in salivary gland cancer. Our aim was to assess the long-term prognostic value of the proliferating cell nuclear antigen (PCNA) in a large group of histologically different salivary gland cancers. We analysed the expression of PCNA in 159 patients with parotid gland cancer by means of immunohistochemistry. The mean follow-up time was 56.6 months. A high expression of PCNA showed a significant correlation to the patients' pathological lymph node stage (p = 0.004). A high PCNA expression significantly indicated a poor 5-year disease-free (p = 0.046) and overall survival rate (p = 0.018). The PCNA expression was the only prognostic factor for a worse 5-year disease-free and overall survival in acinic cell carcinomas (p = 0.004, p = 0.022). The correlation between PCNA expression and survival probabilities of salivary gland cancer might make proliferation markers helpful tools in patient follow-up, prognosis and targeted therapy in salivary gland cancer in future.

MUC4 modulates human glioblastoma cell proliferation and invasion by upregulating EGFR expression.

PubMed

Li, Weihua; Wu, Chunming; Yao, Yiqun; Dong, Bin; Wei, Zhenqing; Lv, Xiupeng; Zhang, Jian; Xu, Yinghui

2014-04-30

Glioblastoma (GBM), the most common primary brain tumor, is the leading cause of deaths related to tumors in the central nervous system. The prognosis of GBM patients is currently poor, and the mechanisms underlying GBM genesis remain unclear. The expression of MUC4, a high-molecular-weight and highly glycosylated protein, has been studied in many cancers. However, information on MUC4 expression in GBM is limited. In this study, we found that MUC4 was overexpressed in GBM cell lines and tissues. The proliferation and invasive potential of GBM cells were significantly increased by the ectopic expression of MUC4. By contrast, RNA interference targeting MUC4 in GBM cells significantly decreased the proliferation and invasive potential of GBM cells. We also found that the expression of epidermal growth factor receptor (EGFR) was modulated by MUC4. EGFR inhibition by siRNA reversed the MUC4-induced proliferation and invasion. These results indicated that MUC4 expression in GBM was important in GBM cell proliferation and invasion, which may be partly associated with EGFR overexpression. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

REGγ regulates ERα degradation via ubiquitin–proteasome pathway in breast cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chai, Fan; Liang, Yan; Bi, Jiong

2015-01-02

Highlights: • High expression of REGγ is correlated with ERα status and poor clinical features. • Cell growth, mobility and invasion are significantly impaired by REGγ knockdown. • REGγ indirectly regulates ERα protein expression. - Abstract: REGγ is a proteasome coactivator which regulates proteolytic activity in eukaryotic cells. Abundant lines of evidence have showed that REGγ is over expressed in a number of human carcinomas. However, its precise role in the pathogenesis of cancer is still unclear. In this study, by examining 200 human breast cancer specimens, we demonstrated that REGγ was highly expressed in breast cancers, and the expressionmore » of REGγ was positively correlated with breast cancer patient estrogen receptor alpha (ERα) status. Moreover, the expression of REGγ was found positively associated with poor clinical features and low survival rates in ERα positive breast cancer patients. Further cell culture studies using MCF7 and BT474 breast cancer cell lines showed that cell proliferation, motility, and invasion capacities were decreased significantly by REGγ knockdown. Lastly, we demonstrated that REGγ indirectly regulates the degradation of ERα protein via ubiquitin–proteasome pathway. In conclusion, our findings provide the evidence that REGγ expression was positively correlated with ERα status and poor clinical prognosis in ERα positive breast cancer patients. As well, we disclose a new connection between the two molecules that are both highly expressed in most breast cancer cases.« less

Prognostic and clinicopathological significance of Cacna2d1 expression in epithelial ovarian cancers: a retrospective study

PubMed Central

Yu, Dandan; Holm, Ruth; Goscinski, Mariusz Adam; Trope, Claes G; Nesland, Jahn M; Suo, Zhenhe

2016-01-01

Ovarian cancer is the most lethal gynecologic malignancy, in which cancer stem cells (CSC) have been reported to be the driving force of relapse and therapy-resistance. It is therefore important to explore CSC markers in ovarian cancer. This project aimed to explore the correlation between the expression of potential CSC maker Cacna2d1 and clinicopathological parameters in 238 epithelial ovarian cancer (EOC) samples. Immunohistochemically, positive Cacna2d1 expression was observed in 83.6% (199/238) of the EOC tumors, among which 107 tumors (44.9%) were highly positive and 92 (38.7%) tumors were weakly positive for the Cacna2d1 protein expression. Among the 158 serous carcinomas, the Cacna2d1 positivity was 148 (93.7%), in which 88 (55.7%) were highly positive, and 60 (38.0%) were weakly positive for the Cacna2d1 protein expression. Most strikingly, the Cacna2d1 was specifically expressed in the infiltration front areas of the EOC tumors. Statistical analyses showed that positive expression of Cacna2d1 was significantly associated with advanced FIGO stage (P<0.001), histological subtype (P=0.017) and tumor differentiation (P=0.015). Positive Cacna2d1 protein expression was significantly associated with poor overall survival (OS) and shorter progression free survival (PFS) in both total EOCs and serous carcinomas, although multivariate analyses did not reach statistical significance. In summary, our results suggest Cacna2d1 protein may play a crucial role in promoting aggressive EOC behavior and progression, and Cacna2d1 may serve as a novel predictive prognostic marker and a potential target for therapeutic intervention in EOCs. PMID:27725913

Evaluation of the collaborative network of highly correlating skin proteins and its change following treatment with glucocorticoids

PubMed Central

2010-01-01

Background Glucocorticoids (GC) represent the core treatment modality for many inflammatory diseases. Its mode of action is difficult to grasp, not least because it includes direct modulation of many components of the extracellular matrix as well as complex anti-inflammatory effects. Protein expression profile of skin proteins is being changed with topical application of GC, however, the knowledge about singular markers in this regard is only patchy and collaboration is ill defined. Material/Methods Scar formation was observed under different doses of GC, which were locally applied on the back skin of mice (1 to 3 weeks). After euthanasia we analyzed protein expression of collagen I and III (picrosirius) in scar tissue together with 16 additional protein markers, which are involved in wound healing, with immunhistochemistry. For assessing GC's effect on co-expression we compared our results with a model of random figures to estimate how many significant correlations should be expected by chance. Results GC altered collagen and protein expression with distinct results in different areas of investigation. Most often we observed a reduced expression after application of low dose GC. In the scar infiltrate a multivariate analysis confirmed the significant impact of both GC concentrations. Calculation of Spearman's correlation coefficient similarly resulted in a significant impact of GC, and furthermore, offered the possibility to grasp the entire interactive profile in between all variables studied. The biological markers, which were connected by significant correlations could be arranged in a highly cross-linked network that involved most of the markers measured. A marker highly cross-linked with more than 3 significant correlations was indicated by a higher variation of all its correlations to the other variables, resulting in a standard deviation of > 0.2. Conclusion In addition to immunohistochemical analysis of single protein markers multivariate analysis of co-expressions by use of correlation coefficients reveals the complexity of biological relationships and identifies complex biological effects of GC on skin scarring. Depiction of collaborative clusters will help to understand functional pathways. The functional importance of highly cross-linked proteins will have to be proven in subsequent studies. PMID:20509951

Ischemia and reperfusion induce differential expression of calpastatin and its homologue high molecular weight calmodulin-binding protein in murine cardiomyocytes.

PubMed

Parameswaran, Sreejit; Sharma, Rajendra K

2014-01-01

In the heart, calpastatin (Calp) and its homologue high molecular weight calmodulin-binding protein (HMWCaMBP) regulate calpains (Calpn) by inhibition. A rise in intracellular myocardial Ca2+ during cardiac ischemia activates Calpn thereby causing damage to myocardial proteins, which leads to myocyte death and consequently to loss of myocardial structure and function. The present study aims to elucidate expression of Calp and HMWCaMBP with respect to Calpn during induced ischemia and reperfusion in primary murine cardiomyocyte cultures. Ischemia and subsequently reperfusion was induced in ∼ 80% confluent cultures of neonatal murine cardiomyocytes (NMCC). Flow cytometric analysis (FACS) has been used for analyzing protein expression concurrently with viability. Confocal fluorescent microscopy was used to observe protein localization. We observed that ischemia induces increased expression of Calp, HMWCaMBP and Calpn. Calpn expressing NMCC on co-expressing Calp survived ischemic induction compared to NMCC co-expressing HMWCaMBP. Similarly, living cells expressed Calp in contrast to dead cells which expressed HMWCaMBP following reperfusion. A significant difference in the expression of Calp and its homologue HMWCaMBP was observed in localization studies during ischemia. The current study adds to the existing knowledge that HMWCaMBP could be a putative isoform of Calp. NMCC on co-expressing Calp and Calpn-1 survived ischemic and reperfusion inductions compared to NMCC co-expressing HMWCaMBP and Calpn-1. A significant difference in expression of Calp and HMWCaMBP was observed in localization studies during ischemia.

Gene expression regulation of the TLR9 and MyD88-dependent pathways in rock bream against rock bream iridovirus (RBIV) infection.

PubMed

Jung, Myung-Hwa; Jung, Sung-Ju

2017-11-01

Rock bream iridovirus (RBIV), which is a member of the Megalocytivirus genus, causes severe mass mortalities in rock bream in Korea. To date, the innate immune defense mechanisms of rock bream against RBIV is unclear. In this study, we assessed the expression levels of genes related to TLR9 and MyD88-dependent pathways in RBIV-infected rock bream in high, low or no mortality conditions. In the high mortality group (100% mortality at 15 days post infection (dpi)), high levels of TLR9 and MyD88 expressions (6.4- and 2.4-fold, respectively) were observed at 8 d and then reduced (0.6- and 0.1-fold, respectively) with heavy viral loads at 10 dpi (2.21 × 10 7 /μl). Moreover, TRAF6, IRF5, IL1β, IL8, IL12 and TNFα expression levels showed no statistical significance until 10 dpi. Conversely, in the low mortality group (28% expected mortality at 35 dpi), TLR9, MyD88 and TRAF6 expression levels were significantly higher than those in the control group at several sampling points until 30 dpi. Higher levels of IRF5, IL1β, IL8, IL12 and TNFα expression were also observed, however, these were not significantly different from those of the control group. In the no mortality group (0% mortality at 40 dpi), significantly higher levels of MyD88 (2 d, 4 d and 40 dpi), TRAF6 (2 dpi), IL1β (4 dpi) and IL8 (2 d and 4 dpi) expression were observed. In summary, RBIV-infected rock bream induces innate immune response, which could be a major contributing factor to effective fish control over viral transcription. MyD88, TRAF6, IL1β and IL8-related immune responses were activated in fish survivor condition (low or no mortality group). This is a critical factor for RBIV disease recovery; however, these immune responses did not efficiently respond in fish dead condition (high mortality group). Copyright © 2017 Elsevier Ltd. All rights reserved.

Expression of NF-κB and PTEN in osteosarcoma and its clinical significance

PubMed Central

Gong, Teng; Su, Xuetao; Xia, Qun; Wang, Jinggui; Kan, Shilian

2017-01-01

We investigated the role of nuclear factor-κB (NF-κB) and phosphatase and tensin homolog deleted in chromosome 10 (PTEN) in the pathogenesis of osteosarcoma and its relationship with prognosis. Immunohistochemical method was used to detect the expression of NF-κB and PTEN in osteosarcoma and adjacent tissues. RT-PCR was used to detect the expression of NF-κB and PTEN mRNA in osteosarcoma and adjacent tissues. Western blotting was used to detect the expression of NF-κB and PTEN in osteosarcoma and adjacent tissues and compare their differences. The expression of NF-κB and PTEN was detected in osteosarcoma and adjacent tissues. The positive rate of NF-κB was 75.3 and 32.9%, respectively; while the positive rate of PTEN was 67.1 and 90.4%, respectively. The positive expression of NF-κB and PTEN was statistically significant. There was a negative correlation between NF-κB and PTEN expression (r=−0.502, p<0.05). The positive and negative expression of NF-κB and PTEN was statistically significant for the five-year survival (p<0.05). At gene and protein level, osteosarcoma tissues had higher expression of NF-κB, and lower expression of PTEN, which was significantly different from the adjacent tissues. In osteosarcoma, NF-κB is highly expressed, but PTEN is expressed at low level, and the two are negatively correlated. This is of great significance for the early diagnosis of osteosarcoma and prognosis. PMID:29151913

Pure versus combined Merkel cell carcinomas: immunohistochemical evaluation of cellular proteins (p53, Bcl-2, and c-kit) reveals significant overexpression of p53 in combined tumors.

PubMed

Lai, Jonathan H; Fleming, Kirsten E; Ly, Thai Yen; Pasternak, Sylvia; Godlewski, Marek; Doucette, Steve; Walsh, Noreen M

2015-09-01

Merkel cell polyomavirus is of oncogenic significance in approximately 80% of Merkel cell carcinomas. Morphological subcategories of the tumor differ in regard to viral status, the rare combined type being uniformly virus negative and the predominant pure type being mainly virus positive. Indications that different biological subsets of the tumor exist led us to explore this diversity. In an Eastern Canadian cohort of cases (75 patients; mean age, 76 years [range, 43-91]; male/female ratio, 43:32; 51 [68%] pure and 24 [34%] combined tumors), we semiquantitatively compared the immunohistochemical expression of 3 cellular proteins (p53, Bcl-2, and c-kit) in pure versus combined groups. Viral status was known in a subset of cases. The significant overexpression of p53 in the combined group (mean [SD], 153.8 [117.8] versus 121.6 [77.9]; P = .01) and the increased epidermal expression of this protein (p53 patches) in the same group lend credence to a primary etiologic role for sun damage in these cases. Expression of Bcl-2 and c-kit did not differ significantly between the 2 morphological groups. A relative increase in c-kit expression was significantly associated with a virus-negative status (median [interquartile range], 100 [60-115] versus 70 [0-100]; P = .03). Emerging data reveal divergent biological pathways in Merkel cell carcinoma, each with a characteristic immunohistochemical profile. Virus-positive tumors (all pure) exhibit high retinoblastoma protein and low p53 expression, whereas virus-negative cases (few pure and all combined) show high p53 and relatively high c-kit expression. The potential biological implications of this dichotomy call for consistent stratification of these tumors in future studies. Copyright © 2015 Elsevier Inc. All rights reserved.

The expression of MUC mucin in cholangiocarcinoma.

PubMed

Mall, Anwar S; Tyler, Marilyn G; Ho, Sam B; Krige, Jake E J; Kahn, Delawir; Spearman, Wendy; Myer, Landon; Govender, Dhirendra

2010-12-15

Cholangiocarcinoma (CC) is a highly malignant epithelial cancer of the biliary tract, the cellular and molecular pathogenesis of which remains unclear. Malignant transformation of glandular epithelial cells is associated with the altered expression of mucin. We investigated the type of mucins expressed in CC. Twenty-six patients with histologically confirmed CC were included in this study. The expression of mucin was studied by immunohistochemistry using antibodies to MUC1, MUC1 core, MUC2, MUC3, MUC4, MUC5AC, and MUC6. There was extensive (>50%) expression of mucin, mainly MUC1 in 11/25 and MUC5AC in 12/26 cases. In the case of MUC3, 6/26 cases expressed mucin extensively, whilst only 1/26 had MUC2, MUC4, and MUC6 expression. Well-differentiated tumors significantly expressed MUC3 extensively compared to poor or moderately differentiated tumors (p=0.003). Fifteen of 25 cases had metastatic disease. MUC1 was extensively expressed in 9/15 cases with metastatic disease. In contrast, MUC1 expression was present in 2/10 cases where metastases were absent. Hilar lesions were less likely to express MUC1, but this was not statistically significant. Fifteen of 25 cases had metastatic disease. Extensive MUC3 expression was significantly associated with well-differentiated tumors, whilst there was an approaching significance between the extensive expression of MUC1 and metastasis in cholangiocarcinoma. Copyright © 2010 Elsevier GmbH. All rights reserved.

Expression Differentiation Is Constrained to Low-Expression Proteins over Ecological Timescales

PubMed Central

Margres, Mark J.; Wray, Kenneth P.; Seavy, Margaret; McGivern, James J.; Herrera, Nathanael D.; Rokyta, Darin R.

2016-01-01

Protein expression level is one of the strongest predictors of protein sequence evolutionary rate, with high-expression protein sequences evolving at slower rates than low-expression protein sequences largely because of constraints on protein folding and function. Expression evolutionary rates also have been shown to be negatively correlated with expression level across human and mouse orthologs over relatively long divergence times (i.e., ∼100 million years). Long-term evolutionary patterns, however, often cannot be extrapolated to microevolutionary processes (and vice versa), and whether this relationship holds for traits evolving under directional selection within a single species over ecological timescales (i.e., <5000 years) is unknown and not necessarily expected. Expression is a metabolically costly process, and the expression level of a particular protein is predicted to be a tradeoff between the benefit of its function and the costs of its expression. Selection should drive the expression level of all proteins close to values that maximize fitness, particularly for high-expression proteins because of the increased energetic cost of production. Therefore, stabilizing selection may reduce the amount of standing expression variation for high-expression proteins, and in combination with physiological constraints that may place an upper bound on the range of beneficial expression variation, these constraints could severely limit the availability of beneficial expression variants. To determine whether rapid-expression evolution was restricted to low-expression proteins owing to these constraints on highly expressed proteins over ecological timescales, we compared venom protein expression levels across mainland and island populations for three species of pit vipers. We detected significant differentiation in protein expression levels in two of the three species and found that rapid-expression differentiation was restricted to low-expression proteins. Our results suggest that various constraints on high-expression proteins reduce the availability of beneficial expression variants relative to low-expression proteins, enabling low-expression proteins to evolve and potentially lead to more rapid adaptation. PMID:26546003

Collagen Triple Helix Repeat Containing-1 (CTHRC1) Expression in Oral Squamous Cell Carcinoma (OSCC): Prognostic Value and Clinico-Pathological Implications

PubMed Central

Lee, Chia Ee; Vincent-Chong, Vui King; Ramanathan, Anand; Kallarakkal, Thomas George; Karen-Ng, Lee Peng; Ghani, Wan Maria Nabillah; Rahman, Zainal Ariff Abdul; Ismail, Siti Mazlipah; Abraham, Mannil Thomas; Tay, Keng Kiong; Mustafa, Wan Mahadzir Wan; Cheong, Sok Ching; Zain, Rosnah Binti

2015-01-01

BACKGROUND: Collagen Triple Helix Repeat Containing 1 (CTHRC1) is a protein often found to be over-expressed in various types of human cancers. However, correlation between CTHRC1 expression level with clinico-pathological characteristics and prognosis in oral cancer remains unclear. Therefore, this study aimed to determine mRNA and protein expression of CTHRC1 in oral squamous cell carcinoma (OSCC) and to evaluate the clinical and prognostic impact of CTHRC1 in OSCC. METHODS: In this study, mRNA and protein expression of CTHRC1 in OSCCs were determined by quantitative PCR and immunohistochemistry, respectively. The association between CTHRC1 and clinico-pathological parameters were evaluated by univariate and multivariate binary logistic regression analyses. Correlation between CTHRC1 protein expressions with survival were analysed using Kaplan-Meier and Cox regression models. RESULTS: Current study demonstrated CTHRC1 was significantly overexpressed at the mRNA level in OSCC. Univariate analyses indicated a high-expression of CTHRC1 that was significantly associated with advanced stage pTNM staging, tumour size ≥ 4 cm and positive lymph node metastasis (LNM). However, only positive LNM remained significant after adjusting with other confounder factors in multivariate logistic regression analyses. Kaplan-Meier survival analyses and Cox model demonstrated that patients with high-expression of CTHRC1 protein were associated with poor prognosis and is an independent prognostic factor in OSCC. CONCLUSION: This study indicated that over-expression of CTHRC1 potentially as an independent predictor for positive LNM and poor prognosis in OSCC. PMID:26664254

c-Met in esophageal squamous cell carcinoma: an independent prognostic factor and potential therapeutic target.

PubMed

Ozawa, Yohei; Nakamura, Yasuhiro; Fujishima, Fumiyoshi; Felizola, Saulo J A; Takeda, Kenichiro; Okamoto, Hiroshi; Ito, Ken; Ishida, Hirotaka; Konno, Takuro; Kamei, Takashi; Miyata, Go; Ohuchi, Noriaki; Sasano, Hironobu

2015-06-03

c-Met is widely known as a poor prognostic factor in various human malignancies. Previous studies have suggested the involvement of c-Met and/or its ligand, hepatocyte growth factor (HGF), in esophageal squamous cell carcinoma (ESCC), but the correlation between c-Met status and clinical outcome remains unclear. Furthermore, the identification of a novel molecular therapeutic target might potentially help improve the clinical outcome of ESCC patients. The expression of c-Met and HGF was immunohistochemically assessed in 104 surgically obtained tissue specimens. The correlation between c-Met/HGF expression and patients' clinicopathological features, including survival, was evaluated. We also investigated changes in cell functions and protein expression of c-Met and its downstream signaling pathway components under treatments with HGF and/or c-Met inhibitor in ESCC cell lines. Elevated expression of c-Met was significantly correlated with tumor depth and pathological stage. Patients with high c-Met expression had significantly worse survival. In addition, multivariate analysis identified the high expression of c-Met as an independent prognostic factor. Treatment with c-Met inhibitor under HGF stimulation significantly inhibited the invasive capacity of an ESCC cell line with elevated c-Met mRNA expression. Moreover, c-Met and its downstream signaling inactivation was also detected after treatment with c-Met inhibitor. The results of our study identified c-Met expression as an independent prognostic factor in ESCC patients and demonstrated that c-Met could be a potential molecular therapeutic target for the treatment of ESCC with elevated c-Met expression.

The Role of Id2 Protein in Neuroblatoma in Children.

PubMed

Wieczorek, Aleksandra; Balwierz, Walentyna

2015-09-01

Id (DNA binding and/or differentiation) proteins occur physiologically during ontogenesis and negatively regulate the activity of other helix-loop-helix (HLH) proteins. Id2 protein causes block of cells differentiation in the S phase of the cell cycle and regulates the activity of Rb protein. The role of Id2 protein in physiological cell cycle progression and in neuroblastoma (NBL) pathogenesis was proposed by Lasorella. The aim of the study was evaluation of Id2 expression and its prognostic significance in NBL cells coming from primary tumors and evaluation of its prognostic significance, and correlation of Id2 expression with known prognostic factors. Sixty patients with primary NBL treated from 1991 to 2005 were included in the analysis. We found 50 patients with high and 10 patients with low intensity of Id2 expression. The median percentage of NBL cells with Id2 expression was 88 %. We found no correlation between the number of NBL cells or the intensity of Id2 expression and OS and DFS. In patients with stage 4 NBL, almost all patients had high expression of Id2 and it was significantly more common than in other disease stages (p = 0,03). We found no correlation between Id2 expression and other known prognostic factor in NBL patients. We assume that Id2 is not prognostic factor. However, due to its abundant expression in most of NBL cells and its role in cell cycle, it may be potential therapeutic target. Exact knowledge of expression time may be helpful in explaining mechanisms of oncogenesis.

Identification of Rubisco rbcL and rbcS in Camellia oleifera and their potential as molecular markers for selection of high tea oil cultivars.

PubMed

Chen, Yongzhong; Wang, Baoming; Chen, Jianjun; Wang, Xiangnan; Wang, Rui; Peng, Shaofeng; Chen, Longsheng; Ma, Li; Luo, Jian

2015-01-01

Tea oil derived from seeds of Camellia oleifera Abel. is high-quality edible oil in China. This study isolated full-length cDNAs of Rubisco subunits rbcL and rbcS from C. oleifera. The rbcL has 1,522 bp with a 1,425 bp coding region, encoding 475 amino acids; and the rbcS has 615 bp containing a 528 bp coding region, encoding 176 amino acids. The expression level of the two genes, designated as Co-rbcL and Co-rbcS, was determined in three C. oleifera cultivars: Hengchong 89, Xianglin 1, and Xianglin 14 whose annual oil yields were 546.9, 591.4, and 657.7 kg ha(-1), respectively. The Co-rbcL expression in 'Xianglin 14' was significantly higher than 'Xianglin 1', and 'Xianglin 1' was greater than 'Hengchong 89'. The expression levels of Co-rbcS in 'Xianglin 1' and 'Xianglin 14' were similar but were significantly greater than in 'Hengchong 89'. The net photosynthetic rate of 'Xianglin 14' was significantly higher than 'Xianglin 1', and 'Xianglin 1' was higher than 'Hengchong 89'. Pearson's correlation analysis showed that seed yields and oil yields were highly correlated with the expression level of Co-rbcL at P < 0.001 level; and the expression of Co-rbcS was correlated with oil yield at P < 0.01 level. Net photosynthetic rate was also correlated with oil yields and seed yields at P < 0.001 and P < 0.01 levels, respectively. Our results suggest that Co-rbcS and Co-rbcL in particular could potentially be molecular markers for early selection of high oil yield cultivars. In combination with the measurement of net photosynthetic rates, the early identification of potential high oil production cultivars would significantly shorten plant breeding time and increase breeding efficiency.

Dasatinib is preclinically active against Src-overexpressing human transitional cell carcinoma of the urothelium with activated Src signaling.

PubMed

Levitt, Jonathan M; Yamashita, Hideyuki; Jian, Weiguo; Lerner, Seth P; Sonpavde, Guru

2010-05-01

Dasatinib is an orally administered multitargeted kinase inhibitor that targets Src family tyrosine kinases, Abl, c-Kit, and PDGFR. A preclinical study was conducted to evaluate dasatinib alone or combined with cisplatin for human transitional cell carcinoma (TCC). Expression of Src in a human TCC tissue microarray was evaluated by immunohistochemistry. The activity of dasatinib and/or cisplatin was evaluated in six human TCC cell lines. Western blot was done to assess Src and phosphorylated-Src (p-Src) expression. The activity of dasatinib alone and in combination with cisplatin was determined in murine subcutaneous xenografts. Sixty-two percent to 75% of human TCC expressed Src. Dasatinib displayed significant antiproliferative activity at nanomolar concentrations against two human TCC cell lines (RT4 and Hu456) that exhibited high Src and p-Src expression and were cisplatin-resistant. RT4 cells were the most sensitive and displayed the highest level of Src pathway activation (p-Src/Src ratio). Dasatinib downregulated p-Src in either sensitive or resistant cells. TCC cells that were sensitive to cisplatin (5637 and TCC-SUP) were highly resistant to dasatinib and exhibited low Src expression. Dasatinib showed antitumor activity in RT4 murine xenografts, and the combination of dasatinib and cisplatin was significantly more active than placebo. Combination dasatinib plus cisplatin significantly inhibited proliferation and promoted apoptosis in vivo. In conclusion, dasatinib displayed significant preclinical antitumor activity against Src-overexpressing human TCC with active Src signaling and was highly active in combination with cisplatin in vivo. Further clinical development might be warranted in selected human subjects.

Molecular cloning, phylogenetic analysis, and expression profiling of endoplasmic reticulum molecular chaperone BiP genes from bread wheat (Triticum aestivum L.).

PubMed

Zhu, Jiantang; Hao, Pengchao; Chen, Guanxing; Han, Caixia; Li, Xiaohui; Zeller, Friedrich J; Hsam, Sai L K; Hu, Yingkao; Yan, Yueming

2014-10-01

The endoplasmic reticulum chaperone binding protein (BiP) is an important functional protein, which is involved in protein synthesis, folding assembly, and secretion. In order to study the role of BiP in the process of wheat seed development, we cloned three BiP homologous cDNA sequences in bread wheat (Triticum aestivum), completed by rapid amplification of cDNA ends (RACE), and examined the expression of wheat BiP in wheat tissues, particularly the relationship between BiP expression and the subunit types of HMW-GS using near-isogenic lines (NILs) of HMW-GS silencing, and under abiotic stress. Sequence analysis demonstrated that all BiPs contained three highly conserved domains present in plants, animals, and microorganisms, indicating their evolutionary conservation among different biological species. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) revealed that TaBiP (Triticum aestivum BiP) expression was not organ-specific, but was predominantly localized to seed endosperm. Furthermore, immunolocalization confirmed that TaBiP was primarily located within the protein bodies (PBs) in wheat endosperm. Three TaBiP genes exhibited significantly down-regulated expression following high molecular weight-glutenin subunit (HMW-GS) silencing. Drought stress induced significantly up-regulated expression of TaBiPs in wheat roots, leaves, and developing grains. The high conservation of BiP sequences suggests that BiP plays the same role, or has common mechanisms, in the folding and assembly of nascent polypeptides and protein synthesis across species. The expression of TaBiPs in different wheat tissue and under abiotic stress indicated that TaBiP is most abundant in tissues with high secretory activity and with high proportions of cells undergoing division, and that the expression level of BiP is associated with the subunit types of HMW-GS and synthesis. The expression of TaBiPs is developmentally regulated during seed development and early seedling growth, and under various abiotic stresses.

[Expression and clinical significance of Pokemon in non-small cell lung cancer].

PubMed

Zhao, Zhihong; Wang, Shengfa; Zhang, Tiewa

2007-12-20

Proto-oncogene Pokemon is the special transcription inhibitor of ARF,which can regulate cell growth and differentiation by ARF-P53 path.It may be the important monitoring target of tumor because of being upstream region of many tumor suppressor genes and proto-oncogenes.The aim of this study is to explore the clinical significance of Pokemon gene in non-small cell lung cancer(NSCLC). Immunohistochemistry was applied to detect the expression of Pokemon protein in 92 cases of NSCLC and 20 cases of paracancerous lung tissues.Correlation between abnormal expression of Pokemon with pathologic characteristics and prognosis of NSCLC was analyzed. Pokemon was not expressed in paracancerous lung tissues and was found in 66 of 92(71.7%) cases of lung cancer tissues.Expression of Pokemon was closely related to TNM stages(P=0.011).Survival rate of patients with negative Pokemon expression was significantly higher than that of those with positive Pokemon expression(P=0.0015).Pokemon expression was demonstrated as independent prognostic factor of NSCLC. Pokemon is expressed in NSCLC and it may be identified as a new diagnostic marker.High expression of Pokemon may indicate poor prognosis of patients with NSCLC.

Road rage: an exploratory study on aggressive driving experience on Indian roads.

PubMed

Sagar, Rajesh; Mehta, Manju; Chugh, Geetanjali

2013-06-01

Driving on Indian roads is a stressful experience. A lacuna of research on aggressive driving experiences in the Indian set-up highlights the need to address this growing concern for individuals, society and mental health professionals. To explore and compare driving-related anger triggers and anger expression among high- and low-angry Indian drivers. Two hundred randomly chosen drivers from the city of Delhi were administered a semi-structured questionnaire intended to understand driving-related aggression. Honking, overtaking from the wrong side, loud music in other cars and hot and humid climate significantly increased the risk of experiencing anger among high-angry drivers. High-angry drivers were significantly more likely to engage in direct and aggressive expression of anger, including overtaking, verbal abuse, yelling and arguing, not giving space to other drivers, fighting, and hitting and bumping other cars in protest. Passive anger expressions such as holding grudges against other drivers and eating or drinking something to cool down were significantly more likely to be used by low-angry drivers. Drivers who are high on anger have a significantly higher risk of experiencing anger triggered by a variety of individual and environmental factors on Indian roads and are more susceptible to engage in aggressive driving behaviour.

Rice Bran Protein Hydrolysates Improve Insulin Resistance and Decrease Pro-inflammatory Cytokine Gene Expression in Rats Fed a High Carbohydrate-High Fat Diet

PubMed Central

Boonloh, Kampeebhorn; Kukongviriyapan, Veerapol; Kongyingyoes, Bunkerd; Kukongviriyapan, Upa; Thawornchinsombut, Supawan; Pannangpetch, Patchareewan

2015-01-01

A high carbohydrate-high fat (HCHF) diet causes insulin resistance (IR) and metabolic syndrome (MS). Rice bran has been demonstrated to have anti-dyslipidemic and anti-atherogenic properties in an obese mouse model. In the present study, we investigated the beneficial effects of rice bran protein hydrolysates (RBP) in HCHF-induced MS rats. After 12 weeks on this diet, the HCHF-fed group was divided into four subgroups, which were orally administered RBP 100 or 500 mg/kg, pioglitazone 10 mg/kg, or tap water for a further 6 weeks. Compared with normal diet control group, the MS rats had elevated levels of blood glucose, lipid, insulin, and HOMA-IR. Treatment with RBP significantly alleviated all those changes and restored insulin sensitivity. Additionally, RBP treatment increased adiponectin and suppressed leptin levels. Expression of Ppar-γ mRNA in adipose tissues was significantly increased whereas expression of lipogenic genes Srebf1 and Fasn was significantly decreased. Levels of mRNA of proinflammatory cytokines, Il-6, Tnf-α, Nos-2 and Mcp-1 were significantly decreased. In conclusion, the present findings support the consumption of RBP as a functional food to improve insulin resistance and to prevent the development of metabolic syndrome. PMID:26247962

The allostatic impact of chronic ethanol on gene expression: A genetic analysis of chronic intermittent ethanol treatment in the BXD cohort

PubMed Central

van der Vaart, Andrew D.; Wolstenholme, Jennifer T.; Smith, Maren L.; Harris, Guy M.; Lopez, Marcelo F.; Wolen, Aaron R.; Becker, Howard C.; Williams, Robert W.; Miles, Michael F.

2016-01-01

The transition from acute to chronic ethanol exposure leads to lasting behavioral and physiological changes such as increased consumption, dependence, and withdrawal. Changes in brain gene expression are hypothesized to underlie these adaptive responses to ethanol. Previous studies on acute ethanol identified genetic variation in brain gene expression networks and behavioral responses to ethanol across the BXD panel of recombinant inbred mice. In this work, we have performed the first joint genetic and genomic analysis of transcriptome shifts in response to chronic intermittent ethanol (CIE) by vapor chamber exposure in a BXD cohort. CIE treatment is known to produce significant and sustained changes in ethanol consumption with repeated cycles of ethanol vapor. Using Affymetrix microarray analysis of prefrontal cortex (PFC) and nucleus accumbens (NAC) RNA, we compared CIE expression responses to those seen following acute ethanol treatment, and to voluntary ethanol consumption. Gene expression changes in PFC and NAC after CIE overlapped significantly across brain regions and with previously published expression following acute ethanol. Genes highly modulated by CIE were enriched for specific biological processes including synaptic transmission, neuron ensheathment, intracellular signaling, and neuronal projection development. Expression quantitative trait locus (eQTL) analyses identified genomic loci associated with ethanol-induced transcriptional changes with largely distinct loci identified between brain regions. Correlating CIE-regulated genes to ethanol consumption data identified specific genes highly associated with variation in the increase in drinking seen with repeated cycles of CIE. In particular, multiple myelin-related genes were identified. Furthermore, genetic variance in or near dynamin3 (Dnm3) on Chr1 at ~164 Mb may have a major regulatory role in CIE-responsive gene expression. Dnm3 expression correlates significantly with ethanol consumption, is contained in a highly ranked functional group of CIE-regulated genes in the NAC, and has a cis-eQTL within a genomic region linked with multiple CIE-responsive genes. PMID:27838001

Comparative prognostic value of epidermal growth factor quantitative protein expression compared with FISH for head and neck squamous cell carcinoma.

PubMed

Pectasides, Eirini; Rampias, Theodore; Kountourakis, Panteleimon; Sasaki, Clarence; Kowalski, Diane; Fountzilas, George; Zaramboukas, Thomas; Rimm, David; Burtness, Barbara; Psyrri, Amanda

2011-05-01

Epidermal growth factor receptor (EGFR) overexpression correlates with recurrence and with treatment resistance in head and neck squamous cell carcinoma (HNSCC). The aim of this study was to evaluate the relationship of EGFR gene copy number utilizing FISH and protein expression with automated quantitative analysis (AQUA) and to correlate those with patient outcome. A tissue microarray composed of 102 HNSCC treated with (chemo)radiation was constructed and analyzed for EGFR copy number by FISH (Vysis; Abbott Laboratories) and EGFR protein expression using AQUA analysis of EGFR staining scored on a scale of 0 to 255. We evaluated associations of EGFR FISH status and AQUA score with clinicopathologic parameters and survival prognosis. Eleven (17.2%) of 64 tumors with FISH results showed EGFR high polysomy and/or gene amplification (FISH positive). Protein levels assessed by AQUA in FISH-positive cases were significantly higher (P = 0.04) than in FISH-negative cases. Using the continuous AQUA scores for EGFR expression, AQUA and FISH showed significant agreement (Pearson's ρ = 0.353, P = 0.04). Patients with high tumor EGFR protein expression had inferior 5-year overall survival (27.7%) compared with those with low tumor EGFR expression (54%; P = 0.029). There was no significant association between EGFR FISH status and overall survival (P = 0.201). In the multivariate model, high tumor EGFR protein expression status remained an independent prognostic factor for overall survival (P = 0.047). EGFR protein content correlates with gene copy number if protein content is quantitated and automatically analyzed, as with AQUA. EGFR protein levels assessed by AQUA strongly predict for patient outcome in HNSCC, whereas EGFR FISH status does not provide prognostic information. ©2011 AACR.

DNA-dependent protein kinase catalytic subunit functions in metastasis and influences survival in advanced-stage laryngeal squamous cell carcinoma.

PubMed

He, Sha-Sha; Chen, Yong; Shen, Xiao-Ming; Wang, Hong-Zhi; Sun, Peng; Dong, Jun; Guo, Gui-Fang; Chen, Ju-Gao; Xia, Liang-Ping; Hu, Pei-Li; Qiu, Hui-Juan; Liu, Shou-Sheng; Zhou, Yi-Xin; Wang, Wei; Hu, Wei-Han; Cai, Xiu-Yu

2017-01-01

Background: DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is known to function in several types of cancer. In this study, we investigated the expression and clinicopathologic significance of DNA-PKcs in laryngeal squamous cell carcinoma (LSCC). Methods: We conducted a retrospective study of 208 patients with advanced-stage LSCC treated at Sun Yat-sen University Cancer Center, Guangzhou, China. We assessed DNA-PKcs and p16INK4a (p16) status using immunohistochemistry. We examined the association between DNA-PKcs expression and clinicopathologic features and survival outcomes. To evaluate the independent prognostic relevance of DNA-PKcs, we used univariate and multivariate Cox regression models. We estimated overall survival (OS) and distant metastasis-free survival (DMFS) using the Kaplan-Meier method. Results: Immunohistochemical analyses revealed that 163/208 (78.4%) of the LSCC tissue samples exhibited high DNA-PKcs expression. High DNA-PKcs expression was significantly associated with survival outcomes ( P = 0.016) and distant metastasis ( P = 0.02; chi-squared test). High DNA-PKcs expression was associated with a significantly shorter OS and DMFS than low DNA-PKcs expression ( P = 0.029 and 0.033, respectively; log-rank test), and was associated with poor OS in the p16-positive subgroup ( P = 0.047). Multivariate analysis identified DNA-PKcs as an independent prognostic indicator of OS and DMFS in all patients ( P = 0.039 and 0.037, respectively). Conclusions : Our results suggest that patients with LSCC in whom DNA-PKcs expression is elevated have a higher incidence of distant metastasis and a poorer prognosis. DNA-PKcs may represent a marker of tumor progression in patients with p16-positive LSCC.

Altered Left Ventricular Ion Channel Transcriptome in a High-Fat-Fed Rat Model of Obesity: Insight into Obesity-Induced Arrhythmogenesis

PubMed Central

Yon, Marianne; Pickavance, Lucy; Yanni Gerges, Joseph; Davis, Gershan; Wilding, John; Jian, Kun; Hart, George; Boyett, Mark

2016-01-01

Introduction. Obesity is increasingly common and is associated with an increased prevalence of cardiac arrhythmias. The aim of this study was to see whether in obesity there is proarrhythmic gene expression of ventricular ion channels and related molecules. Methods and Results. Rats were fed on a high-fat diet and compared to control rats on a normal diet (n = 8). After 8 weeks, rats on the high-fat diet showed significantly greater weight gain and higher adiposity. Left ventricle samples were removed at 8 weeks and mRNA expression of ion channels and other molecules was measured using qPCR. Obese rats had significant upregulation of Cav1.2, HCN4, Kir2.1, RYR2, NCX1, SERCA2a, and RYR2 mRNA and downregulation of ERG mRNA. In the case of HCN4, it was confirmed that there was a significant increase in protein expression. The potential effects of the mRNA changes on the ventricular action potential and intracellular Ca2+ transient were predicted using computer modelling. Modelling predicted prolongation of the ventricular action potential and an increase in the intracellular Ca2+ transient, both of which would be expected to be arrhythmogenic. Conclusion. High-fat diet causing obesity results in arrhythmogenic cardiac gene expression of ion channels and related molecules. PMID:27747100

Protein disorder is positively correlated with gene expression in E. coli

PubMed Central

Paliy, Oleg; Gargac, Shawn M.; Cheng, Yugong; Uversky, Vladimir N.; Dunker, A. Keith

2009-01-01

We considered on a global scale the relationship between the predicted fraction of protein disorder and RNA and protein expression in E. coli. Fraction of protein disorder correlated positively with both measured RNA expression levels of E. coli genes in three different growth media and with predicted abundance levels of E. coli proteins. Though weak, the correlation was highly significant. Correlation of protein disorder with RNA expression did not depend on the growth rate of E. coli cultures and was not caused by a small subset of genes showing exceptionally high concordance in their disorder and expression levels. Global analysis was complemented by detailed consideration of several groups of proteins. PMID:18465893

Cultural Differences in Affect Intensity Perception in the Context of Advertising

PubMed Central

Pogosyan, Marianna; Engelmann, Jan B.

2011-01-01

Cultural differences in the perception of positive affect intensity within an advertising context were investigated among American, Japanese, and Russian participants. Participants were asked to rate the intensity of facial expressions of positive emotions, which displayed either subtle, low intensity, or salient, high intensity expressions of positive affect. In agreement with previous findings from cross-cultural psychological research, current results demonstrate both cross-cultural agreement and differences in the perception of positive affect intensity across the three cultures. Specifically, American participants perceived high arousal (HA) images as significantly less calm than participants from the other two cultures, while the Japanese participants perceived low arousal (LA) images as significantly more excited than participants from the other cultures. The underlying mechanisms of these cultural differences were further investigated through difference scores that probed for cultural differences in perception and categorization of positive emotions. Findings indicate that rating differences are due to (1) perceptual differences in the extent to which HA images were discriminated from LA images, and (2) categorization differences in the extent to which facial expressions were grouped into affect intensity categories. Specifically, American participants revealed significantly higher perceptual differentiation between arousal levels of facial expressions in high and intermediate intensity categories. Japanese participants, on the other hand, did not discriminate between high and low arousal affect categories to the same extent as did the American and Russian participants. These findings indicate the presence of cultural differences in underlying decoding mechanisms of facial expressions of positive affect intensity. Implications of these results for global advertising are discussed. PMID:22084635

Genes with mutation significance were highly associated with the clinical pattern of patients with breast cancer.

PubMed

Ding, Wan-Jun; Zeng, Tao; Wang, Li-Jun; Lei, Hong-Bo; Ge, Wei; Wang, Zhi

2017-11-17

In the United States, breast cancer is the second leading cause of cancer death in women. Over the past 20 years, breast cancer incidence and mortality rates increased rapidly in developing regions. We aimed to identify the gene mutation patterns that associated with the clinical patterns, including survival status, histo-pathological classes and so forth, of breast cancer. We retrieved 1098 cases of the clinical information, and level-3 legacy data of mRNA expression level, protein expression data and mutation files from GDC data portal. The genes with mutation significance were obtained. We studied the impacts of mutation types on the expression levels of mRNA and protein. Different statistics methods were used to calculate the correlation between the mutation types and the expression data or histo-clinical measures. There were 24 genes with mutation significance identified. The most mutated genes were selected to study the role of specific mutations played on the patients with breast cancer. One interesting finding was the missense mutations on TP53 were related with high expression levels of mRNA and protein. The missense mutations on TP53 were highly related with the morphology, race, ER status, PR status and HER2 Status, while the truncated mutations were only related with the morphology, ER status and PR status. The missense mutation on PIK3CA was highly associated with the morphology, race, ER status and PR status. The mutants with different mutants and the wild type of the most mutated genes had different impacts on the histo-clinical measures that might help personalized therapy.

Cultural differences in affect intensity perception in the context of advertising.

PubMed

Pogosyan, Marianna; Engelmann, Jan B

2011-01-01

Cultural differences in the perception of positive affect intensity within an advertising context were investigated among American, Japanese, and Russian participants. Participants were asked to rate the intensity of facial expressions of positive emotions, which displayed either subtle, low intensity, or salient, high intensity expressions of positive affect. In agreement with previous findings from cross-cultural psychological research, current results demonstrate both cross-cultural agreement and differences in the perception of positive affect intensity across the three cultures. Specifically, American participants perceived high arousal (HA) images as significantly less calm than participants from the other two cultures, while the Japanese participants perceived low arousal (LA) images as significantly more excited than participants from the other cultures. The underlying mechanisms of these cultural differences were further investigated through difference scores that probed for cultural differences in perception and categorization of positive emotions. Findings indicate that rating differences are due to (1) perceptual differences in the extent to which HA images were discriminated from LA images, and (2) categorization differences in the extent to which facial expressions were grouped into affect intensity categories. Specifically, American participants revealed significantly higher perceptual differentiation between arousal levels of facial expressions in high and intermediate intensity categories. Japanese participants, on the other hand, did not discriminate between high and low arousal affect categories to the same extent as did the American and Russian participants. These findings indicate the presence of cultural differences in underlying decoding mechanisms of facial expressions of positive affect intensity. Implications of these results for global advertising are discussed.

Prognostic Role of Mucin Antigen MUC4 for Cholangiocarcinoma: A Meta-Analysis.

PubMed

Li, Bingmin; Tang, Haowen; Zhang, Aiqun; Dong, Jiahong

2016-01-01

Surgery carries the best hope for cure in the treatment of cholangiocarcinoma (CC), whereas surgical outcome is not fully satisfactory. Bio-molecular markers have been used to improve tumor staging and prognosis prediction. Mucin antigen MUC4 (MUC4) has been implicated as a marker for poor survival in various tumors. However, prognostic significance of MUC4 for patients with CC remains undefined. The aim of the present meta-analysis was to investigate the association between MUC4 expression and overall survival (OS) of patients with resected CC. The meta-analysis was conducted in adherence to the MOOSE guidelines. PubMed, Embase databases, Cochrane Library and the Chinese SinoMed were systematically searched to identify eligible studies from the initiation of the databases to April, 2016. OSs were pooled by using hazard ratio (HR) with corresponding 95% confidence interval (CI). Random effect models were utilized because of the between-study heterogeneities. Five studies reporting on 249 patients were analyzed: 94 (37.75%) were in positive or high expression group and 155 (62.25%) in negative or low expression group. The pooled HR for positive or high expression group was found to be 3.04 (95% CI 2.25-4.12) when compared with negative or low expression group with slight between-study heterogeneities (I2 3.10%, P = 0.39). The result indicated that a positive or high expression level of MUC4 was significantly related to poor survival in patients with resected CC. A commensurate result was identified by sensitivity analysis. The main limitations of the present meta-analysis were the rather small size of the studies included and relatively narrow geographical distribution of population. The result of this meta-analysis indicated that a positive or high expression level of MUC4 was significantly related to poor survival in patients with resected CC.

Prognostic Role of Mucin Antigen MUC4 for Cholangiocarcinoma: A Meta-Analysis

PubMed Central

Zhang, Aiqun; Dong, Jiahong

2016-01-01

Background and Objective Surgery carries the best hope for cure in the treatment of cholangiocarcinoma (CC), whereas surgical outcome is not fully satisfactory. Bio-molecular markers have been used to improve tumor staging and prognosis prediction. Mucin antigen MUC4 (MUC4) has been implicated as a marker for poor survival in various tumors. However, prognostic significance of MUC4 for patients with CC remains undefined. The aim of the present meta-analysis was to investigate the association between MUC4 expression and overall survival (OS) of patients with resected CC. Methods The meta-analysis was conducted in adherence to the MOOSE guidelines. PubMed, Embase databases, Cochrane Library and the Chinese SinoMed were systematically searched to identify eligible studies from the initiation of the databases to April, 2016. OSs were pooled by using hazard ratio (HR) with corresponding 95% confidence interval (CI). Random effect models were utilized because of the between-study heterogeneities. Results Five studies reporting on 249 patients were analyzed: 94 (37.75%) were in positive or high expression group and 155 (62.25%) in negative or low expression group. The pooled HR for positive or high expression group was found to be 3.04 (95% CI 2.25–4.12) when compared with negative or low expression group with slight between-study heterogeneities (I2 3.10%, P = 0.39). The result indicated that a positive or high expression level of MUC4 was significantly related to poor survival in patients with resected CC. A commensurate result was identified by sensitivity analysis. The main limitations of the present meta-analysis were the rather small size of the studies included and relatively narrow geographical distribution of population. Conclusion The result of this meta-analysis indicated that a positive or high expression level of MUC4 was significantly related to poor survival in patients with resected CC. PMID:27305093

FLT3-ITD and MLL-PTD influence the expression of MDR-1, MRP-1, and BCRP mRNA but not LRP mRNA assessed with RQ-PCR method in adult acute myeloid leukemia.

PubMed

Nasilowska-Adamska, Barbara; Solarska, Iwona; Paluszewska, Monika; Malinowska, Iwona; Jedrzejczak, Wieslaw W; Warzocha, Krzysztof

2014-04-01

Fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) and mixed-lineage leukemia gene-partial tandem duplication (MLL-PTD) are aberrations associated with leukemia which indicate unsatisfactory prognosis. Downstream regulatory targets of FLT3-ITD and MLL-PTD are not well defined. We have analyzed the expression of MDR-1, multidrug resistant protein-1 (MRP-1), breast cancer resistance protein (BCRP), and lung resistance protein (LRP) messenger RNA (mRNA) in relation to the mutational status of FLT3-ITD and MLL-PTD in 185 acute myeloid leukemia (AML) adult patients. The real-time quantitative polymerase chain reaction method was performed to assess the expression of the MDR-1, MRP-1, BCRP, and LRP mRNA, and the results were presented as coefficients calculated using an intermediate method according to Pfaffl's rule. Significantly higher expressions of MDR-1 mRNA were found in patients who did not harbor FLT3-ITD (0.20 vs. 0.05; p = 0.0001) and MRP-1 mRNA in patients with this mutation (0.96 vs. 0.70; p = 0.002) and of BCRP mRNA in patients with MLL-PTD (0.61 vs. 0.38; p = 0.03). In univariate analysis, the high expression of MDR-1 mRNA (≥0.1317) negatively influenced the outcome of induction therapy (p = 0.05), whereas the high expression of BCRP mRNA (≥1.1487) was associated with a high relapse rate (RR) (p = 0.013). We found that the high expression of MDR-1 (≥0.1317), MRP-1 (≥0.8409), and BCRP mRNA (≥1.1487) significantly influenced disease-free survival (DFS; p = 0.059, 0.032, and 0.009, respectively) and overall survival (0.048, 0.014, and 0.059, respectively). Moreover, a high expression of BCRP mRNA (≥1.1487) proved to be an independent prognostic factor for RR (p = 0.01) and DFS (p = 0.002) in multivariate analysis. The significant correlation between the expression of MDR-1, MRP-1, and BCRP mRNA and FLT3-ITD or MLL-PTD in AML patients requires further investigation.

Neovascular PSMA expression is a common feature in malignant neoplasms of the thyroid

PubMed Central

Heitkötter, Birthe; Steinestel, Konrad; Trautmann, Marcel; Grünewald, Inga; Barth, Peter; Gevensleben, Heidrun; Bögemann, Martin; Wardelmann, Eva; Hartmann, Wolfgang; Rahbar, Kambiz; Huss, Sebastian

2018-01-01

Aim PSMA (prostate-specific membrane antigen) is physiologically expressed in normal prostate tissue and over expressed in prostate cancer cells, therefore constituting a potential target for antibody-based radioligand therapy. Very recent imaging findings reported PSMA-PET/CT uptake in various thyroid lesions. We were therefore encouraged to systematically analyse PSMA expression in different benign and malignant thyroid lesions. Methods Immunohistochemistry was used to detect PSMA expression in 101 thyroid lesions, while neovasculature was identified by CD34 immunostaining. Results PSMA expression in the neovasculature was significantly more frequent in malignant tumors (36/63; 57.1%) compared to benign diseases (5/38; 13.2%; p = 0.0001). In addition, PSMA expression levels in the neovasculature of poorly and undifferentiated thyroid cancers were significantly higher compared to differentiated thyroid tumors (p = 0.021). However, one case with a strong expression in follicular adenoma was identified. Conclusions We conclude that neovascular PSMA expression is common in thyroid cancer but may also rarely be found in benign thyroid diseases, such as follicular adenoma. High expression in the tumor-associated neovasculature is predominantly found in poorly differentiated and undifferentiated (anaplastic) thyroid cancer. This knowledge is highly relevant when interpreting PSMA/PET-CT scans from patients with prostate cancer. In addition, our findings might provide a rationale for further evaluation of PSMA-targeted anti-neovascular or radioligand therapy in metastatic dedifferentiated thyroid cancer. PMID:29515776

A clinicopathological analysis of primary mucosal malignant melanoma.

PubMed

Izumi, Daisuke; Ishimoto, Takatsugu; Yoshida, Naoya; Nakamura, Kenichi; Kosumi, Keisuke; Tokunaga, Ryuma; Sugihara, Hidetaka; Sawayama, Hiroshi; Karashima, Ryuichi; Imamura, Yu; Ida, Satoshi; Hiyoshi, Yukiharu; Iwagami, Shiro; Baba, Yoshifumi; Sakamoto, Yasuo; Miyamoto, Yuji; Watanabe, Masayuki; Baba, Hideo

2015-07-01

Primary mucosal malignant melanoma (PMMM) is a rare and highly lethal neoplasm associated with a poor prognosis. CXC chemokine receptor 4 (CXCR4) is expressed on various tumor cells, including malignant melanoma. Recent data indicate that CXCL12 and CXCR4 play a critical role in the behavior of cancer cells and in the survival of cancer patients. However, there has been no study that has addressed the expression and function of CXCR4/CXCL12 signaling in PMMM. Immunohistochemical staining for CXCL12 and Ki67 in biopsy tissues from 10 cases of PMMM was performed. We analyzed the correlations between the clinicopathological features and expression levels of CXCL12 and Ki67. Six cases showed a high level of CXCL12 expression, while four cases had a low level of expression. High expression of CXCL12 correlated with a poor prognosis, although statistical significance was not reached (p = 0.054). Ki67 was highly expressed in five cases, while the expression in the other five cases was low. There was no correlation between the Ki67 expression and prognosis. The findings of this study suggest that CXCL12 expression may play an important role in the biological behavior of PMMM and may be associated with a poor prognosis of PMMM patients.

Downregulation of bone morphogenetic protein receptor 2 promotes the development of neuroblastoma.

PubMed

Cui, Ximao; Yang, Yili; Jia, Deshui; Jing, Ying; Zhang, Shouhua; Zheng, Shan; Cui, Long; Dong, Rui; Dong, Kuiran

2017-01-29

Neuroblastoma (NB) is the most common extracranial solid tumor of childhood. In this study, we examined the expression of bone morphogenetic protein receptor 2 (BMPR2) in primary NB and adjacent non-tumor samples (adrenal gland). BMPR2 expression was significantly downregulated in NB tissues, particularly in high-grade NB, and was inversely related to the expression of the NB differentiation markers ferritin and enolase. The significance of the downregulation was further explored in cultured NB cells. While enforced expression of BMPR2 decreased cell proliferation and colony-forming activity, shRNA-mediated knockdown of BMPR2 led to increased cell growth and clonogenicity. In mice, NB cells harboring BMPR2 shRNA showed significantly increased tumorigenicity compared with control cells. We also performed a retrospective analysis of NB patients and identified a significant positive correlation between tumor BMPR2 expression and overall survival. These findings suggest that BMPR2 may play an important role in the development of NB. Copyright © 2016 Elsevier Inc. All rights reserved.

Osteocalcin protects pancreatic beta cell function and survival under high glucose conditions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kover, Karen, E-mail: kkover@cmh.edu; University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108; Yan, Yun

Diabetes is characterized by progressive beta cell dysfunction and loss due in part to oxidative stress that occurs from gluco/lipotoxicity. Treatments that directly protect beta cell function and survival in the diabetic milieu are of particular interest. A growing body of evidence suggests that osteocalcin, an abundant non-collagenous protein of bone, supports beta cell function and proliferation. Based on previous gene expression data by microarray, we hypothesized that osteocalcin protects beta cells from glucose-induced oxidative stress. To test our hypothesis we cultured isolated rat islets and INS-1E cells in the presence of normal, high, or high glucose ± osteocalcin for up tomore » 72 h. Oxidative stress and viability/mitochondrial function were measured by H{sub 2}O{sub 2} assay and Alamar Blue assay, respectively. Caspase 3/7 activity was also measured as a marker of apoptosis. A functional test, glucose stimulated insulin release, was conducted and expression of genes/protein was measured by qRT-PCR/western blot/ELISA. Osteocalcin treatment significantly reduced high glucose-induced H{sub 2}O{sub 2} levels while maintaining viability/mitochondrial function. Osteocalcin also significantly improved glucose stimulated insulin secretion and insulin content in rat islets after 48 h of high glucose exposure compared to untreated islets. As expected sustained high glucose down-regulated gene/protein expression of INS1 and BCL2 while increasing TXNIP expression. Interestingly, osteocalcin treatment reversed the effects of high glucose on gene/protein expression. We conclude that osteocalcin can protect beta cells from the negative effects of glucose-induced oxidative stress, in part, by reducing TXNIP expression, thereby preserving beta cell function and survival. - Highlights: • Osteocalcin reduces glucose-induced oxidative stress in beta cells. • Osteocalcin preserves beta cell function and survival under stress conditions. • Osteocalcin reduces glucose-induced TXNIP expression in beta cells.« less

Effects of Curcuma comosa on the expression of atherosclerosis-related cytokine genes in rabbits fed a high-cholesterol diet.

PubMed

Charoenwanthanang, Puttavee; Lawanprasert, Somsong; Phivthong-Ngam, Laddawal; Piyachaturawat, Pawinee; Sanvarinda, Yupin; Porntadavity, Sureerut

2011-04-12

Curcuma comosa has been known to have potential use in cardiovascular diseases, but its immunoregulatory role in atherosclerosis development and liver toxicity has not been well studied. We therefore investigated the effects of Curcuma comosa on the expression of atherosclerosis-related cytokine genes in rabbits fed a high-cholesterol diet. Twelve male New Zealand White rabbits were treated with 1.0% cholesterol for one month and were subsequently treated with 0.5% cholesterol either alone, or in combination with 5mg/kg/day of simvastatin or with 400mg/kg/day of Curcuma comosa powder for three months. The expression of IL-1, MCP-1, TNF-α, IL-10, and TGF-β in the isolated abdominal aorta and liver were determined by real-time RT-PCR. Liver toxicity was determined by hepatic enzyme activity. Curcuma comosa significantly decreased the expression of pro-inflammatory cytokines, leading to a stronger reduction in IL-1, MCP-1, and TNF-α expression compared to that was suppressed by simvastatin treatment. However, neither Curcuma comosa nor simvastatin affected the expression of anti-inflammation cytokines. In the liver, Curcuma comosa insignificantly decreased the expression of pro-inflammatory cytokines and significantly increased the expression of the anti-inflammatory cytokine IL-10 without altering the activity of hepatic enzymes. In contrast, simvastatin significantly increased the MCP-1 and TNF-α expressions and serum ALT level, without affecting the expression of anti-inflammatory cytokines. In this study, we demonstrated that Curcuma comosa exerts anti-inflammatory activity in the aorta and liver without causing liver toxicity, indicating that Curcuma comosa is a potential candidate as an alternative agent in cardiovascular disease therapy. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Global gene expression analysis of apple fruit development from the floral bud to ripe fruit

PubMed Central

Janssen, Bart J; Thodey, Kate; Schaffer, Robert J; Alba, Rob; Balakrishnan, Lena; Bishop, Rebecca; Bowen, Judith H; Crowhurst, Ross N; Gleave, Andrew P; Ledger, Susan; McArtney, Steve; Pichler, Franz B; Snowden, Kimberley C; Ward, Shayna

2008-01-01

Background Apple fruit develop over a period of 150 days from anthesis to fully ripe. An array representing approximately 13000 genes (15726 oligonucleotides of 45–55 bases) designed from apple ESTs has been used to study gene expression over eight time points during fruit development. This analysis of gene expression lays the groundwork for a molecular understanding of fruit growth and development in apple. Results Using ANOVA analysis of the microarray data, 1955 genes showed significant changes in expression over this time course. Expression of genes is coordinated with four major patterns of expression observed: high in floral buds; high during cell division; high when starch levels and cell expansion rates peak; and high during ripening. Functional analysis associated cell cycle genes with early fruit development and three core cell cycle genes are significantly up-regulated in the early stages of fruit development. Starch metabolic genes were associated with changes in starch levels during fruit development. Comparison with microarrays of ethylene-treated apple fruit identified a group of ethylene induced genes also induced in normal fruit ripening. Comparison with fruit development microarrays in tomato has been used to identify 16 genes for which expression patterns are similar in apple and tomato and these genes may play fundamental roles in fruit development. The early phase of cell division and tissue specification that occurs in the first 35 days after pollination has been associated with up-regulation of a cluster of genes that includes core cell cycle genes. Conclusion Gene expression in apple fruit is coordinated with specific developmental stages. The array results are reproducible and comparisons with experiments in other species has been used to identify genes that may play a fundamental role in fruit development. PMID:18279528

Global gene expression analysis of apple fruit development from the floral bud to ripe fruit.

PubMed

Janssen, Bart J; Thodey, Kate; Schaffer, Robert J; Alba, Rob; Balakrishnan, Lena; Bishop, Rebecca; Bowen, Judith H; Crowhurst, Ross N; Gleave, Andrew P; Ledger, Susan; McArtney, Steve; Pichler, Franz B; Snowden, Kimberley C; Ward, Shayna

2008-02-17

Apple fruit develop over a period of 150 days from anthesis to fully ripe. An array representing approximately 13000 genes (15726 oligonucleotides of 45-55 bases) designed from apple ESTs has been used to study gene expression over eight time points during fruit development. This analysis of gene expression lays the groundwork for a molecular understanding of fruit growth and development in apple. Using ANOVA analysis of the microarray data, 1955 genes showed significant changes in expression over this time course. Expression of genes is coordinated with four major patterns of expression observed: high in floral buds; high during cell division; high when starch levels and cell expansion rates peak; and high during ripening. Functional analysis associated cell cycle genes with early fruit development and three core cell cycle genes are significantly up-regulated in the early stages of fruit development. Starch metabolic genes were associated with changes in starch levels during fruit development. Comparison with microarrays of ethylene-treated apple fruit identified a group of ethylene induced genes also induced in normal fruit ripening. Comparison with fruit development microarrays in tomato has been used to identify 16 genes for which expression patterns are similar in apple and tomato and these genes may play fundamental roles in fruit development. The early phase of cell division and tissue specification that occurs in the first 35 days after pollination has been associated with up-regulation of a cluster of genes that includes core cell cycle genes. Gene expression in apple fruit is coordinated with specific developmental stages. The array results are reproducible and comparisons with experiments in other species has been used to identify genes that may play a fundamental role in fruit development.

Downregulation of TXNIP leads to high proliferative activity and estrogen-dependent cell growth in breast cancer.

PubMed

Park, Jun Won; Lee, Su Hyung; Woo, Gye-Hyung; Kwon, Hyo-Jung; Kim, Dae-Yong

2018-04-06

TXNIP is a potent tumor suppressor with reduced expression in various types of human cancer. The prognostic and predictive power of TXNIP has been recognized in human breast cancer. The aim of this study is to investigate the clinical relevance and functional roles of TXNIP downregulation in breast cancer. We examined TXNIP expression at the protein level in tissue microarray (TMA)-based human breast cancers and its correlation with clinical parameters and molecular markers on immunohistochemistry (IHC). Compared with normal tissues, TXNIP expression was significantly decreased in human breast cancer tissues and animal mammary tumors, along with tumor progression. TXNIP was restored immediately after histone deacetylase inhibitor treatment in breast cancer cells, implying transcriptional regulation of TXNIP by histone modification. Decreased TXNIP protein levels were more common in tumors showing high proliferative activity, such as high Ki-67 labeling indexes and low p27 expression. TXNIP knockdown led to increased in vitro and in vivo breast cancer cell growth accompanied by p27 reduction and GLUT1 induction. Interestingly, estrogen receptor (ER)-positive breast cancer samples showed higher TXNIP expression compared to ER-negative samples. TXNIP expression decreased when ER signaling was activated by estradiol, while its expression increased under ER blockage by anti-estrogen fulvestrant. In addition, TXNIP knockdown in breast cancer cells caused significant reduction in the cell-growth inhibitory effect of anti-estrogen fulvestrant. In conclusion, our data demonstrated that TXNIP functions to suppress high proliferative activity and estrogen-dependent cell growth in breast cancer. Copyright © 2018 Elsevier Inc. All rights reserved.

Molecular and Histopathological Changes in Mouse Intestinal Tissue After Proton Exposure

NASA Technical Reports Server (NTRS)

Purgason, Ashley; Wu, Honglu

2010-01-01

Whole body exposure to protons in mice causes significant apoptosis in the crypts of the small intestine. Increasing numbers of crypts contained more apoptotic lesions as the dose of exposure increased. 16 genes associated with apoptotic pathways were shown to have significantly altered expression as compared to control samples for at least one of the doses of proton exposure 1 gene, Trp53inp1, was significantly up-regulated across all three doses. Those animals exposed to 0.1 Gy of proton irradiation showed greater amounts of significant alterations in gene expression as compared to 1 Gy and 2 Gy exposures. The differences in gene expression changes of low and high dose proton irradiated mice may offer insight into the molecular mechanisms of the possible high sensitivity at low proton doses. RAIDD (CRADD) may be responsible for the hypersensitivity observed in the duodenum of mice exposed to low doses of protons. Caspase-1 may also play a role in the hypersensitivity seen following proton irradiation at a dose of 0.1 Gy. FOXO3A may be involved in the down-regulation of GILZ observed at high doses of proton exposure.

[Expressions of Ras and Sos1 in epithelial ovarian cancer tissues and their clinical significance].

PubMed

Xiao, Zheng-Hua; Linghu, Hua; Liu, Qian-Fen

2016-11-20

To detect the expressions of Ras and Sos1 proteins in human epithelial ovarian cancer (EOC) tissues and explore their correlation with the clinicopathological features of the patients. The expressions of Ras and Sos1 proteins were detected immunohistochemically in 62 EOC tissues, 5 borderline ovarian cancer tissues, 15 benign epithelial ovarian neoplasm tissues, and 18 normal ovarian tissues. The EOC tissues showed significantly higher expression levels of both Ras and Sos1 than the other tissues tested (P<0.05). In EOC tissues, Ras and Sos1 proteins were expressed mostly on the cell membrane and in the cytoplasm. The expression level of Ras was correlated with pathological types of the tumor (P<0.05) and was the highest in serous cystadenomcarcinoma; Sos1 expression did not show significant correlation with the clinicopathological indexes of the patients. High expressions of both Ras and Sos1 proteins were associated with shorter progression-free survival of the patients, but this association was not statistically significant. Ras and Sos1 protein may participate in in the occurrence and development of EOC. The tissue-specific variation of Ras expression can lend support to a specific diagnosis of ovarian serous adenocarcinoma. The association of Ras and Sos1 protein expression with the tumor-free survival time of the patients awaits further investigation with a larger sample size.

Thymidylate synthase (TS) protein expression as a prognostic factor in advanced colorectal cancer: a comparison with TS mRNA expression.

PubMed

Nakagawa, Tateo; Shimada, Mitsuo; Kurita, Nobuhiro; Iwata, Takashi; Nishioka, Masanori; Yoshikawa, Kozo; Higashijima, Jun; Utsunomiya, Tohru

2012-06-01

The role of intratumoral thymidylate synthase (TS) mRNA or protein expression is still controversial and little has been reported regarding relation of them in colorectal cancer. Forty-six patients with advanced colorectal cancer who underwent surgical resection were included. TS mRNA expression was determined by the Danenberg tumor profile method based on laser-captured micro-dissection of the tumor cells. TS protein expression was evaluated using immunohistochemical staining. TS mRNA expression tended to relate TS protein expression. Statistical significance was not found in overall survival between the TS mRNA high group and low group regardless of performing adjuvant chemotherapy. The overall survival in the TS protein negative group was significantly higher than that in positive group in all and the patients without adjuvant chemotherapy. Multivariate analysis showed TS protein expression was as an independent prognostic factor. TS protein expression tends to be related TS mRNA expression and is an independent prognostic factor in advanced colorectal cancer.

Effects of growth, diving history, and high altitude on blood oxygen capacity in harbor seals

NASA Technical Reports Server (NTRS)

Kodama, A. M.; Elsner, R.; Pace, N.

1977-01-01

Blood volume and body composition for diving and nondiving harbor seals were measured at six-week intervals during a 10-month period of captitivity. Whole body hematocrit, red cell volume per kg of lean body mass, and total circulating hemoglobin per kg lean body mass were significantly higher in the diving group, but relatively large blood volumes expressed in terms of body weight (11-12%) were found in both groups. A pair of harbor seals exposed to high altitude for about three months registered significant increases in red cell volume, blood hemoglobin levels, and blood volume expressed in terms of body weight; results of alveolar gas analyses indicate that hyperventilation also occurred. These typical mammalian responses to hypoxia suggest that the harbor seal's large blood volume and high hemoglobin content are an expression of phylogenetic control, and that in spite of its adaptability to apnea during its diving life, the animal cannot be considered preacclimatized to high altitude.

Effects of wort gravity and nitrogen level on fermentation performance of brewer's yeast and the formation of flavor volatiles.

PubMed

Lei, Hongjie; Zhao, Haifeng; Yu, Zhimin; Zhao, Mouming

2012-03-01

Normal gravity wort and high gravity wort with different nitrogen levels were used to examine their effects on the fermentation performance of brewer's yeast and the formation of flavor volatiles. Results showed that both the wort gravity and nitrogen level had significant impacts on the growth rate, viability, flocculation, and gene expression of brewer's yeast and the levels of flavor volatiles. The sugar (glucose, maltose, and maltotriose) consumption rates and net cell growth decreased when high gravity worts were used, while these increased with increasing nitrogen level. Moreover, high gravity resulted in lower expression levels of ATF1, BAP2, BAT1, HSP12, and TDH, whereas the higher nitrogen level caused higher expression levels for these genes. Furthermore, the lower nitrogen level resulted in increases in the levels of higher alcohols and esters at high wort gravity. All these results demonstrated that yeast physiology and flavor balance during beer brewing were significantly affected by the wort gravity and nitrogen level.

Polo-like kinase 1 is a therapeutic target in high-risk neuroblastoma.

PubMed

Ackermann, Sandra; Goeser, Felix; Schulte, Johannes H; Schramm, Alexander; Ehemann, Volker; Hero, Barbara; Eggert, Angelika; Berthold, Frank; Fischer, Matthias

2011-02-15

High-risk neuroblastoma remains a therapeutic challenge for pediatric oncologists. The Polo-like kinase 1 (PLK1) is highly expressed in many human cancers and is a target of the novel small-molecule inhibitor BI 2536, which has shown promising anticancer activity in adult malignancies. Here, we investigated the effect of BI 2536 on neuroblastoma cells in vitro and in vivo to explore PLK1 as a potential target in high-risk neuroblastoma therapy. PLK1 transcript levels were analyzed by microarrays in 476 primary neuroblastoma specimens, and correlation with prognostic markers and patient outcome was examined. To explore the effect of PLK1 inhibition on neuroblastoma cells, 7 cell lines were treated with BI 2536 and changes in growth properties were determined. Furthermore, nude mice with IMR-32 and SK-N-AS xenografts were treated with BI 2536. PLK1 is highly expressed in unfavorable neuroblastoma and in neuroblastoma cell lines. Expression of PLK1 is associated with unfavorable prognostic markers such as stage 4, age >18 months, MYCN amplification, unfavorable gene expression-based classification, and adverse patient outcome (P < 0.001 each). On treatment with nanomolar doses of BI 2536, all neuroblastoma cell lines analyzed showed significantly reduced proliferation, cell cycle arrest, and cell death. Moreover, BI 2536 abrogated growth of neuroblastoma xenografts in nude mice. Elevated PLK1 expression is significantly associated with high-risk neuroblastoma and unfavorable patient outcome. Inhibition of PLK1 using BI 2536 exhibits strong antitumor activity on human neuroblastoma cells in vitro and in vivo, opening encouraging new perspectives for the treatment of high-risk neuroblastoma. ©2010 AACR.

Partially hydrolyzed guar gum supplement reduces high-fat diet increased blood lipids and oxidative stress and ameliorates FeCl3-induced acute arterial injury in hamsters

PubMed Central

Kuo, Dar-Chih; Hsu, Shih-Ping; Chien, Chiang-Ting

2009-01-01

Increased reactive oxygen species (ROS) and hyperlipidemia can promote arterial thrombus. We evaluated the potential of a partially hydrolyzed guar gum (PHGG) as dietary fiber on lipid profiles and FeCl3-induced arterial thrombosis in the high fat-diet fed hamsters. Our in vitro results found that PHGG is efficient to scavenge O2-•, H2O2, and HOCl. High fat-diet increased plasma triglyceride, total cholesterol, LDL, VLDL, methylguanidine and dityrosine level and accelerated FeCl3-induced arterial thrombosis formation (from 463 ± 51 to 303 ± 45 sec). Low dose PHGG supplement significantly decreased the total cholesterol, LDL, methylguanidine and dityrosine level and delayed the time for arterial thrombosis formation (528 ± 75 sec). High dose PHGG supplement decreased the level in triglyceride, total cholesterol, LDL and VLDL and further delayed the time for arterial thrombus (671 ± 36 sec). The increased Bax protein and decreased Bcl-2 and HSP-70 protein expression was found in the carotid and femoral arteries of high fat-diet hamsters. Low and high dose of PHGG supplement decreased Bax expression and increased Bcl-2 and HSP-70 protein expression. We found that FeCl3 significantly enhanced intercellular adhesion molecule-1 and 4-hydroxynonenal expression in the endothelial site of damaged artery after 150-sec FeCl3 stimulation. PHGG supplement decreased the endothelial ICAM-1 and 4-hydroxynonenal expression after 150-sec FeCl3 stimulation. Based on these results, we conclude that PHGG supplement can increase antioxidant protein expression and thus decrease oxidative stress induced arterial injury. PMID:19272178

Secretory leukocyte protease inhibitor expression and high-risk HPV infection in anal lesions of HIV positive patients

PubMed Central

NUOVO, Gerard J.; GRINSZTEJN, Beatriz; FRIEDMAN, Ruth K.; VELOSO, Valdiléa G.; CUNHA, Cynthia B.; COUTINHO, José R.; VIANNA-ANDRADE, Cecilia; OLIVEIRA, Nathalia S.; WOODHAM, Andrew W.; DA SILVA, Diane M.; KAST, W. Martin

2016-01-01

Objective The aim of the current study was to evaluate secretory leukocyte protease inhibitor (SLPI) expression in anal biopsies from HIV-positive (HIV+) individuals, and compare that to anal intraepithelial neoplasia (AIN) diagnoses and human papillomavirus (HPV) status. Design This is a cross-sectional study of a cohort of 54 HIV+ (31 males and 23 females) from an AIDS clinic in Rio de Janeiro, Brazil. Methods The study material consisted of anorectal tissue biopsies obtained from HIV+ subjects, which were used to construct tissue microarray paraffin blocks for immunohistochemical analysis of SLPI expression. Biopsies were evaluated by an expert pathologist and classified as low-grade anal intraepithelial neoplasia (AIN1), high-grade anal intraepithelial neoplasia (AIN2/3), or normal squamous epithelium. Additionally, DNA from the biopsies was extracted and analyzed for the presence of low- or high-risk HPV DNA. Results Histologically normal squamous epithelium from the anorectal region showed strong positive SLPI staining in 17/20 (85%) samples. In comparison, 9/17 (53%) dysplastic squamous epithelial samples from AIN1 patients showed strong SLPI staining, and only 5/17 (29%) samples from AIN2-3 patients exhibited strong SPLI staining, which both were significantly fewer than those from normal tissue (p=0.005). Furthermore, there was a significantly higher proportion of samples in which oncogenic high-risk HPV genotypes were detected in low SLPI expressing tissues than that in tissues with high SLPI expression (p=0.040). Conclusion Taken together these results suggest that low SLPI expression is associated with high-risk HPV infections in the development of AIN. PMID:27149102

Contaminant loading in remote Arctic lakes affects cellular stress-related proteins expression in feral charr.

USGS Publications Warehouse

Wiseman, Steve; Jorgensen, Even H.; Maule, Alec G.; Vijayan, Mathilakath M.

2011-01-01

The remote Arctic lakes on Bjornoya Island, Norway, offer a unique opportunity to study possible affect of lifelong contaminant exposure in wild populations of landlocked Arctic charr (Salvelinus alpinus). This is because Lake Ellasjoen has persistent organic pollutant (POP) levels that are significantly greater than in the nearby Lake Oyangen. We examined whether this differential contaminant loading was reflected in the expression of protein markers of exposure and effect in the native fish. We assessed the expressions of cellular stress markers, including cytochrome P4501A (Cyp1A), heat shock protein 70 (hsp70), and glucocorticoid receptor (GR) in feral charr from the two lakes. The average polychlorinated biphenyl (PCB) load in the charr liver from Ellasjoen was approximately 25-fold higher than in individuals from Oyangen. Liver Cyp1A protein expression was significantly higher in individuals from Ellasjoen compared with Oyangen, confirming differential PCB exposure. There was no significant difference in hsp70 protein expression in charr liver between the two lakes. However, brain hsp70 protein expression was significantly elevated in charr from Ellasjoen compared with Oyangen. Also, liver GR protein expression was significantly higher in the Ellasjoen charr compared with Oyangen charr. Taken together, our results suggest changes to cellular stress-related protein expression as a possible adaptation to chronic-contaminant exposure in feral charr in the Norwegian high-Arctic.

Prognostic value of the autophagy markers LC3 and p62/SQSTM1 in early-stage non-small cell lung cancer.

PubMed

Schläfli, Anna M; Adams, Olivia; Galván, José A; Gugger, Mathias; Savic, Spasenija; Bubendorf, Lukas; Schmid, Ralph A; Becker, Karl-Friedrich; Tschan, Mario P; Langer, Rupert; Berezowska, Sabina

2016-06-28

Autophagy is a cellular degrading process that promotes tumor cell survival or cell death in cancer, depending on the progress of oncogenesis. Protein light chain 3 (LC3) and p62/SQSTM1 (p62) are associated with autophagosomal membranes that engulf cytoplasmic content for subsequent degradation. We studied LC3 and p62 expression using immunohistochemistry in a large cohort of 466 stage I/II non-small cell lung cancer (NSCLC) using a tissue microarray. We evaluated dot-like cytoplasmic expression of LC3 and dot-like, cytoplasmic and nuclear staining for p62 in relation to clinico-pathological parameters.LC3 expression correlated with all p62 patterns, as those correlated among each other (p < 0.001 each). There was no correlation with stage, age or gender. A combination of high LC3/high p62 dot-like staining (suggesting impaired autophagy) showed a trend for better outcome (p = 0.11). Interestingly, a combined low cytoplasmic/low nuclear p62 expression regardless of dot-like staining was an independent prognostic factor for longer survival (p = 0.006; HR=1.96), in addition to tumor stage (p = 0.004; HR=1.4).The autophagy markers LC3 and p62 are differentially expressed in NSCLC, pointing towards a biologically significant role. High LC3 levels seem to be linked to lower tumor aggressiveness, while high general p62 expression was significantly associated with aggressive tumor behavior.

Prognostic value of the autophagy markers LC3 and p62/SQSTM1 in early-stage non-small cell lung cancer

PubMed Central

Schläfli, Anna M.; Adams, Olivia; Galván, José A.; Gugger, Mathias; Savic, Spasenija; Bubendorf, Lukas; Schmid, Ralph A.; Becker, Karl-Friedrich; Tschan, Mario P.; Langer, Rupert; Berezowska, Sabina

2016-01-01

Autophagy is a cellular degrading process that promotes tumor cell survival or cell death in cancer, depending on the progress of oncogenesis. Protein light chain 3 (LC3) and p62/SQSTM1 (p62) are associated with autophagosomal membranes that engulf cytoplasmic content for subsequent degradation. We studied LC3 and p62 expression using immunohistochemistry in a large cohort of 466 stage I/II non-small cell lung cancer (NSCLC) using a tissue microarray. We evaluated dot-like cytoplasmic expression of LC3 and dot-like, cytoplasmic and nuclear staining for p62 in relation to clinico-pathological parameters. LC3 expression correlated with all p62 patterns, as those correlated among each other (p < 0.001 each). There was no correlation with stage, age or gender. A combination of high LC3/high p62 dot-like staining (suggesting impaired autophagy) showed a trend for better outcome (p = 0.11). Interestingly, a combined low cytoplasmic/low nuclear p62 expression regardless of dot-like staining was an independent prognostic factor for longer survival (p = 0.006; HR=1.96), in addition to tumor stage (p = 0.004; HR=1.4). The autophagy markers LC3 and p62 are differentially expressed in NSCLC, pointing towards a biologically significant role. High LC3 levels seem to be linked to lower tumor aggressiveness, while high general p62 expression was significantly associated with aggressive tumor behavior. PMID:27250032

CXCL14 and NOS1 expression in specimens from patients with stage I-IIIA nonsmall cell lung cancer after curative resection.

PubMed

Ji, Xiaoqin; Shen, Zetian; Zhao, Benxin; Yuan, Xi; Zhu, Xixu

2018-03-01

Many studies show that CXC chemokine ligand 14 (CXCL14) is highly expressed in tumor-associated stromal cells, promoting tumor cell growth, and invasion. Because of its unclear receptors, CXCL14-initiated intracellular signal cascades remain largely unknown. However, CXCL14 can regulate nitric oxide synthase 1 (NOS1) as its intracellular molecular target. In this paper, we investigated the expression of CXCL14 and NOS1 in specimens from patients with stage I-IIIA nonsmall cell lung cancer (NSCLC) after curative resection, and evaluated the prognostic significance of this gene expression in stromal fibroblasts and cancer cells.Immunohistochemistry was used to detect the expression of CXCL14 and NOS1 in 106 formalin fixed, paraffin-embedded specimens from patients with stage I-IIIA NSCLC. The chi-square test was performed to examine the correlation of CXCL14 and NOS1 expression level with clinicopathological features. The effects of the expression of CXCL14 or NOS1 on progression-free survival (PFS) and overall survival (OS) were determined by Kaplan-Meier and Cox hazard proportional model.The percentages of high CXCL14 expression in stromal fibroblasts and that in cancer cells were 46.2% (49/106) and 23.6% (25/106), respectively. The positive expression rates of NOS1 in cancer cells were 42.5% (45/106). The result indicated that there was a significant positive correlation between CXCL14 expression level in stromal fibroblasts and that in cancer cells (χ = 4.158, P = .041). In addition, the expression of CXCL14 in stromal fibroblasts was significantly correlated with NOS1 expression in cancer cells (χ = 16.156, P < .001). The 5-year PFS rates with low and high CXCL14 expression in stromal fibroblasts were 66.7% and 14.3% (χ = 44.008, P < .001), respectively, and the 5-year OS rates with those were 87.1% and 43.5% (χ = 21.531, P < .001), respectively. The 5-year PFS rates with negative and positive expression of NOS1 in cancer cells were 62.3% and 15.6% (χ = 33.756, P < .001), respectively, and the 5-year OS rates with those were 86.4% and 40.1% (χ = 24.430, P < 0.01), respectively.Both the high expression of CXCL14 in stromal fibroblasts and the positive expression of NOS1 in cancer cells are independent negative predictors of PFS and OS in patients with stage I-IIIA NSCLC after curative resection.

CXCR6 expression in non-small cell lung carcinoma supports metastatic process via modulating metalloproteinases.

PubMed

Mir, Hina; Singh, Rajesh; Kloecker, Goetz H; Lillard, James W; Singh, Shailesh

2015-04-30

Lung cancer (LuCa) is the leading cause of cancer-related deaths worldwide regardless of the gender. High mortality associated with LuCa is due to metastasis, molecular mechanisms of which are yet to be defined. Here, we present evidence that chemokine receptor CXCR6 and its only natural ligand, CXCL16, are significantly expressed by non-small cell lung cancer (NSCLC) and are involved in the pathobiology of LuCa. CXCR6 expression was significantly higher in two subtypes of NSCLC (adenocarcinomas-ACs and squamous cell carcinoma-SCCs) as compared to non-neoplastic tissue. Additionally, serum CXCL16 was significantly elevated in LuCa cases as compared to healthy controls. Similar to CXCR6 tissue expression, serum level of CXCL16 in AC patients was significantly higher than SCC patients. Biological significance of this axis was validated using SCC and AC cell lines. Expression of CXCR6 was higher in AC cells, which also showed higher migratory and invasive potential than SCC. Differences in migratory and invasive potential between AC and SCC were due to differential expression of metalloproteinases following CXCL16 stimulation. Hence, our findings suggest clinical and biological significance of CXCR6/CXCL16 axis in LuCa, which could be used as potential prognostic marker and therapeutic target.

CXCR6 expression in non-small cell lung carcinoma supports metastatic process via modulating metalloproteinases

PubMed Central

Mir, Hina; Singh, Rajesh; Kloecker, Goetz H.; Lillard, James W.; Singh, Shailesh

2015-01-01

Lung cancer (LuCa) is the leading cause of cancer-related deaths worldwide regardless of the gender. High mortality associated with LuCa is due to metastasis, molecular mechanisms of which are yet to be defined. Here, we present evidence that chemokine receptor CXCR6 and its only natural ligand, CXCL16, are significantly expressed by non-small cell lung cancer (NSCLC) and are involved in the pathobiology of LuCa. CXCR6 expression was significantly higher in two subtypes of NSCLC (adenocarcinomas-ACs and squamous cell carcinoma-SCCs) as compared to non-neoplastic tissue. Additionally, serum CXCL16 was significantly elevated in LuCa cases as compared to healthy controls. Similar to CXCR6 tissue expression, serum level of CXCL16 in AC patients was significantly higher than SCC patients. Biological significance of this axis was validated using SCC and AC cell lines. Expression of CXCR6 was higher in AC cells, which also showed higher migratory and invasive potential than SCC. Differences in migratory and invasive potential between AC and SCC were due to differential expression of metalloproteinases following CXCL16 stimulation. Hence, our findings suggest clinical and biological significance of CXCR6/CXCL16 axis in LuCa, which could be used as potential prognostic marker and therapeutic target. PMID:25888629

Potential role of leptin expression in hepatocellular carcinoma

PubMed Central

Wang, S‐N; Yeh, Y‐T; Yang, S‐F; Chai, C‐Y; Lee, K‐T

2006-01-01

Background Obesity is associated with hepatocellular carcinoma (HCC). The association may result from the aberrant expression of adipokines. Aim To explore the potential biological effect and prognostic value of leptin, one of the adipokines, in HCC. Methods Immunohistochemistry was used to evaluate the expression of leptin in 68 patients with HCC. The expression of Ki‐67 and microvessel density (MVD) of tumorous lesions in HCC were also analysed. The result of leptin expression was further correlated with Ki‐67 expression, intratumour MVD, clinicopathological characteristics, overall survival and the postoperative use of medroxyprogesterone acetate (MPA). Results High leptin expression was seen in 60.3% of patients with HCC and was significantly correlated with intratumour MVD (high v low; 59.2 (standard deviation 3.2) v 44.2 (19.5), p = 0.004), but not with Ki‐67 expression. No marked correlation was seen between leptin expression and clinicopathological characteristics. However, using a multivariate Cox's proportional hazards model, leptin expression was a predictor for improved overall survival of patients with HCC (odds ratio 0.16; 95% confidence interval 0.03 to 0.87; p = 0.033). In addition, the Kaplan–Meier survival curve showed that high leptin expression was associated with a better survival in patients with HCC, treated postoperatively with MPA (p = 0.008, log rank test). Conclusion High leptin expression was associated with an increased intratumour MVD and thus may be associated with HCC development. In addition, high leptin expression was a predictor for improved survival of patients with HCC, treated postoperatively with MPA. PMID:16565221

Expression of protease-activated receptor-2 (PAR-2) is related to advanced clinical stage and adverse prognosis in ovarian clear cell carcinoma.

PubMed

Aman, Murasaki; Ohishi, Yoshihiro; Imamura, Hiroko; Shinozaki, Tomoko; Yasutake, Nobuko; Kato, Kiyoko; Oda, Yoshinao

2017-06-01

Recent studies demonstrated that protease-activated receptor-2 (PAR-2) correlates with tumor progression in various tissues. On the other hand, oxidative stress arising from endometriosis has been considered a cause of carcinogenesis in ovarian clear cell carcinoma (OCCC). We previously demonstrated that oxidative stress up-regulates PAR-2 expression, and we conducted the present study to investigate the PAR-2 expression and its relation to clinicopathological factors and oxidative stress in OCCC. We performed an immunohistochemical evaluation in 95 cases of OCCC. For the evaluation of oxidative stress markers, 31 cases of ovarian endometrioid carcinoma (OEC) were also examined. No significant differences in the expression of cyclooxygenase-2 and inducible nitric oxide synthase were observed between OCCC and OEC. Sixty-two percent of the OCCC cases showed high 8-hydroxydeoxyguanosine expression, whereas all of the OEC cases showed almost negative immunoreactivities. The presence of endometriosis did not affect the expression of these oxidative stress markers or prognosis. High PAR-2 expression was observed in 20% (14/71) of the early International Federation of Gynecology and Obstetrics (FIGO) stage cases and 58% (14/24) of the advanced FIGO stage cases. High PAR-2 expression was significantly correlated with advanced FIGO stage and shorter overall survival. We found no correlations between PAR-2 expression and oxidative stress in OCCC. Our results suggest that PAR-2 plays an important role in the progression of OCCC. The expression of 8-hydroxydeoxyguanosine is a characteristic finding of OCCC, indicating that the injury of DNA by oxidative stress may be involved in the carcinogenesis of OCCC. Copyright © 2017 Elsevier Inc. All rights reserved.

The prognostic value of long noncoding RNA Sox2ot expression in various cancers: A systematic review and meta-analysis.

PubMed

Song, Xiaoyang; Yao, Hongyan; Liu, Jinlin; Wang, Qiang

2018-05-19

Several investigations have explored the prognostic value of long noncoding RNA Sox2 overlapping transcript (lncRNA Sox2ot) expression in human cancers, however, with inconsistent results. The aim of this study was to evaluate the prognostic role of lncRNA Sox2ot expression in various cancers. PubMed, Web of Science, Embase, and Cochrane Library were comprehensively searched to retrieve relevant studies. The relationships between lncRNA Sox2ot expression and prognostic parameters were detected, including overall survival (OS), tumor differentiation, clinical stage, distant metastasis, lymph node metastasis and so on. A total of 10 studies involving 943 cancer patients were finally included into the study. High lncRNA Sox2ot expression was significantly related to shorter OS in cancers (HR = 2.06, 95%CI = 1.67-2.55, P < 0.01). The cancer patients with high lncRNA Sox2ot expression tended to have worse tumor differentiation (P = 0.04), advanced clinical stage (P < 0.01), earlier distant metastasis (P < 0.01), and earlier lymph node metastasis (P = 0.01) compared to those with low lncRNA Sox2ot expression. However, there was no distinct correlation between lncRNA Sox2ot expression and age (P = 0.87), gender (P = 0.48), tumor size (P = 0.08), or vascular invasion (P = 0.07). High lncRNA Sox2ot expression was significantly associated with worse OS, advanced clinical stage, worse tumor differentiation, earlier distant metastasis, and earlier lymph node metastasis in various cancers. LncRNA Sox2ot expression might a promising prognostic factor in various cancers. Copyright © 2018 Elsevier B.V. All rights reserved.

[The expression and significance of chemokines eotaxin and RANTES in the rat model of allergic rhinitis].

PubMed

Tian, Cuiling; Lei, Xiaoping; Shui, Minhong; Zhang, Yanhong; Jia, Qianwei; Tu, Jing; Lian, Gang; Tang, Siquan

2014-07-01

To explore the expression and significance of Eotaxin and RANTES in the rat model of allergic rhinitis (AR). 20 female SD rats in 6-7 weeks were randomly divided into control group and AR group (n = 10, respectively). AR rat model was made with ovalbumin stimulation. To detect pathological changes in mucosa and chemokine Eotaxin, RANTES in their nasal and lung tissues after execution. Compared with the control group, Lung EOS cell counted higher in AR group and the difference was significant (P < 0.01); the AR rats nasal mucosa and lung tissue of Eotaxin, RANTES expression was significantly increased (P < 0.01). There exist high expression of Eotaxin, RANTES, infiltration of eosinophils in nasal and lung tissue of model rats with allergic rhinitis, inferring that the upper and lower respiratory tract inflammatory response has obvious consistency.

YAP promotes tumorigenesis and cisplatin resistance in neuroblastoma.

PubMed

Yang, Chao; Tan, Juan; Zhu, Jun; Wang, Shan; Wei, Guanghui

2017-06-06

The transcriptional co-activator Yes-associated protein (YAP) is essential for Hippo pathway-driven tumorigenesis in various cancers. However, the expression and function of YAP in neuroblastoma remains elusive. Here, we show that YAP was highly expressed in Neuroblastoma (NB) and expression levels correlated with advanced tumor staging. Knockdown of YAP significantly impaired neuroblastoma proliferation, tumorigenesis, and invasion in vitro. Injection of the YAP inhibitor, Peptide 17, dramatically prevented neuroblastoma subcutaneous tumor growth by efficiently downregulating YAP expression in tumors. Additionally, less proliferative and more apoptotic cells were found in the Peptide 17 treatment group. Furthermore, YAP inhibition significantly inhibited cisplatin-resistant neuroblastoma proliferation, tumorigenesis, and invasion in vitro. The combination of Peptide 17 with low-dose cisplatin efficiently impaired cisplatin-resistant NB subcutaneous tumor growth, being as effective as high-dose cisplatin. Notably, the combination therapy caused lesser liver toxicity in mice compared to the high-dose cisplatin treatment group. Collectively, this work identifies YAP as a novel regulator of neuroblastoma proliferation, tumorigenesis, and invasion and indicates that YAP is a potential therapeutic target for cisplatin-resistant neuroblastoma.

Prognostic significance of muc4 expression in gallbladder carcinoma.

PubMed

Lee, Hyeon Kook; Cho, Min-Sun; Kim, Tae Hun

2012-10-27

Mucins are high molecular glycoproteins and play protective and lubricating roles in various epithelial tissues. Deregulated expression of mucins is involved in carcinogenesis and tumor invasion. MUC4 expression has been identified as a poor prognostic factor in pancreatobiliary carcinomas. To date, the relation between MUC4 expression and prognosis in gallbladder carcinoma remains to be determined. Authors examined MUC4 expression in gallbladder carcinoma and investigated its impact on prognosis. The expression profiles of MUC4, MUC1, MUC2 mucins in gallbladder carcinoma tissues from 63 patients were investigated using immunohistochemical staining. For gallbladder carcinoma, positive staining of MUC4, MUC1, and MUC2 was 55.6%, 81.0%, 28.6%, respectively. There was a significant correlation between the expression of MUC4 and the expression of MUC1 or MUC2 (p = 0.004, p = 0.009, respectively). Univariate analysis showed that MUC4 expression (p = 0.047), differentiation (p < 0.05), T-stage (p < 0.05) and lymph node metastasis (p < 0.001) were significantly associated with poor survival. Expression of MUC1 and MUC2 was not correlated to survival. The backward stepwise multivariate analysis showed that MUC4 expression (p = 0.039) and lymph node metastasis (p = 0.001) were significant independent risk factors. In combined assessment of MUC4 and MUC2 expression, MUC4 positive and MUC2 negative group showed a significantly worse outcome than MUC4 negative groups(MUC4-/MUC2+ and MUC4-/MUC2-) and MUC4/MUC2 co-expression group(MUC4+/MUC2+) (p < 0.05). MUC4 expression in gallbladder carcinoma is an independent poor prognostic factor. Therefore, MUC4 expression may be a useful marker to predict the outcome of patients with surgically resected gallbladder carcinoma. MUC2 expression may have prognostic value when combined with MUC4 expression.

Prognostic significance of muc4 expression in gallbladder carcinoma

PubMed Central

2012-01-01

Background Mucins are high molecular glycoproteins and play protective and lubricating roles in various epithelial tissues. Deregulated expression of mucins is involved in carcinogenesis and tumor invasion. MUC4 expression has been identified as a poor prognostic factor in pancreatobiliary carcinomas. To date, the relation between MUC4 expression and prognosis in gallbladder carcinoma remains to be determined. Authors examined MUC4 expression in gallbladder carcinoma and investigated its impact on prognosis. Methods The expression profiles of MUC4, MUC1, MUC2 mucins in gallbladder carcinoma tissues from 63 patients were investigated using immunohistochemical staining. Results For gallbladder carcinoma, positive staining of MUC4, MUC1, and MUC2 was 55.6%, 81.0%, 28.6%, respectively. There was a significant correlation between the expression of MUC4 and the expression of MUC1 or MUC2 (p = 0.004, p = 0.009, respectively). Univariate analysis showed that MUC4 expression (p = 0.047), differentiation (p < 0.05), T-stage (p < 0.05) and lymph node metastasis (p < 0.001) were significantly associated with poor survival. Expression of MUC1 and MUC2 was not correlated to survival. The backward stepwise multivariate analysis showed that MUC4 expression (p = 0.039) and lymph node metastasis (p = 0.001) were significant independent risk factors. In combined assessment of MUC4 and MUC2 expression, MUC4 positive and MUC2 negative group showed a significantly worse outcome than MUC4 negative groups(MUC4-/MUC2+ and MUC4-/MUC2-) and MUC4/MUC2 co-expression group(MUC4+/MUC2+) (p < 0.05). Conclusions MUC4 expression in gallbladder carcinoma is an independent poor prognostic factor. Therefore, MUC4 expression may be a useful marker to predict the outcome of patients with surgically resected gallbladder carcinoma. MUC2 expression may have prognostic value when combined with MUC4 expression. PMID:23101681

Expression and prognostic examination of heat shock proteins (HSP 27, HSP 70, and HSP 90) in medulloblastoma.

PubMed

Hauser, Péter; Hanzély, Zoltán; Jakab, Zsuzsanna; Oláh, Lászlóné; Szabó, Erika; Jeney, András; Schuler, Dezso; Fekete, Gyoörgy; Bognár, László; Garami, Miklós

2006-07-01

Expression of heat shock proteins (HSPs) is of prognostic significance in several tumor types. HSP expression levels were determined in medulloblastomas and tested whether HSPs expression was associated with prognostic parameters. Expression of antiapoptotic HSP 27, HSP 70, and HSP 90 was investigated by immunohistochemistry, on paraffin-embedded sections from 65 patients. Expression of HSPs was validated on internal vascular controls and by Western blotting analysis. Sample evaluation was based on the estimated percentage of HSP positive tumor cells. For survival analysis Kaplan-Meier method, for statistical analysis chi2 test, univariate analysis, and log rank test were applied. Expression of HSPs varied in medulloblastomas. On the basis of the average expression rate of HSPs, at HSP 27 and HSP 90 with a 10% cut off, and at HSP 70 with a 70% cut off 2 groups were created. The amount of expression of any of the HSP types was not significantly associated with known prognostic factors (age of patient, extent of resection, presence of metastasis) and histologic subtype. After an average follow-up period of 4.30 years, no significant difference was observed in survival depending on the expression of HSP 27 or HSP 70 or HSP 90. The high expression of HSPs indicates that these proteins are potential therapeutic targets.

Evaluation of Microvascularity by CD34 Expression in Esophagus and Oral Squamous Cell Carcinoma.

PubMed

Shahsavari, Fatemeh; Farhadi, Sareh; Sadri, Donia; Sedehi, Marzieh

2015-06-01

The present study was scheduled to evaluate microvascularity by CD34 expression in esophagus and oral squamous cell carcinoma. This study was scheduled using 40 paraffin blocked samples including 20 of oral SCC and 20 of esophagus ones and Immunohistochemical staining was conducted using CD34 monoclonal antibody. Exact fisher test was used to evaluate frequency of expression between two studied groups. There was significant correlation between age and tumor size with CD34 expression in oral SCC samples (p < 0.05) and no significant correlation between sex and tumor differentiation level (grading) (p > 0.05). Also, there was no significant correlation between age, sex, tumor size and tumor differentiation level (grading) with CD34 expression in esophagus SCC samples (p > 0.05). There was no significant difference of CD34 expression frequency in oral and esophagus SCC (p = 0/583). Finally, CD34 expression was reported 'high' for major cases of esophagus and oral SCCs. It seems, other angiogenetic or nonangiogenetic factors except CD34 may play more important role and explain the different clinical behavior of SCC at recent different locations. Other factors would be considered along with CD34 expression to interpret different clinical behavior of SCC at recent different locations.

Expression of the membrane mucins MUC4 and MUC15, potential markers of malignancy and prognosis, in papillary thyroid carcinoma.

PubMed

Nam, Kee-Hyun; Noh, Tae-Woong; Chung, So-Hyang; Lee, So Hee; Lee, Mi Kyung; Hong, Soon Won; Chung, Woong Youn; Lee, Eun Jig; Park, Cheong Soo

2011-07-01

Papillary thyroid carcinoma (PTC) is the most frequent carcinoma of the thyroid gland and has a relatively good prognosis. However, it is important to identify PTC characteristics that indicate high risk for recurrence and metastasis. To date, overexpression of the membrane mucin, MUC1, has been investigated as a key molecular event in the pathogenesis of aggressive PTC. However, other membrane-associated mucins, matrix metalloproteinase-13 (MMP-13) and tissue inhibitor of metalloproteinase-13 (TIMP-3), have not been studied yet. The aim of this study was to evaluate the expression levels of MUC4, MUC15, MMP-13, and TIMP-3 and their prognostic significance in PTC. We analyzed MUC4, MUC15, MMP-13, and TIMP-3 expression in 10 PTC and 10 normal thyroid tissue samples using real-time reverse transcription-polymerase chain reaction. Tissue array blocks were obtained from 98 PTC cases. Tumor regions and nontumor regions were analyzed in tissue array blocks and immunohistochemistry studies were conducted using sectioned slides. Semiquantitative scores were correlated with clinicopathological factors of 98 PTC patients. MUC4- and MUC15-specific mRNA was increased by 78-fold and 4.75-fold, respectively, in PTC samples compared with normal thyroid tissues. MMP-13 and TIMP-3 gene expression levels were decreased by approximately 0.39-fold and 0.53-fold, respectively. By immunohistochemistry, MUC4 and MUC15 expression levels were increased in PTC samples compared with normal thyroid tissues (p < 0.001). MMP-13 and TIMP-3 expression levels were decreased in PTC samples compared with normal thyroid tissues (p < 0.001). High MUC4 scores were significantly correlated with small tumor size and papillary thyroid microcarcinoma subtype. High MUC15 scores were significantly correlated with age (≥45 years), distant metastasis, and multifocality. MUC4 and MUC15 were overexpressed in PTC, and high MUC15 expression was associated with high malignant potential. MUC15 may serve as a prognostic marker and potential novel therapeutic target in PTC.

Keratin 5 overexpression is associated with serous ovarian cancer recurrence and chemotherapy resistance.

PubMed

Ricciardelli, Carmela; Lokman, Noor A; Pyragius, Carmen E; Ween, Miranda P; Macpherson, Anne M; Ruszkiewicz, Andrew; Hoffmann, Peter; Oehler, Martin K

2017-03-14

This study investigated the clinical significance of keratin 5 and 6 expression in serous ovarian cancer progression and chemotherapy resistance. KRT5 and KRT6 (KRT6A, KRT6B & KRT6C) gene expression was assessed in publically available serous ovarian cancer data sets, ovarian cancer cell lines and primary serous ovarian cancer cells. Monoclonal antibodies which detect both K5/6 or only K5 were used to assess protein expression in ovarian cancer cell lines and a cohort of high grade serous ovarian carcinomas at surgery (n = 117) and after neoadjuvant chemotherapy (n = 21). Survival analyses showed that high KRT5 mRNA in stage III/IV serous ovarian cancers was significantly associated with reduced progression-free (HR 1.38, P < 0.0001) and overall survival (HR 1.28, P = 0.013) whilst high KRT6 mRNA was only associated with reduced progression-free survival (HR 1.2, P = 0.031). Both high K5/6 (≥ 10%, HR 1.78 95% CI; 1.03-2.65, P = 0.017) and high K5 (≥ 10%, HR 1.90, 95% CI; 1.12-3.19, P = 0.017) were associated with an increased risk of disease recurrence. KRT5 but not KRT6C mRNA expression was increased in chemotherapy resistant primary serous ovarian cancer cells compared to chemotherapy sensitive cells. The proportion of serous ovarian carcinomas with high K5/6 or high K5 immunostaining was significantly increased following neoadjuvant chemotherapy. K5 can be used to predict serous ovarian cancer prognosis and identify cancer cells that are resistant to chemotherapy. Developing strategies to target K5 may therefore improve serous ovarian cancer survival.

High glucose promotes the migration of retinal pigment epithelial cells through increased oxidative stress and PEDF expression

PubMed Central

Farnoodian, Mitra; Halbach, Caroline; Slinger, Cassidy; Pattnaik, Bikash R.; Sorenson, Christine M.

2016-01-01

Defects in the outer blood-retinal barrier have significant impact on the pathogenesis of diabetic retinopathy and macular edema. However, the detailed mechanisms involved remain largely unknown. This is, in part, attributed to the lack of suitable animal and cell culture models, including those of mouse origin. We recently reported a method for the culture of retinal pigment epithelial (RPE) cells from wild-type and transgenic mice. The RPE cells are responsible for maintaining the integrity of the outer blood-retinal barrier whose dysfunction during diabetes has a significant impact on vision. Here we determined the impact of high glucose on the function of RPE cells. We showed that high glucose conditions resulted in enhanced migration and increased the level of oxidative stress in RPE cells, but minimally impacted their rate of proliferation and apoptosis. High glucose also minimally affected the cell-matrix and cell-cell interactions of RPE cells. However, the expression of integrins and extracellular matrix proteins including pigment epithelium-derived factor (PEDF) were altered under high glucose conditions. Incubation of RPE cells with the antioxidant N-acetylcysteine under high glucose conditions restored normal migration and PEDF expression. These cells also exhibited increased nuclear localization of the antioxidant transcription factor Nrf2 and ZO-1, reduced levels of β-catenin and phagocytic activity, and minimal effect on production of vascular endothelial growth factor, inflammatory cytokines, and Akt, MAPK, and Src signaling pathways. Thus high glucose conditions promote RPE cell migration through increased oxidative stress and expression of PEDF without a significant effect on the rate of proliferation and apoptosis. PMID:27440660

SCF/C-Kit/JNK/AP-1 Signaling Pathway Promotes Claudin-3 Expression in Colonic Epithelium and Colorectal Carcinoma.

PubMed

Wang, Yaxi; Sun, Tingyi; Sun, Haimei; Yang, Shu; Li, Dandan; Zhou, Deshan

2017-04-06

Claudin-3 is a major protein of tight junctions (TJs) in the intestinal epithelium and is critical for maintaining cell-cell adhesion, barrier function, and epithelium polarity. Recent studies have shown high claudin-3 levels in several solid tumors, but the regulation mechanism of claudin-3 expression remains poorly understood. In the present study, colorectal cancer (CRC) tissues, HT-29 and DLD-1 CRC cell lines, CRC murine model (C57BL/6 mice) and c-kit loss-of-function mutant mice were used. We demonstrated that elevated claudin-3 levels were positively correlated with highly expressed c-kit in CRC tissues based upon analysis of protein expression. In vitro, claudin-3 expression was clearly increased in CRC cells by overexpressed c-kit or stimulated by exogenous recombinant human stem cell factor (rhSCF), while significantly decreased by the treatment with c-kit or c-Jun N-terminal kinase (JNK) inhibitors. Chromatin immunoprecipitation (ChIP) and luciferase reporter assay showed that SCF/c-kit signaling significantly promoted activator protein-1 (AP-1) binding with CLDN-3 promoter and enhanced its transcription activity. Furthermore, decreased expression of claudin-3 was obtained in the colonic epithelium from the c-Kit loss-of-function mutant mice. In conclusion, SCF/c-kit-JNK/AP-1 signaling pathway significantly promoted claudin-3 expression in colonic epithelium and CRC, which could contribute to epithelial barrier function maintenance and to CRC development.

Differential expression and prognostic value of the chemokine receptor CXCR4 in bronchopulmonary neuroendocrine neoplasms

PubMed Central

Specht, Elisa; Wirtz, Ralph M.; Sayeg, Manal; Baum, Richard P.; Schulz, Stefan; Lupp, Amelie

2015-01-01

Introduction For many tumors, the overexpression of the chemokine receptor CXCR4 is associated with increased malignancy and poor patient outcomes. However, comprehensive data for neuroendocrine neoplasms of the lung are still lacking. Methods CXCR4 expression was evaluated in a panel of bronchopulmonary neuroendocrine neoplasms (BP-NEN) comprising typical carcinoids (n = 26), atypical carcinoids (n = 30), and small cell lung cancers (SCLC, n = 34). Samples were analyzed by immunohistochemistry using the novel monoclonal rabbit anti-human CXCR4 antibody UMB-2 and by qRT-PCR. The expression was correlated with clinical data and overall patient survival. Results CXCR4 was predominantly localized at the plasma membrane of the tumor cells. CXCR4 was expressed with a high intensity in almost all of the 30 SCLC samples. In contrast, it was detected infrequently and with low intensity in the typical carcinoid and atypical carcinoid samples. There was a significant correlation between the immunohistochemistry and qRT-PCR data. Additionally, there was a significant negative relationship between CXCR4 expression and overall survival. Conclusions With increasing malignancy, BP-NEN clearly differ in the extent of CXCR4 expression. As in other tumor entities, CXCR4 overexpression significantly correlates with negative patient outcome. Due to its particular high expression rate in SCLC, CXCR4 may serve as a promising new target for diagnostic and pharmacological intervention as well as for peptide receptor-based radionuclide therapy. PMID:25671300

Biological significance of long non-coding RNA FTX expression in human colorectal cancer.

PubMed

Guo, Xiao-Bo; Hua, Zhu; Li, Chen; Peng, Li-Pan; Wang, Jing-Shen; Wang, Bo; Zhi, Qiao-Ming

2015-01-01

The purpose of this study was to determine the expression of long non-coding RNA (lncRNA) FTX and analyze its prognostic and biological significance in colorectal cancer (CRC). A quantitative reverse transcription PCR was performed to detect the expression of long non-coding RNA FTX in 35 pairs of colorectal cancer and corresponding noncancerous tissues. The expression of long non-coding RNA FTX was detected in 187 colorectal cancer tissues and its correlations with clinicopathological factors of patients were examined. Univariate and multivariate analyses were performed to analyze the prognostic significance of Long Non-coding RNA FTX expression. The effects of long non-coding RNA FTX expression on malignant phenotypes of colorectal cancer cells and its possible biological significances were further determined. Long non-coding RNA FTX was significantly upregulated in colorectal cancer tissues, and low long non-coding RNA FTX expression was significantly correlated with differentiation grade, lymph vascular invasion, and clinical stage. Patients with high long non-coding RNA FTX showed poorer overall survival than those with low long non-coding RNA FTX. Multivariate analyses indicated that status of long non-coding RNA FTX was an independent prognostic factor for patients. Functional analyses showed that upregulation of long non-coding RNA FTX significantly promoted growth, migration, invasion, and increased colony formation in colorectal cancer cells. Therefore, long non-coding RNA FTX may be a potential biomarker for predicting the survival of colorectal cancer patients and might be a molecular target for treatment of human colorectal cancer.

IL-8 as mediator in the microenvironment-leukaemia network in acute myeloid leukaemia.

PubMed

Kuett, Alexander; Rieger, Christina; Perathoner, Deborah; Herold, Tobias; Wagner, Michaela; Sironi, Silvia; Sotlar, Karl; Horny, Hans-Peter; Deniffel, Christian; Drolle, Heidrun; Fiegl, Michael

2015-12-17

The bone marrow microenvironment is physiologically hypoxic with areas being as low as 1% O2, e.g. the stem cell niche. Acute myeloid leukaemia (AML) blasts misuse these bone marrow niches for protection by the local microenvironment, but also might create their own microenvironment. Here we identify IL-8 as a hypoxia-regulated cytokine in both AML cell lines and primary AML samples that is induced within 48 hours of severe hypoxia (1% O2). IL-8 lacked effects on AML cells but induced migration in mesenchymal stromal cells (MSC), an integral part of the bone marrow. Accordingly, MSC were significantly increased in AML bone marrow as compared to healthy bone marrow. Interestingly, mononuclear cells obtained from healthy bone marrow displayed both significantly lower endogenous and hypoxia-induced production of IL-8. IL-8 mRNA expression in AML blasts from 533 patients differed between genetic subgroups with significantly lower expression of IL-8 in acute promyelocytic leukaemia (APL), while in non APL-AML patients with FLT ITD had the highest IL-8 expression. In this subgroup, high IL-8 expression was also prognostically unfavourable. In conclusion, hypoxia as encountered in the bone marrow specifically increases IL-8 expression of AML, which in turn impacts niche formation. High IL-8 expression might be correlated with poor prognosis in certain AML subsets.

Downregulated miR-506 expression facilitates pancreatic cancer progression and chemoresistance via SPHK1/Akt/NF-κB signaling

PubMed Central

Li, J; Wu, H; Li, W; Yin, L; Guo, S; Xu, X; Ouyang, Y; Zhao, Z; Liu, S; Tian, Y; Tian, Z; Ju, J; Ni, B; Wang, H

2016-01-01

The aberrant expression of microRNAs (miRNAs) has emerged as an important hallmark of cancer. However, the molecular mechanisms underlying the changes in miRNA expression remain unclear. In this study, we discovered a novel epigenetic mechanism of miR-506 regulation and investigated its functional significance in pancreatic cancer. Sequencing analysis revealed that the miR-506 promoter is highly methylated in pancreatic cancer tissues compared with non-cancerous tissues. Reduced miR-506 expression was significantly associated with clinical stage, pathologic tumor status, distant metastasis and decreased survival of pancreatic cancer patients. miR-506 inhibited cell proliferation, induced cell cycle arrest at the G1/S transition and enhanced apoptosis and chemosensitivity of pancreatic cancer cells. Furthermore, we identified sphingosine kinase 1 (SPHK1) as a novel target of miR-506, the expression of which inhibited the SPHK1/Akt/NF-κB signaling pathway, which is activated in pancreatic cancer. High SPHK1 expression was significantly associated with poor survival in a large cohort of pancreatic cancer specimens. Our data suggest that miR-506 acts as a tumor suppressor miRNA and is epigenetically silenced in pancreatic cancer. The newly identified miR-506/SPHK1 axis represents a novel therapeutic strategy for future pancreatic cancer treatment. PMID:27065335

Prognostic significance of epidermal growth factor receptor in surgically treated squamous cell lung cancer patients.

PubMed

Niemiec, Joanna; Kołodziejski, Leszek; Dyczek, Sonia; Gasińska, Anna

2004-01-01

Epidermal growth factor receptor (EGFR) is one of signalling pathways activated during premalignant proliferative changes in the airway epithelium. However there is no agreement about prognostic significance of EGFR expression in non-small cell lung cancer (NSCLC). Facts mentioned above prompted us to study EGFR expression in the group of 78 surgically treated squamous cell lung cancer (SqCLC) patients. The EGFR expression was visualized in formalin-fixed, paraffin-embedded sections, using immunohistochemistry. Three methods of assessment of EGFR expression were applied: percentage of cells with membranous EGFR expression--EGFR labellig index (EGFR LI), percentage of fields with membranous EGFR staining (PS%) and staining intensity (absent, weak or strong) in the whole specimen (SI). Mean EGFR LI and PS% values were 30.4 +/- 3.5% and 51.6 +/- 3.9%, respectively. Patients with higher EGFR expression (EGFR LI, PS%, SI) were significantly younger than those with low EGFR expression. EGFR LI was higher in pT3 tumours than in pT1+pT2 tumours, moreover, EGFR expression (EGFR LI, PS%, SI) was significantly higher in G1+G2 tumours than in G3 tumours. There were significant correlations between parameters used for assessment of EGFR expression. PS% < or = 50 indicated shorter disease-specific survival than PS% > 50. However, patients with tumours with both very low and very high EGFR LI (13% > or = EGFR LI > 80%) showed significantly shorter survival than those with medium EGFR LI (13% < GFR LI < or = 80%). Additionally, pTNM and pN significantly influenced patients' survival. In multivariate analysis, EGFR LI and pTNM were independent prognostic parameters influencing disease-specific survival of patients.

Aberrant Expression of Calretinin, D2-40 and Mesothelin in Mucinous and Non-Mucinous Colorectal Carcinomas and Relation to Clinicopathological Features and Prognosis.

PubMed

Foda, Abd AlRahman Mohammad; El-Hawary, Amira Kamal; Hamed, Hazem

2016-10-01

CRC is a heterogeneous disease in terms of morphology, invasive behavior, metastatic capacity, and clinical outcome. Recently, many so-called mesothelial markers, including calretinin, D2-40, WT1, thrombomodulin, mesothelin, and others, have been certified. The aim of this study was to assess the immunohistochemical expression of calretinin and other mesothelial markers (D2-40 and mesothelin) in colorectal mucinous adenocarcinoma (MA) and non mucinous adenocarcinoma (NMA) specimens and relation to clinicopathological features and prognosis using manual tissue microarray technique. We studied tumor tissue specimens from 150 patients with colorectal MA and NMA who underwent radical surgery from January 2007 to January 2012. High-density manual tissue microarrays were constructed using a modified mechanical pencil tip technique, and paraffin sections were submitted for immunohistochemistry using Calretinin, D2-40 and mesothelin expressions. We found that NMA showed significantly more calretinin and D2-40 expression than MA In contrast, no statistically significant difference between NMA and MA was detected in mesothelin expression. There were no statistically significant relations between any of the clinicopathological or histological parameters and any of the three markers. In a univariate analysis, neither calretinin nor D2-40 expressions showed any significant relations to DFS or OS. However, mesothelin luminal expression was significantly associated with worse DFS. Multivariate Cox regression analysis proved that luminal mesothelin expression was an independent negative prognostic factor in NMA. In conclusion, Calretinin, D2-40 and mesothelin are aberrantly expressed in a proportion of CRC cases with more expression in NMA than MA. Aberrant expression of these mesothelial markers was not associated with clinicopathological or histological features of CRCs. Only mesothelin expression appears to be a strong predictor of adverse prognosis.

Phylogenetic distribution and expression of a penicillin-binding protein homologue, Ear and its significance in virulence of Staphylococcus aureus.

PubMed

Singh, Vineet K; Ring, Robert P; Aswani, Vijay; Stemper, Mary E; Kislow, Jennifer; Ye, Zhan; Shukla, Sanjay K

2017-12-01

Staphylococcus aureus is an opportunistic human pathogen that can cause serious infections in humans. A plethora of known and putative virulence factors are produced by staphylococci that collectively orchestrate pathogenesis. Ear protein (Escherichia coli ampicillin resistance) in S. aureus is an exoprotein in COL strain, predicted to be a superantigen, and speculated to play roles in antibiotic resistance and virulence. The goal of this study was to determine if expression of ear is modulated by single nucleotide polymorphisms in its promoter and coding sequences and whether this gene plays roles in antibiotic resistance and virulence. Promoter, coding sequences and expression of the ear gene in clinical and carriage S. aureus strains with distinct genetic backgrounds were analysed. The JE2 strain and its isogenic ear mutant were used in a systemic infection mouse model to determine the competiveness of the ear mutant.Results/Key findings. The ear gene showed a variable expression, with USA300FPR3757 showing a high-level expression compared to many of the other strains tested including some showing negligible expression. Higher expression was associated with agr type 1 but not correlated with phylogenetic relatedness of the ear gene based upon single nucleotide polymorphisms in the promoter or coding regions suggesting a complex regulation. An isogenic JE2 (USA300 background) ear mutant showed no significant difference in its growth, antibiotic susceptibility or virulence in a mouse model. Our data suggests that despite being highly expressed in a USA300 genetic background, Ear is not a significant contributor to virulence in that strain.

Innate immune responses against rock bream iridovirus (RBIV) infection in rock bream (Oplegnathus fasciatus) following poly (I:C) administration.

PubMed

Jung, Myung-Hwa; Jung, Sung-Ju

2017-12-01

Poly (I:C) showed promise as an immunoprotective agents in rock bream against rock bream iridovirus (RBIV) infection. In this study, we evaluated the time-dependent virus replication pattern and antiviral immune responses in RBIV-infected rock bream with and without poly (I:C) administration. In the poly (I:C)+virus-injected group, virus copy numbers were more than 18.9-, 24.0- and 479.2-fold lower than in the virus only injected group at 4 (4.73 × 10 4 and 8.95 × 10 5 /μl, respectively), 7 (3.67 × 10 5 and 8.81 × 10 6 /μl, respectively) and 10 days post infection (dpi) (1.26 × 10 5 and 6.02 × 10 7 /μl, respectively). Moreover, significantly high expression levels of TLR3 (8.6- and 7.7-fold, at 4 and 7 dpi, respectively) and IL1β (3.6-fold at 2 dpi) were observed in the poly (I:C)+virus-injected group, but the expression levels were not significantly in the virus-injected group. However, IL8 and TNFα expression levels showed no statistical significance in both groups. Mx, ISG15 and PKR were significantly highly expressed from 4 to 10 dpi in the virus-injected group. Nevertheless, in the poly (I:C)+virus-injected group, Mx and ISG15 expression were significantly expressed from 2 dpi. In summary, poly (I:C) administration in rock bream induces TLR3, IL1β, Mx and ISG15-mediated immune responses, which could be a critical factor for inhibition of virus replication. Copyright © 2017 Elsevier Ltd. All rights reserved.

Indoleamine 2,3-dioxygenase 1 and overall survival of patients diagnosed with esophageal cancer

PubMed Central

Rosenberg, Ari J.; Wainwright, Derek A.; Rademaker, Alfred; Galvez, Carlos; Genet, Matthew; Zhai, Lijie; Lauing, Kristen L.; Mulcahy, Mary F.; Hayes, John P.; Odell, David D.; Horbinski, Craig; Komanduri, Srinadh; Tetreault, Marie-Pier; Kim, Kwang-Youn A.; Villaflor, Victoria M.

2018-01-01

Background Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme with immunomodulatory properties that has emerged as a potential immunotherapeutic target in human cancer. However, the role, expression pattern, and relevance of IDO1 in esophageal cancer (EC) are poorly understood. Here, we utilize gene expression analysis of the cancer genome atlas (TCGA) and immunohistochemistry (IHC) to better understand the role and prognostic significance of IDO1 in EC. Results High IDO1 mRNA levels were associated with worse overall survival (OS) in both esophageal squamous cell carcinoma (SCC) (P = 0.02) and adenocarcinoma (AC) (P = 0.036). High co-expression of IDO1 and programmed death ligand 1 (PD-L1) was associated with worse OS in SCC (P = 0.0031) and AC (P = 0.0186). IHC for IDO1 in SCC showed a significant correlation with PD-L1 (P < 0.0001) and CD3ε (P < 0.0001). Conclusions EC with high IDO1 and PD-L1 expression is significantly correlated with decreased patient survival, and may correlate with increased T-cells. These data suggest that simultaneous inhibition of IDO1 and PD-(L)1 may overcome important barriers to T-cell mediated immune rejection of EC. Materials and Methods mRNA expression data from TCGA (SCC N = 87; AC N = 97). IHC in a second cohort of EC (N = 93) were stained for IDO1, PD-L1, and CD3ε, followed by light microscopic analysis. PMID:29805749

Comparative gene expression analysis of bovine nuclear-transferred embryos with different developmental potential by cDNA microarray and real-time PCR to determine genes that might reflect calf normality.

PubMed

Kato, Yoko; Li, Xiangping; Amarnath, Dasari; Ushizawa, Koichi; Hashizume, Kazuyoshi; Tokunaga, Tomoyuki; Taniguchi, Masanori; Tsunoda, Yukio

2007-01-01

Placental abnormalities are the main factor in the high incidence of somatic cell clone abnormalities. The expression of several trophoblast cell-specific molecules is enhanced during gestational days 7 to 14. To determine the possible genes whose expression patterns might reflect calf normality, we first compared the gene expression profiles on day 15 between in vitro-fertilized (IVF) embryos and two types of somatic cell nuclear-transferred embryos with either a high (FNT) or low (CNT) incidence of neonatal abnormalities using a cDNA microarray containing 16 of 21 placenta-specific genes developed from tissues collected across gestation. To identify significant genes from the screening of day 15 embryos, genes with a less than two-fold difference in expression between IVF and CNT embryos, and those with a greater than two-fold difference between IVF and FNT and between CNT and FNT were considered to contribute to clone abnormalities. These two comparisons revealed 18 down-regulated and 18 upregulated genes of the 1722 genes examined. We then examined the expression levels of 10 genes with known functions in eight-cell and blastocyst-stage embryos by real-time PCR. The mRNA expression pattern of interferon (IFN)-tau, a trophectoderm-related gene, differed between IVF, CNT, and FNT eight-cell embryos; few or none of the IVF or CNT eight-cell embryos expressed IFN-tau mRNA, but all eight-cell FNT embryos expressed IFN-tau. IFN-tau mRNA expression was significantly higher in IVF blastocysts, however, than in nuclear-transferred blastocysts. Average IFN-tau mRNA expression in FNT blastocysts was not different from that in CNT blastocysts, due to one CNT blastocyst with high expression. The precise relation between early expression of IFN-tau mRNA and inferior developmental potential in cloned embryos should be examined further.

Over-expression of mammaglobin-B in canine mammary tumors.

PubMed

Pandey, Mamta; Sunil Kumar, B V; Gupta, Kuldip; Sethi, Ram Saran; Kumar, Ashwani; Verma, Ramneek

2018-06-15

Mammaglobin, a member of secretoglobin family has been recognized as a breast cancer associated protein. Though the exact function of the protein is not fully known, its expression has been reported to be upregulated in human breast cancer.We focused on studying the expression of mammaglobin-B gene and protein in canine mammary tumor (CMT) tissue. Expression of mammaglobin-B mRNA and protein were assessed by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC), respectively. High levels of mammaglobin-B mRNA expression (6.663 ± 0.841times) was observed in CMT as compared to age and breed matched healthy controls. Further, expression of mammaglobin-B protein was detected in paraffin-embedded mammary tumor tissues from the same subjects by IHC. Mammaglobin-B protein was overexpressed only in 6.67% of healthy mammary glands while, a high level of its expression was scored in 76.7% of the CMT subjects. Moreover, no significant differences in terms of IHC score and qRT-PCR score with respect to CMT histotypes or tumor grades were observed, indicating that mammaglobin-B over-expression occurred irrespective of CMT types or grades. Overall, significantly increased expression of mammaglobin-B protein was found in CMTs with respect to healthy mammary glands, which positively correlates to its transcript. These findings suggest that overexpression of mammaglobin-B is associated with tumors of canine mammary glands.

Relation of glypican-3 and E-cadherin expressions to clinicopathological features and prognosis of mucinous and non-mucinous colorectal adenocarcinoma.

PubMed

Foda, Abd Al-Rahman Mohammad; Mohammad, Mie Ali; Abdel-Aziz, Azza; El-Hawary, Amira Kamal

2015-06-01

Glypican-3 (GPC3) is a member of the membrane-bound heparin sulfate proteoglycans. E-cadherin is an adhesive receptor that is believed to act as a tumor suppressor gene. Many studies had investigated E-cadherin expressions in colorectal carcinoma (CRC) while only one study had investigated GPC3 expression in CRC. This study aims to investigate expression of GCP3 and E-cadherin in colorectal mucinous carcinoma (MA) and non-mucinous adenocarcinoma (NMA) using manual tissue microarray technique. Tumor tissue specimens are collected from 75 cases of MC and 75 cases of NMA who underwent radical surgery from Jan 2007 to Jan 2012 at the Gastroenterology Centre, Mansoura University, Egypt. Their clinicopathological parameters and survival data were revised and analyzed using established statistical methodologies. High-density manual tissue microarrays were constructed using modified mechanical pencil tip technique and immunohistochemistry for GPC3 and E-cadherin was done. NMA showed higher expression of GPC3 than MA with no statistically significant relation. NMA showed a significantly higher E-cadherin expression than MA. GPC3 and E-cadherin positivity rates were significantly interrelated in NMA, but not in MA, group. In NMA group, there was no significant relation between either GPC3 or E-cadherin expression and the clinicopathological features. In a univariate analysis, neither GPC3 nor E-cadherin expression showed a significant impact on disease-free survival (DFS) or overall survival (OS). GPC3 and E-cadherin expressions are not independent prognostic factors in CRC. However, expressions of both are significantly interrelated in NMA patients, suggesting an excellent interplay between both, in contrast to MA. Further molecular studies are needed to further explore the relationship between GCP3 and E-cadherin in colorectal carcinogenesis.

Quantification of STAT3 and VEGF expression for molecular diagnosis of lymph node metastasis in breast cancer

PubMed Central

Chen, Yujuan; Liu, Ya; Wang, Yu; Li, Wen; Wang, Xiaolu; Liu, Xuejuan; Chen, Yao; Ouyang, Chibin; Wang, Jing

2017-01-01

Abstract Background: Axillary lymph node metastasis is associated with increased risk of regional recurrence, distant metastasis, and poor survival in breast malignant neoplasm. Expression of signal transducer and activator of transcription 3 (STAT3) is significantly associated with tumor formation, migration, and invasion in various cancers. In addition, vascular endothelial growth factor (VEGF) expression could promote angiogenesis and increase the risk of tumorigenesis. To determine correlations among STAT3 expression, VEGF, and clinicopathological data on lymph node involvement in breast cancer patients after surgery. Methods: The mRNA expression levels of STAT3 and VEGFs were measured in 45 breast invasive ductal carcinoma tissues, 45 peritumoral tissues, and 45 adjacent nontumor tissues by real-time quantitative reverse transcription-polymerase chain reaction (RT-qPCR). Postoperative pathological examination revealed explicit axillary lymph node involvement in all patients. Results: Average mRNA levels of STAT3 and VEGFs were the highest in breast invasive ductal carcinoma tissues, followed by peritumoral tissues. High expression of STAT3 showed significant positive correlation with high axillary lymph node involvement and progesterone receptor (PR), VEGF-C, VEGF-D, and vascular endothelial growth factor receptor (VEGFR)-3 expression. The expression levels of STAT3, VEGF-C, and VEGFR-3 were significantly higher in the tumor tissues of patients with axillary lymph node metastasis than in those of patients without the metastasis. Expression levels of VEGF-C and VEGFR-3 were also significantly higher in peritumoral tissues of patients with axillary lymph node metastasis. Positive correlations were found between STAT3 and VEGF-C/-D mRNA levels. Conclusion: These data suggest that STAT3/VEGF-C/VEGFR-3 signaling pathway plays an important role in carcinogenesis and lymph-angiogenesis. Our findings suggest that STAT3 may be a potential molecular biomarker for predicting the involvement of axillary lymph nodes in breast cancer, and therapies targeting STAT3 may be important for preventing breast cancer metastasis. PMID:29137038

[Rhein promotes the expression of SIRT1 in kidney tissues of type 2 diabetic rat].

PubMed

Chen, Weidong; Chang, Baochao; Zhang, Yan; Yang, Ping; Liu, Lei

2015-05-01

To observe the effect of rhein on the expression of SIRT1(Sirtuin 1) in kidney of diabetic rats, and to explore the role of rhein in protecting rat kidney against diabetic nephropathy and possible mechanism. The type 2 diabetic rats were induced by high-glucose and high-fat diet combined with streptozotocin (35 mg/kg body mass). Seventy-five eight-week-old male SD rats were randomly divided into 6 groups: normal group, diabetic group, low-, medium- and high-dose (50, 100, 150 mg/kg) rhein treatment groups and 10 mg/kg pioglitazone treatment group. The rats were given corresponding substances intragastrically once a day. At the end of the 16th week, the fasting plasma glucose (FPG), fasting insulin (FINS), triglycerides (TG), total cholesterol (TC), serum creatinine (Scr) and 24 hours urine protein (24 h U-PRO) were determined. The renal hypertrophy index (KM/BM), insulin resistance index (HOMA-IR) were calculated. The pathological changes in renal tissues were examined by PAS staining under a light microscopy. The mean glomerular area (MGA) and mean glomerular volume (MGV) were measured by pathological image analysis system. Western blotting and real-time quantitative PCR were used to determine the expression of SIRT1 in renal tissues at protein and mRNA levels, respectively. The expression of SIRT1 was down-regulated in the kidney of diabetic rats. The levels of FPG, FINS, HOMA-IR, TG, TC, Scr, 24 h U-PRO, KM/BM, MGA and MGV significantly decreased and the histopathology of renal tissues were significantly improved in all treatment groups compared with diabetic group. The expression of SIRT1 mRNA and protein markedly increased in rhein treatment groups and pioglitazone treatment group compared with diabetic group. The indicators in high-dose rhein treatment group were improved more significantly than those in the other groups. Correlation analysis showed that the expression of SIRT1 was negatively correlated with 24 h U-PRO and MGV. The expression of SIRT1 was reduced in kidney tissues of diabetic rats. Rhein could attenuate kidney damage in diabetic rats by improving the insulin resistance and dyslipidemia, and increasing the SIRT1 expression.

Transcriptome Analysis in Haematococcus pluvialis: Astaxanthin Induction by High Light with Acetate and Fe2.

PubMed

He, Bangxiang; Hou, Lulu; Dong, Manman; Shi, Jiawei; Huang, Xiaoyun; Ding, Yating; Cong, Xiaomei; Zhang, Feng; Zhang, Xuecheng; Zang, Xiaonan

2018-01-07

Haematococcus pluvialis is a commercial microalga, that produces abundant levels of astaxanthin under stress conditions. Acetate and Fe 2+ are reported to be important for astaxanthin accumulation in H. pluvialis . In order to study the synergistic effects of high light stress and these two factors, we obtained transcriptomes for four groups: high light irradiation (HL), addition of 25 mM acetate under high light (HA), addition of 20 μM Fe 2+ under high light (HF) and normal green growing cells (HG). Among the total clean reads of the four groups, 156,992 unigenes were found, of which 48.88% were annotated in at least one database (Nr, Nt, Pfam, KOG/COG, SwissProt, KEGG, GO). The statistics for DEGs (differentially expressed genes) showed that there were more than 10 thousand DEGs caused by high light and 1800-1900 DEGs caused by acetate or Fe 2+ . The results of DEG analysis by GO and KEGG enrichments showed that, under the high light condition, the expression of genes related to many pathways had changed, such as the pathway for carotenoid biosynthesis, fatty acid elongation, photosynthesis-antenna proteins, carbon fixation in photosynthetic organisms and so on. Addition of acetate under high light significantly promoted the expression of key genes related to the pathways for carotenoid biosynthesis and fatty acid elongation. Furthermore, acetate could obviously inhibit the expression of genes related to the pathway for photosynthesis-antenna proteins. For addition of Fe 2+ , the genes related to photosynthesis-antenna proteins were promoted significantly and there was no obvious change in the gene expressions related to carotenoid and fatty acid synthesis.

Clinicopathological and prognostic significance of cyclooxygenase-2 expression in head and neck cancer: A meta-analysis

PubMed Central

Guo, Qiaojuan; Ren, Hui; Hu, Yanping; Xie, Tao

2016-01-01

Several studies have assessed the clinicopathological and prognostic value of cyclooxygenase-2 (COX-2) expression in patients with head and neck cancer (HNC), but their results remain controversial. To address this issue, a meta-analysis was carried out. A total of 29 studies involving 2430 patients were subjected to final analysis. Our results indicated that COX-2 expression was not statistically associated with advanced tumor stage (OR, 1.23; 95% CI, 0.98–1.55) but correlated with high risk of lymph node metastasis (OR, 1.28; 95% CI, 1.03–1.60) and advanced TNM stage (OR, 1.33; 95% CI, 1.06–1.66). Moreover, COX-2 expression had significant effect on poor OS (HR, 1.93; 95% CI, 1.29–2.90), RFS (HR, 2.02; 95% CI, 1.00–4.08) and DFS (HR, 5.14; 95% CI, 2.84–9.31). The results of subgroup analyses revealed that COX-2 expression was related with high possibility of lymph node metastasis in oral cancer (OR, 1.49; 95% CI, 1.01–2.20) and advanced TNM stage in oral cancer (OR, 1.58; 95% CI, 1.05–2.37) and no site-specific HNC (OR, 1.64; 95% CI, 1.02–2.62). However, subgroup analyses only showed a tendency without statistically significant association between COX-2 expression and survival. Significant heterogeneity was not found when analyzing clinicopathological data, but it appeared when considering survival data. No publication bias was detected in this study. This meta-analysis suggested that COX-2 expression could act as a prognostic factor for patients with HNC. PMID:27323811

Skin expression of mammalian target of rapamycin and forkhead box transcription factor O1, and serum insulin-like growth factor-1 in patients with acne vulgaris and their relationship with diet.

PubMed

Agamia, N F; Abdallah, D M; Sorour, O; Mourad, B; Younan, D N

2016-06-01

Acne vulgaris is a multifactorial disorder of the pilosebaceous units. Several studies have reported that insulin-like growth factor (IGF)-1, forkhead box transcription factor (Fox)O1 and mammalian target of rapamycin (mTOR) interactions may be the key to understanding the links between genetic and environmental factors in acne vulgaris. To evaluate the immunohistochemical detection of mTOR and FoxO1 in the skin, and the serum level of IGF-1 in patients with acne vulgaris. This study was carried out on 60 participants, including 40 patients with acne and 20 controls. A diet questionnaire was administered to the patients and controls. Serum levels of IGF-1 were measured using enzyme-linked immunosorbent assay, and skin biopsies were taken from lesions on the backs of the patients and controls. FoxO1 and mTOR expression was detected using immunohistochemistry. A significantly higher serum IGF-1 level was found in the patients with acne than in the controls. The cytoplasmic expression of FoxO1 was found to be significantly greater in the acne group, whereas in the control subjects this expression was likely to be nuclear. Both the cytoplasmic expression and the nuclear expression of mTOR were significantly more intense in the patients with acne than in the controls. Excess consumption of a high-glycaemic-load diet was significantly associated with higher serum levels of IGF-1 and cytoplasmic expression of FoxO1 and mTOR. These results suggest that FoxO1, mTOR, serum IGF-1 and a high-glycaemic-load diet may play a role in acne pathogenesis. © 2016 British Association of Dermatologists.

Correlation between spontaneous apoptosis and the expression of angiogenic factors in advanced gastric adenocarcinoma.

PubMed

Ikeguchi, M; Cai, J; Fukuda, K; Oka, S; Katano, K; Tsujitani, S; Maeta, M; Kaibara, N

2001-06-01

The aim of this study was to investigate whether angiogenic factors influence the occurrence of spontaneous apoptosis in advanced gastric cancer. The apoptotic indices (AIs) of 97 tumors from 97 patients with advanced gastric cancer (pT3, pN0, pM0, Stage II) were analyzed by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick end labeling (TUNEL) method. Intratumoral microvessel densities (IMVDs) of tumors stained with anti-CD34 monoclonal antibody were quantified under x 200 magnification using computer-assisted image analysis. The expressions of angiogenic factors, such as vascular endothelial growth factor (VEGF), thymidine phosphorylase (dThdPase), transforming growth factor-alpha (TGF-alpha), and p53 were analyzed immunohistochemically and compared with IMVDs and AIs. The mean IMVD of the 97 tumors was 365/mm2 (range 147-990/mm2). The mean AI of tumors was 2.1% (range 0-11.3%). A significant inverse correlation between the AIs and the IMVDs was shown (p = -0.278, P = 0.0064). The mean IMVDs of tumors with high expressions of dThdPase, TGF-alpha, or p53 were significantly higher than those of tumors with low expressions of these factors. The mean AI of tumors with high expressions of dThdPase was significantly lower than that of tumors with low expressions of dThdPase (P = 0.023). However, no significant correlations were detected between AIs and the expression levels of VEGF, TGF-alpha, or p53. In gastric cancer, dThdPase may play an important role in tumor progression by increasing microvessels and by suppressing apoptosis of cancer cells.

Fiber type dependent upregulation of human skeletal muscle UCP2 and UCP3 mRNA expression by high-fat diet.

PubMed

Schrauwen, P; Hoppeler, H; Billeter, R; Bakker, A H; Pendergast, D R

2001-04-01

To test the hypothesis that consumption of a high-fat diet leads to an increase in UCP mRNA expression in human skeletal muscle. In a group of endurance athletes, with a range in fiber type distribution, we hypothesized that the effect of the high-fat diet on UCP2 and UCP3 mRNA expression is more pronounced in muscle fibers which are known to have a high capacity to shift from carbohydrate to fat oxidation (type IIA fibers). Ten healthy trained athletes (five males, five females) consumed a low-fat diet (17+/-0.9 en% of fat) and high-fat diet (41.4+/-1.4 en% fat) for 4 weeks, separated by a 4 week wash-out period. Muscle biopsies were collected at the end of both dietary periods. Using RT-PCR, levels of UCP2 and UCP3 mRNA expression were measured and the percentage of type I, IIA and IIB fibers were determined using the myofibrillar ATPase method in all subjects. UCP3L mRNA expression tended to be higher on the high-fat diet, an effect which reached significance when only males were considered (P=0.037). Furthermore, diet-induced change in mRNA expression of UCP3T (r: 0.66, P=0.037), UCP3L (r: 0.61, P=0.06) and UCP2 (r: 0.70, P=0.025), but not UCP3S, correlated significantly with percentage dietary fat on the high-fat diet. Plasma FFA levels were not different during the two diets. Finally, the percentage of type IIA fibers was positively correlated with the diet-induced change in mRNA expression for UCP2 (r: 0.7, P=0.03), UCP3L (r: 0.73, P=0.016) and UCP3T (r: 0.68, P=0.03) but not with UCP3S (r: 0.06, NS). UCP2 and UCP3 mRNAs are upregulated by a high-fat diet. This upregulation is more pronounced in humans with high proportions of type IIA fibers, suggesting a role for UCPs in lipid utilization.

The effects of pilates exercise on lipid metabolism and inflammatory cytokines mRNA expression in female undergraduates.

PubMed

Kim, Hyo-Jin; Kim, Jiyeon; Kim, Chang-Sun

2014-09-01

The purpose of the study was to verify the effects of Pilates exercise by observing the impact of 8 weeks of Pilates exercise on lipid metabolism and inflammatory cytokine mRNA expression in female undergraduates in their 20s who had no prior experience in Pilates exercise and had not exercised in the previous 6 months. There were 18 subjects with no prior experience in Pilates exercise. The subjects were separated into the Pilates exercise group (n = 9) and the non-exercise control group (n = 9). The former performed Pilates exercise for 60-70 minutes over 8 weeks with a gradual strength increase of 9-16 in the Rating of Perceived Exercise (RPE). The body composition, creatine kinase in the bloodstream and lipid metabolism (TC, LDL-C, HDL-C, TG) were measured before and after the experiment and Real-Time PCR was used to investigate the mRNA expression of the inflammatory cytokines IL-6 and TNF-⍺. The creatine kinase (CK) in the blood had significant differences between the groups. The test group showed significant increase compared to the control group after 8 weeks of Pilates exercise (p = 0.007). Lipid analysis showed that the level of high-density lipoprotein cholesterol (HDL-C) was significantly different in the two groups (p = 0.049), with the Pilates exercise group exhibiting significantly higher levels compared to the control group. No significant differences were observed in the levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG). IL-6 mRNA expression did not show significant differences between the groups either. Timing and TNF-α mRNA expression showed significant effect in both the exercise and the control groups (p = 0.013) but no correlation. It was found from the study that Pilates exercise for 8 weeks affected CK expression (the muscle damage marker) and induced positive changes in the levels of high-density lipoprotein.

The effects of pilates exercise on lipid metabolism and inflammatory cytokines mRNA expression in female undergraduates

PubMed Central

Kim, Hyo-Jin; Kim, Jiyeon; Kim, Chang-Sun

2014-01-01

[Purpose] The purpose of the study was to verify the effects of Pilates exercise by observing the impact of 8 weeks of Pilates exercise on lipid metabolism and inflammatory cytokine mRNA expression in female undergraduates in their 20s who had no prior experience in Pilates exercise and had not exercised in the previous 6 months. [Methods] There were 18 subjects with no prior experience in Pilates exercise. The subjects were separated into the Pilates exercise group (n = 9) and the non-exercise control group (n = 9). The former performed Pilates exercise for 60-70 minutes over 8 weeks with a gradual strength increase of 9-16 in the Rating of Perceived Exercise (RPE). The body composition, creatine kinase in the bloodstream and lipid metabolism (TC, LDL-C, HDL-C, TG) were measured before and after the experiment and Real-Time PCR was used to investigate the mRNA expression of the inflammatory cytokines IL-6 and TNF-⍺. [Results] The creatine kinase (CK) in the blood had significant differences between the groups. The test group showed significant increase compared to the control group after 8 weeks of Pilates exercise (p = 0.007). Lipid analysis showed that the level of high-density lipoprotein cholesterol (HDL-C) was significantly different in the two groups (p = 0.049), with the Pilates exercise group exhibiting significantly higher levels compared to the control group. No significant differences were observed in the levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG). IL-6 mRNA expression did not show significant differences between the groups either. Timing and TNF-α mRNA expression showed significant effect in both the exercise and the control groups (p = 0.013) but no correlation. [Conclusion] It was found from the study that Pilates exercise for 8 weeks affected CK expression (the muscle damage marker) and induced positive changes in the levels of high-density lipoprotein. PMID:25566463

Parathyroid cell growth in patients with advanced secondary hyperparathyroidism: vitamin D receptor and cyclin-dependent kinase inhibitors, p21 and p27.

PubMed

Tokumoto, Masanori; Tsuruya, Kazuhiko; Fukuda, Kyoichi; Kanai, Hidetoshi; Kuroki, Shoji; Hirakata, Hideki; Iida, Mitsuo

2003-06-01

Uraemic patients with advanced secondary hyperparathyroidism (2HPT) have nodular hyperplastic glands with a decreased vitamin D receptor (VDR) density. Previous studies have shown that nodular hyperplasia expressed a significantly lower VDR density as compared with diffuse hyperplasia, and the VDR density negatively correlated with both the glandular weight and the marker of cell proliferation. However, the mechanism by which the decreased VDR density leads to parathyroid cell proliferation remains unclear. In the myelomonocytic cell line, active vitamin D(3) is known to activate the transcription of both p21 and p27, cyclin-dependent kinase inhibitors (CDKIs), regulating the transition from the G(1) to the S phase of the cell cycle, in a VDR-dependent manner. Moreover, the overexpression of p21 and p27 inhibits cell proliferation. In order to elucidate the mechanism of parathyroid cell proliferation, the expression of CDKIs, p21 and p27, and the VDR was analysed immunohistochemically, and compared among nodular and diffuse hyperplastic parathyroid glands, and histologically normal parathyroid glands. The VDR expression in nodular hyperplasias was significantly decreased compared with either diffuse hyperplasias or normal parathyroid glands. The expression of both p21 and p27 was also significantly lower in nodular hyperplasias than in diffuse hyperplasias or normal parathyroid glands. Sections of parathyroid glands with a high expression of nuclear VDR highly expressed both p21 and p27. In nodular hyperplasias, the expression of both p21 and p27 correlated either positively with the nuclear VDR expression or inversely with the glandular weight. Therefore, the reduced expression of p21 and p27, being VDR dependent, is a major pathogenic factor for nodular parathyroid gland growth in advanced 2HPT.

Prognostic significance of B7-H4 expression in matched primary pancreatic cancer and liver metastases.

PubMed

Qian, Yun; Sang, Yiwen; Wang, Frederick X C; Hong, Bo; Wang, Qi; Zhou, Xinhui; Weng, Tianhao; Wu, Zhigang; Zheng, Min; Zhang, Hong; Yao, Hangping

2016-11-01

Liver metastasis development in pancreatic cancer patients is common and confers a poor prognosis. Clinical relevance of biomarker analysis in metastatic tissue is necessary. B7-H4 has an inhibitory effect on T cell mediated response and may be involved in tumor development. Although B7-H4 expression has been detected in pancreatic cancer, its expression in liver metastases from pancreatic cancer is still unknown. In this study, overall 43 pancreatic cancer liver metastases (with matched primaries in 15/43 cases) and 57 pancreatic cancer cases without liver metastases or other distant metastases were analyzed for their expression of B7-H4 by immunohistochemistry. Survival curves and log-rank tests were used to test the association of B7-H4 expression with survival. B7-H4 was highly expressed in 28 (65.1%) of the 43 liver metastases and 9 (60.0%) of the 15 matched primary tumors. The expression of B7-H4 in liver metastases was significantly higher than in the matched primary tumors (p < 0.05). Patients with high B7-H4 expression in their primary pancreatic cancer had higher risk of developing liver metastases (p < 0.05). In univariate analysis, B7-H4 expression was significantly associated with the risk of death (p < 0.05). And the multivariate analysis identified that B7-H4 was an independent prognostic indicator (p < 0.05). Our results revealed B7-H4 to be associated with poor prognosis in patients with pancreatic cancer liver metastasis. B7-H4 may promote pancreatic cancer metastasis and was promising to be a potential prognostic indicator of pancreatic cancer.

Downregulation of microRNA-206 is a potent prognostic marker for patients with gastric cancer.

PubMed

Yang, Qi; Zhang, Chao; Huang, Bo; Li, Huiyan; Zhang, Rong; Huang, Yuxin; Wang, Jingjie

2013-08-01

MicroRNA-206 (miR-206), as a homolog of miR-1, plays important roles in tumorigenesis and tumor progression of various human malignancies, including breast cancer, endometrial endometrioid carcinoma, rhabdomyosarcoma, glioma, lung cancer, and laryngeal cancer. However, its involvement in gastric cancer has remained unclear. To examine the expression patterns and clinical implications of miR-206 in gastric cancer. Quantitative RT-PCR was performed to evaluate the expression levels of miR-206 in 98 pairs of gastric cancer and normal adjacent mucosa. In addition, the clinicopathologic significance and the prognostic value of miR-206 expression were further determined. At first, miR-206 expression was significantly downregulated in gastric cancer tissues when compared with normal adjacent mucosa (P<0.001). Next, tumors with low miR-206 expression had a greater extent of lymph node metastasis (P=0.01), presence of venous invasion (P=0.008), and hematogenous recurrence (P=0.01), and were at a worse stage (P=0.03) than the tumors with a high miR-206 expression. Then, the gastric cancer patients with a low miR-206 expression had shorter overall survival than those with a high miR-206 expression (P=0.02). Furthermore, multivariate analysis showed that miR-206 expression was an independent prognostic factor for patients with gastric cancer. Our results strongly suggest that the downregulation of miR-206 was significantly correlated with tumor progression and may be a potent prognostic marker of gastric cancer. miR-206 might serve as a promising therapeutic target for the treatment of this cancer.

High Frequency of Programmed Death-ligand 1 Expression in Emphysematous Bullae-associated Lung Adenocarcinomas.

PubMed

Toyokawa, Gouji; Takada, Kazuki; Okamoto, Tatsuro; Kozuma, Yuka; Matsubara, Taichi; Haratake, Naoki; Takamori, Shinkichi; Akamine, Takaki; Katsura, Masakazu; Shoji, Fumihiro; Oda, Yoshinao; Maehara, Yoshihiko

2017-09-01

Emphysematous bullae (EB) are known to be associated with a high incidence of lung cancer; however, the reason for this has yet to be elucidated. The objective of the present study was to clarify the prevalence of programmed death-ligand-1 (PD-L1) expression in EB-associated lung adenocarcinomas. A total of 369 patients with resected lung adenocarcinoma whose preoperative computed tomography findings were available for the examination of EB were analyzed for PD-L1 expression by immunohistochemistry and evaluated to determine the association between PD-L1 expression and EB-related adenocarcinomas. Among 369 patients, EB and cancer adjoining EB (Ca-ADJ) were identified in 81 (22.0%) and 50 (13.6%) patients, respectively. EB and Ca-ADJ were significantly associated with male gender, a smoking habit, a decreased forced expiratory volume in 1 second, a relatively higher tumor grade, advanced T status and stage, the presence of pleural and vessel invasion, invasive pathologic subtypes, and wild-type epidermal growth factor receptor. Seventy patients (19.0%) were positive for PD-L1 expression, whereas the remaining 299 patients (81.0%) were negative. Thirty-six (44.4%) and 29 (58.0%) of 81 and 50 patients with EB and Ca-ADJ, respectively, were positive for PD-L1 expression, which was shown to be significant by the Fisher exact test (P < .001 and P < .001, respectively). Among the 81 lung adenocarcinomas with EB, Ca-ADJ was significantly associated with PD-L1 expression (P = .021). In a multivariate analysis, the presence of Ca-ADJ was found to be an independent predictor of PD-L1 expression. EB-associated lung adenocarcinomas express PD-L1 protein more frequently than those without EB. Copyright © 2016 Elsevier Inc. All rights reserved.

Increased expression of c-Ski as a co-repressor in transforming growth factor-beta signaling correlates with progression of esophageal squamous cell carcinoma.

PubMed

Fukuchi, Minoru; Nakajima, Masanobu; Fukai, Yasuyuki; Miyazaki, Tatsuya; Masuda, Norihiro; Sohda, Makoto; Manda, Ryokuhei; Tsukada, Katsuhiko; Kato, Hiroyuki; Kuwano, Hiroyuki

2004-03-01

Transforming growth factor-beta (TGF-beta) regulates cell growth inhibition, and inactivation of the TGF-beta signaling pathway contributes to tumor development. In our previous study, altered expression of TGF-beta, TGF-beta-specific receptors and Smad4 was shown to correlate with tumor progression in esophageal squamous cell carcinoma (SCC). These components, however, were maintained normally in some patients with esophageal SCC. In our study, the mechanism by which aggressive esophageal SCC maintains these components was investigated, with particular emphasis on the participation of c-Ski and SnoN as transcriptional co-repressors in TGF-beta signaling. Immunohistochemistry for c-Ski and SnoN was carried out on surgical specimens obtained from 80 patients with esophageal SCC. The expression of c-Ski and SnoN was also studied in 6 established cell lines derived from esophageal SCC and compared to an immortalized human esophageal cell line by Western blotting. High levels of expression of c-Ski, detected immunohistologically, were found to correlate with depth of invasion (p = 0.0080) and pathologic stage (p = 0.0447). There was, however, no significant correlation between expression of SnoN and clinicopathologic characteristics. A significant correlation between c-Ski and TGF-beta expression was observed. Moreover, in patients with TGF-beta negative expression, the survival rates of patients with c-Ski positive expression were significantly lower than those of patients with c-Ski negative expression (p = 0.0486). c-Ski was expressed at a high level in 5 of 6 cell lines derived from esophageal SCC compared to immortalized esophageal keratinocytes. Furthermore, the cyclin-dependent kinase (CDK) inhibitor, p21 that was up-regulated by TGF-beta signaling was expressed at a low level in the 5 cell lines. The expression of c-Ski protein as a transcriptional co-repressor in TGF-beta signaling seems to be correlated with tumor progression of esophageal SCC. Copyright 2003 Wiley-Liss, Inc.

Hypocholesterolaemic effect of whole-grain highland hull-less barley in rats fed a high-fat diet.

PubMed

Xia, Xuejuan; Li, Guannan; Song, Jiaxin; Zheng, Jiong; Kan, Jianquan

2018-05-01

Whole-grain highland hull-less barley (WHLB) contains high amounts of bioactive compounds that potentially exhibit cholesterol-lowering effects. This study investigated the hypocholesterolaemic effect of WHLB. A total of seventy-two male Sprague-Dawley rats were divided into four groups and were fed with the normal control diet, high-fat diet (HFD) and HFD containing low or high dose (10 or 48·95 %) of WHLB. High dose of WHLB significantly decreased the organ indexes of liver and abdominal fat and lipid levels of plasma and liver in HFD rats. The lipid regulation effect of WHLB, which was reconfirmed through hepatocyte morphologic observation, was accompanied by a large excretion of bile acids in the small intestinal contents and the faeces. Real-time PCR analyses, which were further reconfirmed through Western blot analyses, revealed that a high dose of WHLB significantly enhanced the hepatic expressions of AMP-activated protein kinase α, cholesterol 7α-hydroxylase, LDL receptor, liver X receptor, and PPARα and decreased the expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase. It also enhanced the ileal expression of farnesoid X receptor and resulted in the decrease of expression of apical sodium-dependent bile acid transporter. WHLB exhibited hypocholesterolaemic effects mainly by inhibiting cholesterol synthesis, cholesterol accumulation in peripheral tissue, and bile acid reabsorption and by stimulating bile acid synthesis.

Expression of regulatory proteins and proliferative activity in relation to phenotypic characteristics of upper urothelial carcinoma.

PubMed

Dolićanin, Zana; Velicković, Ljubinka Janković; Djordjević, Biljana; Visnjić, Milan; Pesić, Ivana; Ristić, Ana; Marjanović, Vesna

2011-07-01

Deregulation of the normal cell cycle is common in upper urothelial carcinoma (UUC). The aim of this study was to investigate the expression of regulatory proteins of the cell cycle (p53, p16, cyclin D1, HER-2) and proliferative Ki-67 activity in UUC, and to determine their interaction and influence on the phenotypic characteristics of UUC. In 44 patients with UUC, histopathological and immunohistochemical analyses (p53, p16, cyclin D1, HER-2, and Ki-67) of tumors were done. Overexpression/altered expression of p53, p16, cyclin D1 or HER-2 was detected in 20%, 57%, 64%, and 57% of tumors, respectively. Eleven (25%) UUC had a high proliferative Ki-67 index. Forty patients (91%) had at least one marker altered, while four (9%) tumors had a wild-type status. Analysis of relationship between expressions of molecular markers showed that only high expression of p53 was significantly associated with altered p16 activity (p < 0.05). High Ki-67 index was associated with the high stage (p < 0.005), solid growth (p < 0.01), high grade (p < 0.05), and multifocality p < 0.05) of UUC, while high expression of p53 was associated with the solid growth (p < 0.05). In regression models that included all molecular markers and phenotypic characteristics, only Ki-67 correlated with the growth (p < 0.0001), stage (p < 0.01), grade (p < 0.05) and multifocality (p < 0.05) of UCC; (Ki-67 and HER-2 expression correlated with the lymphovascular invasion (p < 0.05). This investigation showed that only negative regulatory proteins of the cell cycle, p53 and p16, were significantly associated in UUC, while proliferative marker Ki-67 was in relation to the key phenotypic characteristics of UUC in the best way.

T-lymphokine-activated killer cell-originated protein kinase (TOPK) as a prognostic factor and a potential therapeutic target in glioma

PubMed Central

Duan, Qiuhong; Yuan, Ping; Xue, Peipei; Lu, Hui; Yan, Meng; Guo, Dongsheng; Xu, Sanpeng; Zhang, Xiaohui; Lin, Xuan; Wang, Yong; Dogan, Soner; Zhang, Jianmin; Zhu, Feng; Ke, Changshu; Liu, Lin

2018-01-01

TOPK is overexpressed in various types of cancer and associated with poor outcomes in different types of cancer. In this study, we first found that the expression of T-lymphokine-activated killer cell-originated protein kinase (TOPK) was significantly higher in Grade III or Grade IV than that in Grade II in glioma (P = 0.007 and P < 0.001, respectively). Expression of TOPK was positively correlated with Ki67 (P < 0.001). Knockdown of TOPK significantly inhibited cell growth, colony formation and increased sensitivities to temozolomide (TMZ) in U-87 MG or U-251 cells, while TOPK overexpression promoted cell growth and colony formation in Hs 683 or A-172 cells. Glioma patients expressing high levels of TOPK have poor survival compared with those expressing low levels of TOPK in high-grade or low-grade gliomas (hazard ratio = 0.2995; 95% CI, 0.1262 to 0.7108; P = 0.0063 and hazard ratio = 0.1509; 95% CI, 0.05928 to 0.3842; P < 0.0001, respectively). The level of TOPK was low in TMZ-sensitive patients compared with TMZ-resistant patients (P = 0.0056). In TMZ-resistant population, patients expressing high TOPK have two months’ shorter survival time than those expressing low TOPK. Our findings demonstrated that TOPK might represent as a promising prognostic and predictive factor and potential therapeutic target for glioma. PMID:29487691

TPX2 expression is associated with poor survival in gastric cancer.

PubMed

Tomii, Chiharu; Inokuchi, Mikito; Takagi, Yoko; Ishikawa, Toshiaki; Otsuki, Sho; Uetake, Hiroyuki; Kojima, Kazuyuki; Kawano, Tatsuyuki

2017-01-09

Targeting protein for Xenopus kinesin-like protein 2 (TPX2) is a microtubule-associated protein required for microtubule formation in human cells. Several studies have demonstrated that TPX2 is overexpressed in multiple tumor types and promotes tumor growth and metastasis. However, there have been few reports regarding its role in gastric cancer. In this study, we evaluated TPX2 expression and investigated its correlations with gastric cancer clinicopathological features and prognosis. Tumor samples were obtained from 290 patients with gastric adenocarcinoma who had undergone gastrectomy. The expression of TPX2 protein was examined using immunohistochemical staining. TPX2 messenger RNA (mRNA) levels were evaluated using real-time quantitative reverse transcription PCR in 19 of the gastric cancer tumors and adjacent normal tissues. The mRNA levels of TPX2 were significantly higher in gastric cancer tissues than in matched adjacent normal tissues (p = 0.004). In the immunohistochemical analysis, TPX2 overexpression was found in 123 (42.4%) of 290 patients. High TPX2 expression was positively associated with age, type of histology, depth of tumor, lymph node metastasis, stage, and remote metastasis or recurrence. High TPX2 expression was significantly associated with poorer disease-specific survival (p = 0.004) and relapse-free interval (p = 0.013). Our results indicated that high TPX2 expression was associated with tumor progression and poor survival in gastric cancer.

PTEN loss increases PD-L1 protein expression and affects the correlation between PD-L1 expression and clinical parameters in colorectal cancer.

PubMed

Song, Minmin; Chen, Defeng; Lu, Biyan; Wang, Chenliang; Zhang, Junxiao; Huang, Lanlan; Wang, Xiaoyan; Timmons, Christine L; Hu, Jun; Liu, Bindong; Wu, Xiaojian; Wang, Lei; Wang, Jianping; Liu, Huanliang

2013-01-01

Programmed death ligand-1 (PD-L1) has been identified as a factor associated with poor prognosis in a range of cancers, and was reported to be mainly induced by PTEN loss in gliomas. However, the clinical effect of PD-L1 and its regulation by PTEN has not yet been determined in colorectal cancer (CRC). In the present study, we verified the regulation of PTEN on PD-L1 and further determined the effect of PTEN on the correlation between PD-L1 expression and clinical parameters in CRC. RNA interference approach was used to down-regulate PTEN expression in SW480, SW620 and HCT116 cells. It was showed that PD-L1 protein, but not mRNA, was significantly increased in cells transfected with siRNA PTEN compared with the negative control. Moreover, the capacity of PTEN to regulate PD-L1 expression was not obviously affected by IFN-γ, the main inducer of PD-L1. Tissue microarray immunohistochemistry was used to detect PD-L1 and PTEN in 404 CRC patient samples. Overexpression of PD-L1 was significantly correlated with distant metastasis (P<0.001), TNM stage (P<0.01), metastatic progression (P<0.01) and PTEN expression (P<0.001). Univariate analysis revealed that patients with high PD-L1 expression had a poor overall survival (P<0.001). However, multivariate analysis did not support PD-L1 as an independent prognostic factor (P = 0.548). Univariate (P<0.001) and multivariate survival (P<0.001) analysis of 310 located CRC patients revealed that high level of PD-L1 expression was associated with increased risks of metastatic progression. Furthermore, the clinical effect of PD-L1 on CRC was not statistically significant in a subset of 39 patients with no PTEN expression (distant metastasis: P = 0.102; TNM stage: P = 0.634, overall survival: P = 0.482). PD-L1 can be used to identify CRC patients with high risk of metastasis and poor prognosis. This clinical manifestation may be partly associated with PTEN expression.

THD-Module Extractor: An Application for CEN Module Extraction and Interesting Gene Identification for Alzheimer's Disease.

PubMed

Kakati, Tulika; Kashyap, Hirak; Bhattacharyya, Dhruba K

2016-11-30

There exist many tools and methods for construction of co-expression network from gene expression data and for extraction of densely connected gene modules. In this paper, a method is introduced to construct co-expression network and to extract co-expressed modules having high biological significance. The proposed method has been validated on several well known microarray datasets extracted from a diverse set of species, using statistical measures, such as p and q values. The modules obtained in these studies are found to be biologically significant based on Gene Ontology enrichment analysis, pathway analysis, and KEGG enrichment analysis. Further, the method was applied on an Alzheimer's disease dataset and some interesting genes are found, which have high semantic similarity among them, but are not significantly correlated in terms of expression similarity. Some of these interesting genes, such as MAPT, CASP2, and PSEN2, are linked with important aspects of Alzheimer's disease, such as dementia, increase cell death, and deposition of amyloid-beta proteins in Alzheimer's disease brains. The biological pathways associated with Alzheimer's disease, such as, Wnt signaling, Apoptosis, p53 signaling, and Notch signaling, incorporate these interesting genes. The proposed method is evaluated in regard to existing literature.

THD-Module Extractor: An Application for CEN Module Extraction and Interesting Gene Identification for Alzheimer’s Disease

PubMed Central

Kakati, Tulika; Kashyap, Hirak; Bhattacharyya, Dhruba K.

2016-01-01

There exist many tools and methods for construction of co-expression network from gene expression data and for extraction of densely connected gene modules. In this paper, a method is introduced to construct co-expression network and to extract co-expressed modules having high biological significance. The proposed method has been validated on several well known microarray datasets extracted from a diverse set of species, using statistical measures, such as p and q values. The modules obtained in these studies are found to be biologically significant based on Gene Ontology enrichment analysis, pathway analysis, and KEGG enrichment analysis. Further, the method was applied on an Alzheimer’s disease dataset and some interesting genes are found, which have high semantic similarity among them, but are not significantly correlated in terms of expression similarity. Some of these interesting genes, such as MAPT, CASP2, and PSEN2, are linked with important aspects of Alzheimer’s disease, such as dementia, increase cell death, and deposition of amyloid-beta proteins in Alzheimer’s disease brains. The biological pathways associated with Alzheimer’s disease, such as, Wnt signaling, Apoptosis, p53 signaling, and Notch signaling, incorporate these interesting genes. The proposed method is evaluated in regard to existing literature. PMID:27901073

Prognostic Significance of Human Apurinic/Apyrimidinic Endonuclease (APE/Ref-1) Expression in Rectal Cancer Treated With Preoperative Radiochemotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Jun-Sang, E-mail: k423j@cnu.ac.kr; Cancer Research Institute, Chungnam National University, Daejeon; Kim, Jin-Man

Purpose: Human apurinic endonuclease/redox factor 1 (APE/Ref-1) mediates repair of radiation-induced DNA lesions and regulates transcription via redox-based activation. We investigated the predictive and prognostic significance of APE/Ref-1 expression in pretreatment biopsy specimens in locally advanced rectal cancer (LARC) (cT3-T4 or N+). Methods and Materials: APE/Ref-1 expression was analyzed by immunohistochemistry in pretreatment biopsy specimens obtained from 83 patients with LARC. Patients received preoperative radiotherapy of 50.4 Gy in 28 fractions, combined with oral capecitabine and leucovorin chemotherapy, followed by curative surgery. The prognostic significance of various clinicopathologic characteristics, including APE/Ref-1 protein expression, was evaluated. Results: APE/Ref-1 was expressed inmore » 97% of patient samples. Exclusive APE/Ref-1 nuclear staining was observed in 49 of 83 samples (59%), and mixed nuclear and cytoplasmic staining was observed in 31 samples (37%). APE/Ref-1 nuclear expression levels were low in 49 patients (59%) and high in 34 patients (41%). The level of APE/Ref-1 nuclear expression was not a prognostic factor for overall and disease-free survival. Cytoplasmic expression of APE/Ref-1 was a borderline-significant predictive factor for pathologic tumor response (p = 0.08) and a significant prognostic factor for disease-free survival, as shown by univariate analysis (p = 0.037). Multivariate analysis confirmed that cytoplasmic localization of APE/Ref-1 is a significant predictor of disease-free survival (hazard ratio, 0.45; p = 0.046). Conclusions: APE/Ref-1 was expressed in a majority of pretreatment biopsy specimens from patients with LARC. The level of APE/Ref-1 nuclear expression was not a significant predictive and prognostic factor; however, cytoplasmic localization of the protein was negatively associated with disease-free survival. These results indicate that cytoplasmic expression of APE/Ref-1 represents an adverse prognostic factor for LARC patients who receive preoperative radiochemotherapy.« less

TWEAK Appears as a Modulator of Endometrial IL-18 Related Cytotoxic Activity of Uterine Natural Killers

PubMed Central

Petitbarat, Marie; Rahmati, Mona; Sérazin, Valérie; Dubanchet, Sylvie; Morvan, Corinne; Wainer, Robert; de Mazancourt, Philippe; Chaouat, Gérard; Foidart, Jean-Michel; Munaut, Carine; Lédée, Nathalie

2011-01-01

Background TWEAK (Tumor necrosis factor like WEAK inducer of apoptosis) is highly expressed by different immune cells and triggers multiple cellular responses, including control of angiogenesis. Our objective was to investigate its role in the human endometrium during the implantation window, using an ex-vivo endometrial microhistoculture model. Indeed, previous results suggested that basic TWEAK expression influences the IL-18 related uNK recruitment and local cytotoxicity. Methodology/Principal Findings Endometrial biopsies were performed 7 to 9 days after the ovulation surge of women in monitored natural cycles. Biopsies were cut in micro-pieces and cultured on collagen sponge with appropriate medium. Morphology, functionality and cell death were analysed at different time of the culture. We used this ex vivo model to study mRNA expressions of NKp46 (a uNK cytotoxic receptor) and TGF-beta1 (protein which regulates uNK cytokine production) after adjunction of excess of recombinant IL-18 and either recombinant TWEAK or its antibody. NKp46 protein expression was also detailed by immunohistochemistry in selected patients with high basic mRNA level of IL-18 and either low or high mRNA level of TWEAK. The NKp46 immunostaining was stronger in patients with an IL-18 over-expression and a low TWEAK expression, when compared with patients with both IL-18 and TWEAK high expressions. We did not observe any difference for TWEAK expression when recombinant protein IL-18 or its antibody was added, or conversely, for IL-18 expression when TWEAK or its antibody was added in the culture medium. In a pro-inflammatory environment (obtained by an excess of IL-18), inhibition of TWEAK was able to increase significantly NKp46 and TGF-beta1 mRNA expressions. Conclusions/Significance TWEAK doesn't act on IL-18 expression but seems to control IL-18 related cytotoxicity on uNK cells when IL-18 is over-expressed. Thus, TWEAK appears as a crucial physiological modulator to prevent endometrial uNK cytotoxicity in human. PMID:21249128

Immunotherapy targeting folate receptor induces cell death associated with autophagy in ovarian cancer

PubMed Central

Wen, Yunfei; Graybill, Whitney S.; Previs, Rebecca A.; Hu, Wei; Ivan, Cristina; Mangala, Lingegowda S.; Zand, Behrouz; Nick, Alpa M.; Jennings, Nicholas B.; Dalton, Heather J.; Sehgal, Vasudha; Ram, Prahlad; Lee, Ju-Seog; Vivas-Mejia, Pablo E.; Coleman, Robert L.; Sood, Anil K.

2014-01-01

Purpose Cancer cells are highly dependent on folate metabolism, making them susceptible to drugs that inhibit folate receptor activities. Targeting overexpressed folate receptor alpha (FRα) in cancer cells offers a therapeutic opportunity. We investigated the functional mechanisms of MORAB-003 (farletuzumab), a humanized monoclonal antibody against FRα, in ovarian cancer models. Experimental Design We first examined FRα expression in an array of human ovarian cancer cell lines and then assessed the in vivo effect of MORAB-003 on tumor growth and progression in several orthotopic mouse models of ovarian cancer derived from these cell lines. Molecular mechanisms of tumor cell death induced by MORAB-003 were investigated by cDNA and protein expression profiling analysis. Mechanistic studies were performed to determine the role of autophagy in MORAB-003–induced cell death. Results MORAB-003 significantly decreased tumor growth in the high-FRα IGROV1 and SKOV3ip1 models but not in the low-FRα A2780 model. MORAB-003 reduced proliferation but had no significant effect on apoptosis. Protein expression and cDNA microarray analyses showed that MORAB-003 regulated an array of autophagy-related genes. It also significantly increased expression of LC3 isoform II and enriched autophagic vacuolization. Blocking autophagy with hydroxychloroquine or bafilomycin A1 reversed the growth inhibition induced by MORAB-003. In add, alteration of FOLR1 gene copy number significantly correlated with shorter disease-free survival in patients with ovarian serous cystadenocarcinoma. Conclusions MORAB-003 displays prominent antitumor activity in ovarian cancer models expressing FRα at high levels. Blockade of folate receptor by MORAB-003 induced sustained autophagy and suppressed cell proliferation. PMID:25416196

Heterogeneity of SOX9 and HNF1β in Pancreatic Ducts Is Dynamic.

PubMed

Rezanejad, Habib; Ouziel-Yahalom, Limor; Keyzer, Charlotte A; Sullivan, Brooke A; Hollister-Lock, Jennifer; Li, Wan-Chun; Guo, Lili; Deng, Shaopeng; Lei, Ji; Markmann, James; Bonner-Weir, Susan

2018-03-13

Pancreatic duct epithelial cells have been suggested as a source of progenitors for pancreatic growth and regeneration. However, genetic lineage-tracing experiments with pancreatic duct-specific Cre expression have given conflicting results. Using immunofluorescence and flow cytometry, we show heterogeneous expression of both HNF1β and SOX9 in adult human and murine ductal epithelium. Their expression was dynamic and diminished significantly after induced replication. Purified pancreatic duct cells formed organoid structures in 3D culture, and heterogeneity of expression of Hnf1β and Sox9 was maintained even after passaging. Using antibodies against a second cell surface molecule CD51 (human) or CD24 (mouse), we could isolate living subpopulations of duct cells enriched for high or low expression of HNF1β and SOX9. Only the CD24 high (Hnfβ high /Sox9 high ) subpopulation was able to form organoids. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Blockage of hemichannels alters gene expression in osteocytes in a high magneto-gravitational environment

PubMed Central

Xu, Huiyun; Ning, Dandan; Zhao, Dezhi; Chen, Yunhe; Zhao, Dongdong; Gu, Sumin; Jiang, Jean X.; Shang, Peng

2017-01-01

Osteocytes, the most abundant cells in bone, are highly responsive to external environmental changes. We tested how Cx43 hemichannels which mediate the exchange of small molecules between cells and extracellular environment impact genome wide gene expression under conditions of abnormal gravity and magnetic field. To this end, we subjected osteocytic MLO-Y4 cells to a high magneto-gravitational environment and used microarray to examine global gene expression and a specific blocking antibody was used to assess the role of Cx43 hemichannels. While 3 hr exposure to abnormal gravity and magnetic field had relatively minor effects on global gene expression, blocking hemichannels significantly impacted the expression of a number of genes which are involved in cell viability, apoptosis, mineral absorption, protein absorption and digestion, and focal adhesion. Also, blocking of hemichannels enriched genes in multiple signaling pathways which are enaged by TGF-beta, Jak-STAT and VEGF. These results show the role of connexin hemichannels in bone cells in high magneto-gravitational environments. PMID:27814646

High expression of nucleobindin 2 is associated with poor prognosis in gastric cancer.

PubMed

Altan, Bolag; Kaira, Kyoichi; Okada, Shuichi; Saito, Tsugumichi; Yamada, Eijiro; Bao, Halin; Bao, Pinjie; Takahashi, Kengo; Yokobori, Takehiko; Tetsunari, Oyama; Nishiyama, Masahiko; Yamada, Masanobu

2017-07-01

Nucleobindin 2 has been reported that its high expression is associated with poor outcome and promotes cell migration and lymph node metastasis in breast cancer, colon cancer, and prostate cancer. However, we aimed to investigate the nucleobindin 2 expression in gastric cancer tissues and adjacent non-tumor tissues and its potential relevance to clinicopathological factors and prognosis using immunohistochemical analysis. In our study, nucleobindin 2 level in gastric cancer tissues was higher than in non-tumor tissues. A high expression of nucleobindin 2 is significantly associated with tumor depth, lymph node metastasis, lymphatic invasion, venous invasion, and clinical stage. Furthermore, the expression level of nucleobindin 2 protein was independent predictor of progression-free survival. In summary, nucleobindin 2 might play a crucial role in gastric cancer development and could serve as an independent predictor of prognosis of gastric cancer patients.

A pro-invasive role for the Ca2+-activated K+ channel KCa3.1 in malignant glioma

PubMed Central

Turner, Kathryn L.; Honasoge, Avinash; Robert, Stephanie M.; McFerrin, Michael M.; Sontheimer, Harald

2014-01-01

Glioblastoma multiforme (GBM) are highly motile primary brain tumors. Diffuse tissue invasion hampers surgical resection leading to poor patient prognosis. Recent studies suggest that intracellular Ca2+ acts as a master regulator for cell motility and engages a number of downstream signals including Ca2+-activated ion channels. Querying the REepository of Molecular BRAin Neoplasia DaTa (REMBRANDT), an annotated patient gene database maintained by the National Cancer Institute, we identified the intermediate conductance Ca2+-activated K+ channels, KCa3.1, being overexpressed in 32% of glioma patients where protein expression significantly correlated with poor patient survival. To mechanistically link KCa3.1 expression to glioma invasion, we selected patient gliomas that, when propagated as xenolines in vivo, present with either high or low KCa3.1 expression. In addition we generated U251 glioma cells that stably express an inducible knockdown shRNA to experimentally eliminate KCa3.1 expression. Subjecting these cells to a combination of in vitro and in situ invasion assays, we demonstrate that KCa3.1 expression significantly enhances glioma invasion and that either specific pharmacological inhibition with TRAM-34 or elimination of the channel impairs invasion. Importantly, after intracranial implantation into SCID mice, ablation of KCa3.1 with inducible shRNA resulted in a significant reduction in tumor invasion into surrounding brain in vivo. These results show that KCa3.1 confers an invasive phenotype that significantly worsens a patient’s outlook, and suggests that KCa3.1 represents a viable therapeutic target to reduce glioma invasion. PMID:24585442

Effects of high-pressure oxygen therapy on brain tissue water content and AQP4 expression in rabbits with cerebral hemorrhage.

PubMed

Wu, Jing; Chen, Jiong; Guo, Hua; Peng, Fang

2014-12-01

To investigate the effects of different atmosphere absolutes (ATA) of high-pressure oxygen (HPO) on brain tissue water content and Aquaporin-4 (AQP4) expression in rabbits with cerebral hemorrhage. 180 New Zealand white rabbits were selected and randomly divided into normal group (n = 30), control group (n = 30) and cerebral hemorrhage group (n = 120), and cerebral hemorrhage group was divided into group A, B, C and D with 30 rabbits in each group. The groups received 1.0, 1.8, 2.0 and 2.2 ATA of HPO treatments, respectively. Ten rabbits in each group were killed at first, third and fifth day to detect the brain tissue water content and change of AQP4 expression. In cerebral hemorrhage group, brain tissue water content and AQP4 expression after model establishment were first increased, then decreased and reached the maximum on third day (p < 0.05). Brain tissue water content and AQP4 expression in control group and cerebral hemorrhage group were significantly higher than normal group at different time points (p < 0.05). In contrast, brain tissue water content and AQP4 expression in group C were significantly lower than in group A, group B, group D and control group (p < 0.05). In control group, AQP4-positive cells significantly increased after model establishment, which reached maximum on third day, and positive cells in group C were significantly less than in group A, group B and group D. We also found that AQP4 expression were positively correlated with brain tissue water content (r = 0.719, p < 0.05) demonstrated by significantly increased AQP4 expression along with increased brain tissue water content. In conclusion, HPO can decrease AQP4 expression in brain tissue of rabbits with cerebral hemorrhage to suppress the progression of brain edema and promote repairing of injured tissue. 2.0 ATA HPO exerts best effects, which provides an experimental basis for ATA selection of HPO in treating cerebral hemorrhage.

The α-lipoic acid improves high-fat diet-induced cerebral damage through inhibition of oxidative stress and inflammatory reaction.

PubMed

Liu, Yang; Zhang, Qinghua; Wang, Li; Wang, Hui; Sun, Tao; Xia, Hechun; Yang, Yi; Zhang, Li

2017-12-01

This study is to clarify the protective role of α-lipoic acid in high-fat diet-induced cerebral damage mice. The mice were divided into 5 groups: normal control group, high-fat diet (HFD) group, low-dose α-lipoic acid group for prevention, high-dose α-lipoic acid group for prevention, and high-dose α-lipoic acid group for treatment. The groups' weights and blood glucose changes were monitored. We used HE staining to observe morphological changes in the cerebral cortex. The expression levels of the oxidative stress proteins SOD2, catalase, and the inflammatory pathway proteins p-JNK, p-ERK were measured by western blot and immunochemistry. Compared with the control group, the quantity of cortical neurons in the HFD group was decreased, and the samples exhibited retrogression. However, the lipoic acid significantly protected and promoted the cortical neurons survival. Moreover, compared with the HFD group, the expression levels of SOD2 and catalase in the three α-lipoic acid obtained groups were significantly increased. However, the expression levels of the inflammatory pathway proteins p-JNK and p-ERK were significantly decreased. These results indicate that theα-lipoic acid greatly protects the cortical neurons, and inhibited the oxidative stress and inflammatory reactions in the high-fat diet mice. Copyright © 2017 Elsevier B.V. All rights reserved.

AJUBA increases the cisplatin resistance through hippo pathway in cervical cancer.

PubMed

Bi, Lihong; Ma, Feng; Tian, Rui; Zhou, Yanli; Lan, Weiguang; Song, Quanmao; Cheng, Xiankui

2018-02-20

Though LIM-domain protein AJUBA was identified as a putative oncogene, the function and underlying mechanisms of AJUBA in cervical cancer remain largely unknown. Firstly, AJUBA expression was detected via real-time quantitative PCR in patients' samples. Furthermore, Hela and Siha cells were transfected with AJUBA-overexpressing plasmids, and then exposed to cisplatin, the apoptosis was measured by cytometry assay. In addition, the expression of YAP and TAZ was disclosed through western blot assay. Our results revealed that AJUBA expression was significantly higher in the cervical cancer patients resistant to cisplatin treatment compared with cervical cancer patients sensitive to cisplatin treatment. In addition, overall survival time was significantly shorter in the cervical cancer patients with high AJUBA expression compare with those with low AJUBA expression using kaplan-meier analysis. Hela and Siha cells transfected with AJUBA-expressing plasmids exposed to cisplatin treatment had higher survival rate compared with the cells transfected with empty vector control. Mechanistic studies revealed the AJUBA upregulated the downstream targets YAP and TAZ. These results suggest that high AJUBA level enhances cervical cancer cells drug resistance to cisplatin, also associates with decreased patient survival times. Copyright © 2017 Elsevier B.V. All rights reserved.

Enhancing solubility of deoxyxylulose phosphate pathway enzymes for microbial isoprenoid production

PubMed Central

2012-01-01

Background Recombinant proteins are routinely overexpressed in metabolic engineering. It is well known that some over-expressed heterologous recombinant enzymes are insoluble with little or no enzymatic activity. This study examined the solubility of over-expressed homologous enzymes of the deoxyxylulose phosphate pathway (DXP) and the impact of inclusion body formation on metabolic engineering of microbes. Results Four enzymes of this pathway (DXS, ISPG, ISPH and ISPA), but not all, were highly insoluble, regardless of the expression systems used. Insoluble dxs (the committed enzyme of DXP pathway) was found to be inactive. Expressions of fusion tags did not significantly improve the solubility of dxs. However, hypertonic media containing sorbitol, an osmolyte, successfully doubled the solubility of dxs, with the concomitant improvement in microbial production of the metabolite, DXP. Similarly, sorbitol significantly improved the production of soluble and functional ERG12, the committed enzyme in the mevalonate pathway. Conclusion This study demonstrated the unanticipated findings that some over-expressed homologous enzymes of the DXP pathway were highly insoluble, forming inclusion bodies, which affected metabolite formation. Sorbitol was found to increase both the solubility and function of some of these over-expressed enzymes, a strategy to increase the production of secondary metabolites. PMID:23148661

Application of Genome Wide Association and Genomic Prediction for Improvement of Cacao Productivity and Resistance to Black and Frosty Pod Diseases

PubMed Central

Romero Navarro, J. Alberto; Phillips-Mora, Wilbert; Arciniegas-Leal, Adriana; Mata-Quirós, Allan; Haiminen, Niina; Mustiga, Guiliana; Livingstone III, Donald; van Bakel, Harm; Kuhn, David N.; Parida, Laxmi; Kasarskis, Andrew; Motamayor, Juan C.

2017-01-01

Chocolate is a highly valued and palatable confectionery product. Chocolate is primarily made from the processed seeds of the tree species Theobroma cacao. Cacao cultivation is highly relevant for small-holder farmers throughout the tropics, yet its productivity remains limited by low yields and widespread pathogens. A panel of 148 improved cacao clones was assembled based on productivity and disease resistance, and phenotypic single-tree replicated clonal evaluation was performed for 8 years. Using high-density markers, the diversity of clones was expressed relative to 10 known ancestral cacao populations, and significant effects of ancestry were observed in productivity and disease resistance. Genome-wide association (GWA) was performed, and six markers were significantly associated with frosty pod disease resistance. In addition, genomic selection was performed, and consistent with the observed extensive linkage disequilibrium, high predictive ability was observed at low marker densities for all traits. Finally, quantitative trait locus mapping and differential expression analysis of two cultivars with contrasting disease phenotypes were performed to identify genes underlying frosty pod disease resistance, identifying a significant quantitative trait locus and 35 differentially expressed genes using two independent differential expression analyses. These results indicate that in breeding populations of heterozygous and recently admixed individuals, mapping approaches can be used for low complexity traits like pod color cacao, or in other species single gene disease resistance, however genomic selection for quantitative traits remains highly effective relative to mapping. Our results can help guide the breeding process for sustainable improved cacao productivity. PMID:29184558

TOPK is highly expressed in circulating tumor cells, enabling metastasis of prostate cancer

PubMed Central

Shi, Changhong; Hu, Peizhen; Yan, Wei; Wang, Zhe; Duan, Qiuhong; Lu, Fan; Qin, Lipeng; Lu, Tao; Xiao, Juanjuan; Wang, Yingmei; Zhu, Feng; Shao, Chen

2015-01-01

Circulating tumor cells (CTCs) are important for metastasis in prostate cancer. T-LAK cell-originated protein kinase (TOPK) is highly expressed in cancer cells. Herein, we established a xenograft animal model, isolated and cultured the CTCs, and found CTCs have significantly greater migratory capacity than parental cells. TOPK is more highly expressed in the CTCs than in parental cells and is also highly expressed in the metastatic nodules caused by CTCs in mice. Knocking down TOPK decreased the migration of CTCs both in vitro and in vivo. TOPK was modulated by the PI3K/PTEN and ERK pathways during the metastasis of prostate cancer. High levels of TOPK in the tumors of patients were correlated with advanced stages of prostate cancer, especially for high-risk patients of Gleason score≥8, PSA>20ng/ml. In summary, TOPK was speculated to be one of a potential marker and therapeutic target in advanced prostate cancer. PMID:25881543

Bcl-2-like Protein 11 (BIM) Expression Is Associated with Favorable Prognosis for Patients with Cervical Cancer.

PubMed

Kim, Bo Wook; Cho, Hanbyoul; Ylaya, Kris; Kitano, Haruhisa; Chung, Joon-Yong; Hewitt, Stephen M; Kim, Jae-Hoon

2017-09-01

Bcl-2-like protein 11 (BIM) is a pro-apoptotic member of the Bcl-2 protein family. BIM elicits cell death by binding to pro-survival Bcl-2 proteins. Even though the association of BIM expression with cell death has been investigated, its clinical survival significance in cervical cancer has not. In the current study, the prognostic significance of BIM in cervical cancer was investigated. The study included normal cervical tissues (n=254), cervical intraepithelial neoplasia (CIN) tissues (n=275), and invasive cervical cancer (n=164). In order to identify BIM expression, immunohistochemistry (IHC) was performed, and IHC scoring by quantitative digital image analysis was determined. Then, the association of BIM with prognostic factors was investigated. BIM expression was higher in cervical cancer than normal cervical tissues (p<0.001). Well and moderate differentiation indicated higher BIM expression than did poor differentiation (p=0.001). Also, BIM expression was high in radiation-sensitive cervical cancer relative to radiation-resistant cancer (p=0.049). High BIM expression showed better 5-year disease-free survival (DFS) and overall survival (OS) rates (p=0.049 and π=0.030, respectively) than did low expression. In a multivariate analysis, BIM was shown to be an independent risk factor for DFS and OS in cervical cancer, with hazard ratios of 0.22 (p=0.006) and 0.46 (p=0.046), respectively. BIM is associated with favorable prognostic markers for prediction of DFS and OS in cervical cancer. High BIM expression is a potential prognostic marker as well as a chemotherapeutic target for cervical cancer. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Effects of increased Kindlin-2 expression in bladder cancer stromal fibroblasts.

PubMed

Wu, Jitao; Yu, Cuicui; Cai, Li; Lu, Youyi; Jiang, Lei; Liu, Chu; Li, Yongwei; Feng, Fan; Gao, Zhenli; Zhu, Zhe; Yu, Shengqiang; Yuan, Hejia; Cui, Yuanshan

2017-08-01

Kindlin-2 is a focal adhesion protein highly expressed in bladder cancer stromal fibroblasts. We investigated the prognostic significance of Kindlin-2 in bladder cancer stromal fibroblasts and evaluated the effects of Kindlin-2 on the malignant behaviors of tumor cells. Immunohistochemical staining of 203 paraffin-embedded bladder cancer tissues showed that Kindlin-2 expression correlated with advanced stage, high grade, and relapse of bladder cancer. Kaplan-Meier survival analysis demonstrated that patients exhibiting high Kindlin-2 expression had shorter survival times than those with low Kindlin-2 expression ( p < 0.01). Multivariate analysis revealed that high Kindlin-2 expression leads to poor prognosis in bladder cancer. Using cancer-associated fibroblasts (CAFs) isolated from human bladder cancer tissue, we observed that Kindlin-2 knockdown decreased CAFs activation, resulting in decreased expression of α-smooth muscle actin (α-SMA) and the extracellular matrix protein fibronectin. Kindlin-2 suppression also reduced CAF-induced bladder cancer cell migration and invasion. Moreover, we found that Kindlin-2 activates CAFs and promotes the invasiveness of bladder cancer cells by stimulating TGF-β-induced epithelial-mesenchymal transition. These results support targeting Kindlin-2 and the corresponding activated CAFs in bladder cancer therapy.

Expression of connective tissue growth factor in tumor tissues is an independent predictor of poor prognosis in patients with gastric cancer.

PubMed

Liu, Lu-Ying; Han, Yan-Chun; Wu, Shu-Hua; Lv, Zeng-Hua

2008-04-07

To examine the expression of connective tissue growth factor (CTGF), also known as CCN2, in gastric carcinoma (GC), and the correlation between the expression of CTGF, clinicopathologic features and clinical outcomes of patients with GC. One hundred and twenty-two GC patients were included in the present study. All patients were followed up for at least 5 years. Proteins of CTGF were detected using the Powervision two-step immunostaining method. Of the specimens from 122 GC patients analyzed for CTGF expression, 58 (58/122, 47.5%) had a high CTGF expression in cytoplasm of gastric carcinoma cells and 64 (64/122, 52.5%) had a low CTGF expression. Patients with a high CTGF expression showed a higher incidence of lymph node metastasis than those with a low CTGF expression (P = 0.032). Patients with a high CTGF expression had significantly lower 5-year survival rate than those with a low CTGF expression (27.6% vs 46.9%, P = 0.0178), especially those staging I + II + III (35.7% vs 65.2%, P = 0.0027). GC patients with an elevated CTGF expression have more lymph node metastases and a shorter survival time. CTGF seems to be an independent prognostic factor for the successful differentiation of high-risk GC patients staging I + II + III. Over-expression of CTGF in human GC cells results in an increased aggressive ability.

Efficient expression systems for cysteine proteases of malaria parasites

PubMed Central

Sarduy, Emir Salas; de los A. Chávez Planes, María

2013-01-01

Papain-like cysteine proteases of malaria parasites are considered important chemotherapeutic targets or valuable models for the evaluation of drug candidates. Consequently, many of these enzymes have been cloned and expressed in Escherichia coli for their biochemical characterization. However, their expression has been problematic, showing low yield and leading to the formation of insoluble aggregates. Given that highly-productive expression systems are required for the high-throughput evaluation of inhibitors, we analyzed the existing expression systems to identify the causes of such apparent issues. We found that significant divergences in codon and nucleotide composition from host genes are the most probable cause of expression failure, and propose several strategies to overcome these limitations. Finally we predict that yeast hosts Saccharomyces cerevisiae and Pichia pastoris may be better suited than E. coli for the efficient expression of plasmodial genes, presumably leading to soluble and active products reproducing structural and functional characteristics of the natural enzymes. PMID:23018863

The increase in the expression and hypomethylation of MUC4 gene with the progression of pancreatic ductal adenocarcinoma.

PubMed

Zhu, Yi; Zhang, Jing-jing; Zhu, Rong; Zhu, Yan; Liang, Wen-biao; Gao, Wen-tao; Yu, Jun-bo; Xu, Ze-kuan; Miao, Yi

2011-12-01

The MUC4 gene could have a key role in the progression of pancreatic cancer, but the quantitative measurement of its expression in clinical tissue samples remains a challenge. The correlations between MUC4 promoter methylation status in vivo and either pancreatic cancer progression or MUC4 mRNA expression need to be demonstrated. We used the techniques of quantitative real-time PCR and DNA methylation-specific PCR combined microdissection to precisely detect MUC4 expression and promoter methylation status in 116 microdissected foci from 57 patients with pancreatic ductal adenocarcinoma. Both mRNA expression and hypomethylation frequency increased from normal to precancerous lesions to pancreatic cancer. Multivariate Cox regression analysis showed that high-level MUC4 expression (P = 0.008) and tumor-node-metastasis staging (P = 0.038) were significant independent risk factors for predicting the prognosis of 57 patients. The MUC4 mRNA expression was not significantly correlated with promoter methylation status in 30 foci of pancreatic ductal adenocarcinoma. These results suggest that high mRNA expression and hypomethylation of the MUC4 gene could be involved in carcinogenesis and in the malignant development of pancreatic ductal adenocarcinoma. The MUC4 mRNA expression may become a new prognostic marker for pancreatic cancer. Microdissection-based quantitative real-time PCR and methylation-specific PCR contribute to the quantitative detection of MUC4 expression in clinical samples and reflect the epigenetic regulatory mechanisms of MUC4 in vivo.

Activation of choline kinase drives aberrant choline metabolism in esophageal squamous cell carcinomas.

PubMed

Ma, Wang; Wang, Shuangyuan; Zhang, Tengfei; Zhang, Erik Y; Zhou, Lina; Hu, Chunxiu; Yu, Jane J; Xu, Guowang

2018-06-05

Esophageal squamous cell carcinoma (ESCC) is a major health threat worldwide. Research focused on molecular events associated with ESCC carcinogenesis for diagnosis, treatment and prevention is needed. Our goal is to discover novel biomarkers and investigate the underlying molecular mechanisms of ESCC progression by employing a global metabolomic approach. Sera from 34 ESCC patients and 32 age and sex matched healthy controls were profiled using two-dimensional liquid chromatography-mass spectrometry (2D LC-MS). We identified 120 differential metabolites in ESCC patient serums compared to healthy controls. Several amino acids, serine, arginine, lysine and histidine were significantly changed in ESCC patients. Most importantly, we found dysregulated lipid metabolism as an important characteristic in ESCC patients. Several free fat acids (FFA) and carnitines were found down-regulated in ESCC patients. Choline was significantly increased and phosphatidylcholines (PC) were significantly decreased in ESCC serum. The high expression of choline and low expression of total PC in patient serum were associated with the high expression of choline kinase (Chok) and activated Kennedy pathway in ESCC cells. Chok expression can serve as a significant biomarker for ESCC prognosis. In conclusion, metabolite profiles in the ESCC patient serum were significantly different from those in the healthy controls. Phosphatidylcholines and Chok, the key enzyme in the PC metabolism pathway, may serve as novel biomarkers for ESCC. Copyright © 2018 Elsevier B.V. All rights reserved.

Expression and purification of ELP-intein-tagged target proteins in high cell density E. coli fermentation.

PubMed

Fong, Baley A; Wood, David W

2010-10-19

Elastin-like polypeptides (ELPs) are useful tools that can be used to non-chromatographically purify proteins. When paired with self-cleaving inteins, they can be used as economical self-cleaving purification tags. However, ELPs and ELP-tagged target proteins have been traditionally expressed using highly enriched media in shake flask cultures, which are generally not amenable to scale-up. In this work, we describe the high cell-density expression of self-cleaving ELP-tagged targets in a supplemented minimal medium at a 2.5 liter fermentation scale, with increased yields and purity compared to traditional shake flask cultures. This demonstration of ELP expression in supplemented minimal media is juxtaposed to previous expression of ELP tags in extract-based rich media. We also describe several sets of fed-batch conditions and their impact on ELP expression and growth medium cost. By using fed batch E. coli fermentation at high cell density, ELP-intein-tagged proteins can be expressed and purified at high yield with low cost. Further, the impact of media components and fermentation design can significantly impact the overall process cost, particularly at large scale. This work thus demonstrates an important advances in the scale up of self-cleaving ELP tag-mediated processes.

Expression and purification of ELP-intein-tagged target proteins in high cell density E. coli fermentation

PubMed Central

2010-01-01

Background Elastin-like polypeptides (ELPs) are useful tools that can be used to non-chromatographically purify proteins. When paired with self-cleaving inteins, they can be used as economical self-cleaving purification tags. However, ELPs and ELP-tagged target proteins have been traditionally expressed using highly enriched media in shake flask cultures, which are generally not amenable to scale-up. Results In this work, we describe the high cell-density expression of self-cleaving ELP-tagged targets in a supplemented minimal medium at a 2.5 liter fermentation scale, with increased yields and purity compared to traditional shake flask cultures. This demonstration of ELP expression in supplemented minimal media is juxtaposed to previous expression of ELP tags in extract-based rich media. We also describe several sets of fed-batch conditions and their impact on ELP expression and growth medium cost. Conclusions By using fed batch E. coli fermentation at high cell density, ELP-intein-tagged proteins can be expressed and purified at high yield with low cost. Further, the impact of media components and fermentation design can significantly impact the overall process cost, particularly at large scale. This work thus demonstrates an important advances in the scale up of self-cleaving ELP tag-mediated processes. PMID:20959011

[Suppression of VEGF protein expression by arctigenin in oral squamous cell carcinoma].

PubMed

Pu, Guang-rui; Liu, Fa-yu; Wang, Bo

2015-08-01

To observe arctigenin's inhibitory effect on oral squamous cell carcinoma, and explore the possible mechanism. The expression of VEGF in 32 cases of oral squamous cell cancer and 20 adjacent tissue specimen were detected with immunohistochemistry. Human nude mouse transplantation tumor model of oral squamous cell cancer was prepared with HSC-3 cells line. Transplanted tumor growth and VEGF expression in transplanted tumor tissues were assayed after treatment with arctigenin. One-way ANOVA was used for comparison between groups with SPSS 16.0 software package. Compared with the adjacent tissue, immunohistochemical staining score of VEGF was significantly higher (P<0.01) in oral squamous cell carcinoma tissues. After treatment with arctigenin, the growth of oral squamous cell transplanted tumors in nude mouse was inhibited (P<0.05), and decreased weight in end point of observation was noted (P<0.05). There were significant differences between high dose group and low dose group (P<0.05). Compared with the nude mouse model group, the optical density of VEGF staining was significantly lower in arctigenin group (P<0.05). There were significant differences between high dose group and low dose group (P<0.05). Arctigenin can dose-dependently inhibit the growth of oral squamous cell carcinomas, and this effect may be related to down regulation of VEGF expression.

MYCN amplification confers enhanced folate dependence and methotrexate sensitivity in neuroblastoma

PubMed Central

Lau, Diana T.; Flemming, Claudia L.; Gherardi, Samuele; Perini, Giovanni; Oberthuer, André; Fischer, Matthias; Juraeva, Dilafruz; Brors, Benedikt; Xue, Chengyuan; Norris, Murray D.; Marshall, Glenn M.; Haber, Michelle

2015-01-01

MYCN amplification occurs in 20% of neuroblastomas and is strongly related to poor clinical outcome. We have identified folate-mediated one-carbon metabolism as highly upregulated in neuroblastoma tumors with MYCN amplification and have validated this finding experimentally by showing that MYCN amplified neuroblastoma cell lines have a higher requirement for folate and are significantly more sensitive to the antifolate methotrexate than cell lines without MYCN amplification. We have demonstrated that methotrexate uptake in neuroblastoma cells is mediated principally by the reduced folate carrier (RFC; SLC19A1), that SLC19A1 and MYCN expression are highly correlated in both patient tumors and cell lines, and that SLC19A1 is a direct transcriptional target of N-Myc. Finally, we assessed the relationship between SLC19A1 expression and patient survival in two independent primary tumor cohorts and found that SLC19A1 expression was associated with increased risk of relapse or death, and that SLC19A1 expression retained prognostic significance independent of age, disease stage and MYCN amplification. This study adds upregulation of folate-mediated one-carbon metabolism to the known consequences of MYCN amplification, and suggests that this pathway might be targeted in poor outcome tumors with MYCN amplification and high SLC19A1 expression. PMID:25860940

An in vitro evaluation of anti-aging effect of guluronic acid (G2013) based on enzymatic oxidative stress gene expression using healthy individuals PBMCs.

PubMed

Taeb, Mahsa; Mortazavi-Jahromi, Seyed Shahabeddin; Jafarzadeh, Abdollah; Mirzaei, Mohammad Reza; Mirshafiey, Abbas

2017-06-01

Aging is usually associated with increased levels of oxidants, and may result in damages caused by oxidative stress. There is a direct relationship between aging and increased incidence of inflammatory diseases. The present research intended to study the anti-aging and anti-inflammatory effects of the drug G2013 (guluronic acid) at low and high doses on the genes expression of a number of enzymes involved in oxidative stress (including SOD2, GPX1, CAT, GST, iNOS, and MPO) in peripheral blood mononuclear cells (PBMCs) of healthy individuals under in vitro conditions. Venous blood samples were taken from 20 healthy individuals, the PBMCs were isolated and their RNAs extracted and their cDNAs were synthesized, and the genes expression levels were measured using the qRT-PCR technique. Our results indicated that this drug could, at both low and high doses, significantly reduce the expression of the genes for SOD2, GPX1, CAT, and GST compared to the LPS group (p<0.0001). Moreover, it was noticed that the drug is able to significantly reduce gene expression levels at the high dose and at both doses (low and high), for iNOS and MPO compared to the LPS group (p<0.0001), respectively. The present research showed that G2013, as a novel NSAID drug with immunomodulatory properties, could modulate the expression levels of the genes for SOD2, GPX1, CAT, GST, iNOS, and MPO, to the level of healthy gene expression, and possibly it might reduce the pathological process of aging and age-related inflammatory diseases. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

BMP and TGFbeta pathways in human central chondrosarcoma: enhanced endoglin and Smad 1 signaling in high grade tumors

PubMed Central

2012-01-01

Background As major regulators of normal chondrogenesis, the bone morphogenic protein (BMP) and transforming growth factor β (TGFB) signaling pathways may be involved in the development and progression of central chondrosarcoma. In order to uncover their possible implication, the aim of this study was to perform a systematic quantitative study of the expression of BMPs, TGFBs and their receptors and to assess activity of the corresponding pathways in central chondrosarcoma. Methods Gene expression analysis was performed by quantitative RT-PCR in 26 central chondrosarcoma and 6 healthy articular cartilage samples. Expression of endoglin and nuclear localization of phosphorylated Smad1/5/8 and Smad2 was assessed by immunohistochemical analysis. Results The expression of TGFB3 and of the activin receptor-like kinase ALK2 was found to be significantly higher in grade III compared to grade I chondrosarcoma. Nuclear phosphorylated Smad1/5/8 and Smad2 were found in all tumors analyzed and the activity of both signaling pathways was confirmed by functional reporter assays in 2 chondrosarcoma cell lines. Immunohistochemical analysis furthermore revealed that phosphorylated Smad1/5/8 and endoglin expression were significantly higher in high-grade compared to low-grade chondrosarcoma and correlated to each other. Conclusions The BMP and TGFβ signaling pathways were found to be active in central chondrosarcoma cells. The correlation of Smad1/5/8 activity to endoglin expression suggests that, as described in other cell types, endoglin could enhance Smad1/5/8 signaling in high-grade chondrosarcoma cells. Endoglin expression coupled to Smad1/5/8 activation could thus represent a functionally important signaling axis for the progression of chondrosarcoma and a regulator of the undifferentiated phenotype of high-grade tumor cells. PMID:23088614

High-risk and low-risk human papilloma virus in association to spontaneous preterm labor: a case-control study in a tertiary center, Egypt.

PubMed

Mosbah, Alaa; Barakat, Rafik; Nabiel, Yasmin; Barakat, Ghada

2018-03-01

This study aimed to detect the correlation between human papillomavirus (HPV) and spontaneous preterm labor in Egyptian women and its association to the human papilloma viral load and MPP2 gene expression. We performed an observational comparative case-control study in Department of Obstetric and Gynecology, Mansoura University Hospitals over women presented with spontaneous preterm labor, besides females admitted for giving birth at full term to detect conserved sequence in HPV-L1 gene (GP5/GP6) followed by genotype detection of high- and low-risk HPVs with quantification of the viral load and the MMP2 gene expression using real-time polymerase chain reaction (PCR). The prevalence of HPV was 18.1% in preterm females, but only 4% in full-term women (p value = 0.019*). Twenty percent were PCR positive for HPV 16 and 40% for HPV 18 whereas none of the control was positive for any of the studied high-risk genotypes. Thirty percent were PCR positive for HPV 6 and 10% were positive for HPV 11. MMP2 gene expression was significantly higher in preterm than full term. Human papilloma viral load was found to be positively correlated to the rate of MMP2 expression and the gestational age was significantly related to the viral load and the rate of expression of MMP2 gene. Human pabilloma virus especially high-risk genotypes was correlated to spontaneous preterm labor in Egyptian females through increasing early expression of MMP2 gene. The time of occurrence of preterm labor was affected by the viral load and so the rate of expression of MMP2 gene.

Roles of Soybean Plasma Membrane Intrinsic Protein GmPIP2;9 in Drought Tolerance and Seed Development.

PubMed

Lu, Linghong; Dong, Changhe; Liu, Ruifang; Zhou, Bin; Wang, Chuang; Shou, Huixia

2018-01-01

Aquaporins play an essential role in water uptake and transport in vascular plants. The soybean genome contains a total of 22 plasma membrane intrinsic protein (PIP) genes. To identify candidate PIPs important for soybean yield and stress tolerance, we studied the transcript levels of all 22 soybean PIPs. We found that a GmPIP2 subfamily member, GmPIP2;9, was predominately expressed in roots and developing seeds. Here, we show that GmPIP2;9 localized to the plasma membrane and had high water channel activity when expressed in Xenopus oocytes. Using transgenic soybean plants expressing a native GmPIP2;9 promoter driving a GUS-reporter gene, it was found high GUS expression in the roots, in particular, in the endoderm, pericycle, and vascular tissues of the roots of transgenic plants. In addition, GmPIP2;9 was also highly expressed in developing pods. GmPIP2;9 expression significantly increased in short term of polyethylene glycol (PEG)-mediated drought stress treatment. GmPIP2;9 overexpression increased tolerance to drought stress in both solution cultures and soil plots. Drought stress in combination with GmPIP2;9 overexpression increased net CO 2 assimilation of photosynthesis, stomata conductance, and transpiration rate, suggesting that GmPIP2;9- overexpressing transgenic plants were less stressed than wild-type (WT) plants. Furthermore, field experiments showed that GmPIP2;9 -overexpressing plants had significantly more pod numbers and larger seed sizes than WT plants. In summary, the study demonstrated that GmPIP2;9 has water transport activity. Its relative high expression levels in roots and developing pods are in agreement with the phenotypes of GmPIP2;9 -overexpressing plants in drought stress tolerance and seed development.

Roles of Soybean Plasma Membrane Intrinsic Protein GmPIP2;9 in Drought Tolerance and Seed Development

PubMed Central

Lu, Linghong; Dong, Changhe; Liu, Ruifang; Zhou, Bin; Wang, Chuang; Shou, Huixia

2018-01-01

Aquaporins play an essential role in water uptake and transport in vascular plants. The soybean genome contains a total of 22 plasma membrane intrinsic protein (PIP) genes. To identify candidate PIPs important for soybean yield and stress tolerance, we studied the transcript levels of all 22 soybean PIPs. We found that a GmPIP2 subfamily member, GmPIP2;9, was predominately expressed in roots and developing seeds. Here, we show that GmPIP2;9 localized to the plasma membrane and had high water channel activity when expressed in Xenopus oocytes. Using transgenic soybean plants expressing a native GmPIP2;9 promoter driving a GUS-reporter gene, it was found high GUS expression in the roots, in particular, in the endoderm, pericycle, and vascular tissues of the roots of transgenic plants. In addition, GmPIP2;9 was also highly expressed in developing pods. GmPIP2;9 expression significantly increased in short term of polyethylene glycol (PEG)-mediated drought stress treatment. GmPIP2;9 overexpression increased tolerance to drought stress in both solution cultures and soil plots. Drought stress in combination with GmPIP2;9 overexpression increased net CO2 assimilation of photosynthesis, stomata conductance, and transpiration rate, suggesting that GmPIP2;9-overexpressing transgenic plants were less stressed than wild-type (WT) plants. Furthermore, field experiments showed that GmPIP2;9-overexpressing plants had significantly more pod numbers and larger seed sizes than WT plants. In summary, the study demonstrated that GmPIP2;9 has water transport activity. Its relative high expression levels in roots and developing pods are in agreement with the phenotypes of GmPIP2;9-overexpressing plants in drought stress tolerance and seed development. PMID:29755491

Expression of cancer-related carbonic anhydrases IX and XII in normal skin and skin neoplasms.

PubMed

Syrjänen, Leo; Luukkaala, Tiina; Leppilampi, Mari; Kallioinen, Matti; Pastorekova, Silvia; Pastorek, Jaromir; Waheed, Abdul; Sly, William S; Parkkila, Seppo; Karttunen, Tuomo

2014-09-01

Purpose of the study was to evaluate the presence of hypoxia-inducible, tumour-associated carbonic anhydrases IX and XII in normal skin and a series of cutaneous tumours. Human tumour samples were taken during surgical operations performed on 245 patients and were immunohistochemically stained. A histological score value was calculated for statistical analyses which were performed using SPSS for Windows, versions 17.0 and 20.0. In normal skin, the highest expression of CA IX was detected in hair follicles, sebaceous glands, and basal parts of epidermis. CA XII was detected in all epithelial components of skin. Both CA IX and CA XII expression levels were significantly different in epidermal, appendigeal, and melanocytic tumour categories. Both CA IX and XII showed the most intense immunostaining in epidermal tumours, whereas virtually all melanocytic tumours were devoid of CA IX and XII immunostaining. In premalignant lesions, CA IX expression significantly increased when the tumours progressed to more severe dysplasia forms. Both CA IX and XII are highly expressed in different epithelial components of skin. They are also highly expressed in epidermal tumours, in which CA IX expression levels also correlate with the dysplasia grade. Interestingly, both isozymes are absent in melanocytic tumours. © 2014 APMIS. Published by John Wiley & Sons Ltd.

BRCA1 and BRCA2 expression patterns and prognostic significance in digestive system cancers.

PubMed

Wang, Gui-Hua; Zhao, Chun-Mei; Huang, Ying; Wang, Wei; Zhang, Shu; Wang, Xudong

2018-01-01

The role of BRCA1 and BRCA2 genes is mainly to maintain genome integrity in response to DNA damage through different mechanisms. Deregulation of BRCA1 and BRCA2 is associated with the development of tumor and altered sensitivity to chemotherapeutic agents. In this study, we determined protein expression of BRCA1 and BRCA2 in 4 digestive system cancers (gastric cancer, colorectal cancer, hepatocellular carcinoma, and pancreatic cancer) by immunohistochemistry on tissue microarrays. A total of 1546 samples of 4 types of cancer tissues, their matched adjacent nontumor tissues, and corresponding benign tissues were studied, respectively. Immunohistochemistry expression patterns of the 2 proteins and their correlation with patients' clinical parameters and overall survival were analyzed. The results showed that low expression of cytoplasmic BRCA1 and BRCA2 was commonly associated with advanced tumor-lymph node-metastasis stage, whereas high expression of nuclear BRCA1 was generally correlated with advanced tumor stages in these cancers. High expression of cytoplasmic BRCA1 and BRCA2 had significantly favorable overall survival in digestive system cancers; in contrast, BRCA1 nuclear expression usually predicted poor outcomes. We conclude that BRCA1 and BRCA2 could be used as clinicopathological biomarkers to evaluate the prognosis of digestive system cancers. Copyright © 2017 Elsevier Inc. All rights reserved.

Tuberin Inhibits Production of the Matrix Protein Fibronectin in Diabetes

PubMed Central

Yadav, Mukesh; Tizani, Shaza; Bhandari, Basant; Valente, Anthony J.

2012-01-01

Exposure of proximal tubular epithelial cells to high glucose contributes to the accumulation of tubulointerstitial and matrix proteins in diabetic nephropathy, but how this occurs is not well understood. We investigated the effect of the signaling molecule tuberin, which modulates the mammalian target of rapamycin pathway, on renal hypertrophy and fibronectin expression. We found that the kidney mass was significantly greater in partially tuberin-deficient (TSC2+/−) diabetic rats than wild-type diabetic rats. Furthermore, TSC2+/− rats exhibited significant increases in the basal levels of phospho-tuberin and fibronectin expression in the kidney cortex. Increased levels of phosphorylated tuberin associated with an increase in fibronectin expression in both wild-type and TSC2+/− diabetic rats. Treatment with insulin abrogated the diabetes-induced increase in fibronectin expression. In vitro, high glucose enhanced fibronectin expression in TSC2+/− primary proximal tubular epithelial cells; both inhibition of Akt and inhibition of the mammalian target of rapamycin could prevent this effect of glucose. In addition, forced expression of tuberin in tuberin-null cells abolished the expression of fibronectin protein. Taken together, these data suggest that tuberin plays a central role in the development of renal hypertrophy and in modulating the production of the matrix protein fibronectin in diabetes. PMID:22904348

GLUT-1 Expression in Pancreatic Neoplasia

PubMed Central

Basturk, Olca; Singh, Rajendra; Kaygusuz, Ecmel; Balci, Serdar; Dursun, Nevra; Culhaci, Nil; Adsay, N. Volkan

2011-01-01

Objectives GLUT-1 has been found to have an important role in the upregulation of various cellular pathways and implicated in neoplastic transformation correlating with biological behavior in malignancies. However, literature regarding the significance of GLUT-1 expression in pancreatic neoplasia has been limited and controversial. Methods Immunohistochemical expression of GLUT-1 was tested in a variety of pancreatic neoplasia including ductal adenocarcinomas (DAs), pancreatic intraepithelial neoplasms (PanINs), intraductal papillary mucinous neoplasms (IPMNs), and serous cystadenomas. Results There was a progressive increase in the expression of GLUT-1 from low- to higher-grade dysplastic lesions: All higher-grade PanINs/IPMNs (the ones with moderate/high-grade dysplasia) revealed noticeable GLUT-1 expression. Among the 94 DAs analyzed, there were minimal/moderate expression in 46 and significant expression in 24 DAs. However, all 4 clear-cell variants of DAs revealed significant GLUT-1 immunolabeling, as did areas of clear-cell change seen in other DAs. Moreover, all 12 serous cystadenomas expressed significant GLUT-1. GLUT-1 expression was also directly correlated with DA histological grade (P = 0.016) and tumor size (P = 0.03). Conclusions GLUT-1 may give rise to the distinctive clear-cell appearance of these tumors by inducing the accumulation of glycogen in the cytoplasm. Additionally, because GLUT-1 expression was related to histological grade and tumor size of DA, further studies are warranted to investigate the association of GLUT-1 with prognosis and tumor progression. PMID:21206329

GLUT-1 expression in pancreatic neoplasia: implications in pathogenesis, diagnosis, and prognosis.

PubMed

Basturk, Olca; Singh, Rajendra; Kaygusuz, Ecmel; Balci, Serdar; Dursun, Nevra; Culhaci, Nil; Adsay, N Volkan

2011-03-01

GLUT-1 has been found to have an important role in the upregulation of various cellular pathways and implicated in neoplastic transformation correlating with biological behavior in malignancies. However, literature regarding the significance of GLUT-1 expression in pancreatic neoplasia has been limited and controversial. Immunohistochemical expression of GLUT-1 was tested in a variety of pancreatic neoplasia including ductal adenocarcinomas (DAs), pancreatic intraepithelial neoplasms (PanINs), intraductal papillary mucinous neoplasms (IPMNs), and serous cystadenomas. There was a progressive increase in the expression of GLUT-1 from low- to higher-grade dysplastic lesions: All higher-grade PanINs/IPMNs (the ones with moderate/high-grade dysplasia) revealed noticeable GLUT-1 expression. Among the 94 DAs analyzed, there were minimal/moderate expression in 46 and significant expression in 24 DAs. However, all 4 clear-cell variants of DAs revealed significant GLUT-1 immunolabeling, as did areas of clear-cell change seen in other DAs. Moreover, all 12 serous cystadenomas expressed significant GLUT-1. GLUT-1 expression was also directly correlated with DA histological grade (P = 0.016) and tumor size (P = 0.03). GLUT-1 may give rise to the distinctive clear-cell appearance of these tumors by inducing the accumulation of glycogen in the cytoplasm. Additionally, because GLUT-1 expression was related to histological grade and tumor size of DA, further studies are warranted to investigate the association of GLUT-1 with prognosis and tumor progression.

JiangTang XiaoKe granule attenuates cathepsin K expression and improves IGF-1 expression in the bone of high fat diet induced KK-Ay diabetic mice.

PubMed

Guo, Yubo; Wang, Lili; Ma, Rufeng; Mu, Qianqian; Yu, Na; Zhang, Yi; Tang, Yuqing; Li, Yu; Jiang, Guangjian; Zhao, Dandan; Mo, Fangfang; Gao, Sihua; Yang, Meijuan; Kan, Feifei; Ma, Qun; Fu, Min; Zhang, Dongwei

2016-03-01

To assess the beneficial effects of JiangTang XiaoKe (JTXK) granule on the bone metabolism in high fat diet (HFD) fed KK-Ay diabetic mice. The KK-Ay mice were used as a diabetic model, while C57BL/6 mice were utilized as the non-diabetic control. The left tibia was used for determining bone mineral density (BMD) and bone ash coefficient. The HE and alizarin red S staining of femur were employed to evaluate bone pathology and calcium deposition. The expressions of alkaline phosphatase (ALP), insulin growth factor 1 (IGF-1) and cathepsin K were assessed by western blotting and immunohistochemical staining. JTXK granule significantly improved the bone ash coefficient, the distribution of trabecular bone and the calcification nodules deposition in KK-Ay mice with diabetes. IGF-1 and ALP expressions were significantly decreased, and cathepsin K expression was dramatically increased in the HFD fed KK-Ay diabetic model mice, which can be reversed by JTXK granule treatment. JTXK granule at medium or high dosage was more efficient in improving diabetic bone quality when compared with that in mice with a low dosage. However, the BMD values in each group of KK-Ay diabetic mice were not significantly different. We demonstrate that cathepsin K expression is increased in KK-Ay diabetic mouse model. JTXK granule treatment inhibits osteoclastic bone resorption and promotes the new bone formation by decreasing cathepsin K activity and increasing IGF-1 and ALP levels. These changes may contribute to the increase of bone strength and thus reducing the risk of bone fractures. Copyright © 2016 Elsevier Inc. All rights reserved.

Monocarboxylate transporters MCT1 and MCT4 are independent prognostic biomarkers for the survival of patients with clear cell renal cell carcinoma and those receiving therapy targeting angiogenesis.

PubMed

Cao, Yan-Wei; Liu, Yong; Dong, Zhen; Guo, Lei; Kang, En-Hao; Wang, Yong-Hua; Zhang, Wei; Niu, Hai-Tao

2018-04-12

Prognostic biomarkers for patients with clear cell renal cell carcinoma (ccRCC), particularly those receiving therapy targeting angiogenesis, are not well established. In this study, we examined the correlations of monocarboxylate transporter 1 (MCT1) and MCT4, 2 critical transporters for glycolytic metabolism, with various clinicopathological parameters as well as survival of patients with ccRCC and those treated with vascular endothelial growth factor receptor (VEGFR) inhibitors. A cohort of 150 ccRCC patients were recruited into this study. All patients underwent radical or partial nephrectomy as the first-line treatment, and 38 received targeted therapy (sorafenib or sunitinib) after the surgery. Expression levels of MCT1, MCT4, and CD34 were examined by immunohistochemistry. Correlations between MCT1 or MCT4 expression and different clinicopathological parameters or patient survival were analyzed among all as well as patients receiving targeted therapy. MCT1 or MCT4 expression did not significantly correlate with sex, age, tumor diameter, microvascular density, tumor staging, pathological Furmann grade, or MSKCC (P>0.05). High expression of either MCT1 or MCT4 significantly correlated with reduced overall survival (OS) and progression-free survival (PFS) among the total cohort of ccRCC patients. For patients receiving targeted therapy, high expression of either MCT1 or MCT4 significantly correlated with reduced PFS, but not OS. Both conditions were independent prognostic biomarkers for reduced PFS among all patients or those receiving targeted therapy. MCT1 and MCT4 are prognostic biomarkers for patients with ccRCC or those receiving targeted therapy. High expression of these 2 proteins predicts reduced PFS in these patients. Copyright © 2018 Elsevier Inc. All rights reserved.

Expression of microRNA 638 and sex-determining region Y-box 2 in hepatocellular carcinoma: Association between clinicopathological features and prognosis.

PubMed

Ye, Weikang; Li, Jieke; Fang, Guan; Cai, Xiupeng; Zhang, Yan; Zhou, Chaojun; Chen, Lei; Yang, Wenjun

2018-05-01

The aim of the present study was to determine the expression profile of microRNA 638 (miR-638) and sex-determining region Y-box 2 (SOX2) in hepatocellular carcinoma (HCC), and to investigate their association with clinicopathological features and survival. Reverse transcription-quantitative polymerase chain reaction analysis was used to investigate miR-638 and SOX2 expression in 78 patients with HCC. Western blot and immunohistochemical analyses were performed in order to determine SOX2 protein expression in HCC samples. Combined with the clinical postoperative follow-up data, the expression of miR-638 and SOX2 and the association between this and the prognostic values of patients with HCC were statistically analyzed. The results of the present study confirmed that miR-638 expression in tumor tissues was significantly downregulated (P<0.001), while SOX2 expression was significantly increased, compared with healthy control tissues (P<0.05). In addition, a significant inverse correlation between miR-638 and SOX2 expression was also observed in the HCC tissues (r=-0.675; P<0.05). Clinicopathological correlation analysis demonstrated that reduced miR-638 and elevated SOX2 expression was significantly associated with the Tumor-Node-Metastasis stage and portal vascular invasion (P<0.05). However, no significant differences were observed in other clinicopathological features, including age, sex, tumor size, tumor differentiation and hepatitis status (P>0.05). Notably, follow-up analysis revealed that patients with HCC with low miR-638 expression and high SOX2 expression tended to have a significantly shorter postoperative survival time (P<0.001). It was concluded that miR-638 may serve a vital role in the occurrence and progression of HCC by regulating SOX2 expression and thus, that miR-638 and SOX2 may be critical as novel diagnostic and prognostic biomarkers for HCC.

Smad4/Fascin index is highly prognostic in patients with diffuse type EBV-associated gastric cancer.

PubMed

Son, Byoung Kwan; Kim, Dong-Hoon; Min, Kyueng-Whan; Kim, Eun-Kyung; Kwon, Mi Jung

2018-04-01

Gastric cancer is a heterogeneous disorder for which predicting clinical outcomes is challenging, although various biomarkers have been suggested. The Smad4 and Fascin proteins are known prognostic indicators of different types of malignancy. Smad4 primarily functions as a key regulator of tumor suppression, whereas Fascin exhibits oncogenic function by enhancing tumor infiltration. A combined marker based on these opposing roles may improve prognostic accuracy in gastric cancer. Smad4 and Fascin expression was assessed in tissue microarrays obtained from 285 primary gastric adenocarcinoma, 201 normal tissue, and 51 metastatic adenocarcinoma samples. A Smad4/Fascin index based on the relative expression of each protein was divided into low- and high-expression groups using receiver operating characteristic curves. We compared normal tissue, primary adenocarcinoma, and metastatic adenocarcinoma in Smad4 and Fascin expression and the differences in clinicopathological findings between low Smad4/Fascin and high Smad4/Fascin expression in gastric adenocarcinoma. High Smad4/Fascin expression was significantly associated with worse outcomes, such as old age, advanced T and N category, large tumor size, high histological grade, lymphatic and vascular invasion, and presence of Epstein-Barr virus (EBV) (all p < 0.05). Univariate and multivariate analyses revealed a significant relationship between disease-free or overall survival and Smad4/Fascin index in diffuse-type or EBV-associated gastric cancer (all p < 0.05). A dual marker system using Smad4 and Fascin may be a reliable indicator for predicting clinical outcomes in patients with diffuse-type or EBV-associated gastric cancer. Copyright © 2018 Elsevier GmbH. All rights reserved.

Ectopic High Expression of E2-EPF Ubiquitin Carrier Protein Indicates a More Unfavorable Prognosis in Brain Glioma.

PubMed

Zhang, Xiaohui; Zhao, Fangbo; Zhang, Shujun; Song, Yichun

2017-04-01

Ubiquitination of proteins meant for elimination is a primary method of eukaryotic cellular protein degradation. The ubiquitin carrier protein E2-EPF is a key degradation enzyme that is highly expressed in many tumors. However, its expression and prognostic significance in brain glioma are still unclear. The aim of this study was to reveal how the level of E2-EPF relates to prognosis in brain glioma. Thirty low-grade and 30 high-grade brain glioma samples were divided into two tissue microarrays each. Levels of E2-EPF protein were examined by immunohistochemistry and immunofluorescence. Quantitative real-time polymerase chain reaction was used to analyze the level of E2-EPF in 60 glioma and 3 normal brain tissue samples. The relationship between E2-EPF levels and prognosis was analyzed by Kaplan-Meier survival curves. E2-EPF levels were low in normal brain tissue samples but high in glioma nuclei. E2-EPF levels gradually increased as glioma grade increased (p < 0.05). Ectopic E2-EPF levels in high-grade glioma were significantly higher than in low-grade glioma (p < 0.01). The 5-year survival rate of glioma patients with high E2-EPF levels was shorter than in patients with low expression (p < 0.05). Furthermore, the 5-year survival rate of patients with ectopic E2-EPF was significantly shorter than patients with only nuclear E2-EPF (p < 0.01). These results suggest that higher E2-EPF levels, especially ectopic, are associated with higher grade glioma and shorter survival. E2-EPF levels may play a key role in predicting the prognosis for patients with brain glioma.

Males are from Mars, and females are from Venus: sex-specific fetal brain gene expression signatures in a mouse model of maternal diet-induced obesity.

PubMed

Edlow, Andrea G; Guedj, Faycal; Pennings, Jeroen L A; Sverdlov, Deanna; Neri, Caterina; Bianchi, Diana W

2016-05-01

Maternal obesity is associated with adverse neurodevelopmental outcomes in children, including autism spectrum disorders, developmental delay, and attention-deficit hyperactivity disorder. The underlying mechanisms remain unclear. We previously identified second-trimester amniotic fluid and term cord blood gene expression patterns suggesting dysregulated brain development in fetuses of obese compared with lean women. We sought to investigate the biological significance of these findings in a mouse model of maternal diet-induced obesity. We evaluated sex-specific differences in fetal growth, brain gene expression signatures, and associated pathways. Female C57BL/6J mice were fed a 60% high-fat diet or 10% fat control diet for 12-14 weeks prior to mating. During pregnancy, obese dams continued on the high-fat diet or transitioned to the control diet. Lean dams stayed on the control diet. On embryonic day 17.5, embryos were weighed and fetal brains were snap frozen. RNA was extracted from male and female forebrains (10 per diet group per sex) and hybridized to whole-genome expression arrays. Significantly differentially expressed genes were identified using a Welch's t test with the Benjamini-Hochberg correction. Functional analyses were performed using ingenuity pathways analysis and gene set enrichment analysis. Embryos of dams on the high-fat diet were significantly smaller than controls, with males more severely affected than females (P = .01). Maternal obesity and maternal obesity with dietary change in pregnancy resulted in significantly more dysregulated genes in male vs female fetal brains (386 vs 66, P < .001). Maternal obesity with and without dietary change in pregnancy was associated with unique brain gene expression signatures for each sex, with an overlap of only 1 gene. Changing obese dams to a control diet in pregnancy resulted in more differentially expressed genes in the fetal brain than maternal obesity alone. Functional analyses identified common dysregulated pathways in both sexes, but maternal obesity and maternal dietary change affected different aspects of brain development in males compared with females. Maternal obesity is associated with sex-specific differences in fetal size and fetal brain gene expression signatures. Male fetal growth and brain gene expression may be more sensitive to environmental influences during pregnancy. Maternal diet during pregnancy has a significant impact on the embryonic brain transcriptome. It is important to consider both fetal sex and maternal diet when evaluating the effects of maternal obesity on fetal neurodevelopment. Copyright © 2016 Elsevier Inc. All rights reserved.

Influence of TRAIL gene on biomechanical properties of the human leukemic cell line Jurkat.

PubMed

Yao, Weijuan; Chen, Kai; Wang, Xinjuan; Xie, Lide; Wen, Zongyao; Yan, Zongyi; Chien, Shu

2002-12-01

We cloned the cDNA fragment of human TNF-related apoptosis inducing ligand (TRAIL) into RevTet-On, a Tet-regulated and high-level gene expression system. Making use of the TRAIL gene expression system in Jurkat as a cell model, we studied the influence of TRAIL gene on the biomechanics properties of Jurkat through measuring changes of cellular biomechanics properties before and after the TRAIL gene expression, which was induced by adding tetracycline derivative doxycycline (Dox). The results indicated that the TRAIL gene expression led to significant changes in cellular biomechanics properties. The osmotic fragility increased and the cell stiffness increased after the expression of TRAIL gene. Thus, the apoptosis-inducing TRAIL gene caused significant changes in the biomechanics properties of Jurkat cells.

High-fat diet induced insulin resistance in pregnant rats through pancreatic pax6 signaling pathway.

PubMed

Wu, Hao; Liu, Yunyun; Wang, Hongkun; Xu, Xianming

2015-01-01

To explore the changes in pancreas islet function of pregnant rats after consumption of high-fat diet and the underlying mechanism. Thirty pregnant Wistar rats were randomly divided into two groups: high-fat diet group and normal control group. Twenty days after gestation, fasting blood glucose concentration (FBG) and fasting serum insulin concentration (FINS) were measured. Then, oral glucose tolerance test (OGTT) and insulin release test (IRT) were performed. Finally, all the rats were sacrificed and pancreas were harvested. Insulin sensitivity index (ISI) and insulin resistance index (HOMA-IR) were calculated according to FBG and FINS. RT-PCR and Real-time PCR were performed to study the expression of paired box 6 transcription factor (Pax6) and its target genes in pancreatic tissues. The body weight was significantly increased in the high-fat diet group compared with that of normal control rats (P<0.05). The fasting plasma glucose of rats in high-fat diet group was significantly increased compared with that of normal control rats (6.62 mmol/L vs. 4.96 mmol/L, P<0.05), however there was no significant difference in fasting serum insulin concentration between the two groups. OGTT and IRT were abnormal in the high-fat diet group. The high-fat diet rats were more prone to impaired glucose tolerance and insulin resistance. The level of the expression of Pax6 transcription factor and its target genes in pancreas, such as pancreatic and duodenal homeobox factor-1 (Pdx1), v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA) and glucose transporter 2 (Glut2) were decreased significantly compared with those of normal control group. High-fat diet feeding during pregnancy may induce insulin resistance in maternal rats by inhibiting pancreatic Pax6 and its target genes expression.

MicroRNA-31 expression in relation to BRAF mutation, CpG island methylation and colorectal continuum in serrated lesions.

PubMed

Ito, Miki; Mitsuhashi, Kei; Igarashi, Hisayoshi; Nosho, Katsuhiko; Naito, Takafumi; Yoshii, Shinji; Takahashi, Hiroaki; Fujita, Masahiro; Sukawa, Yasutaka; Yamamoto, Eiichiro; Takahashi, Taiga; Adachi, Yasushi; Nojima, Masanori; Sasaki, Yasushi; Tokino, Takashi; Baba, Yoshifumi; Maruyama, Reo; Suzuki, Hiromu; Imai, Kohzoh; Yamamoto, Hiroyuki; Shinomura, Yasuhisa

2014-12-01

The CpG island methylator phenotype (CIMP) is a distinct form of epigenomic instability. Many CIMP-high colorectal cancers (CRCs) with BRAF mutation are considered to arise from serrated pathway. We recently reported that microRNA-31 (miR-31) is associated with BRAF mutation in colorectal tumors. Emerging new approaches have revealed gradual changes in BRAF mutation and CIMP-high throughout the colorectum in CRCs. Here, we attempted to identify a possible association between miR-31 and epigenetic features in serrated pathway, and hypothesized that miR-31 supports the "colorectal continuum" concept. We evaluated miR-31 expression, BRAF mutation and epigenetic features including CIMP status in 381 serrated lesions and 222 non-serrated adenomas and examined associations between them and tumor location (rectum; sigmoid, descending, transverse and ascending colon and cecum). A significant association was observed between high miR-31 expression and CIMP-high status in serrated lesions with BRAF mutation (p = 0.0001). In contrast, miR-31 was slightly but insignificantly associated with CIMP status in the cases with wild-type BRAF. miR-31 expression in sessile serrated adenomas (SSAs) with cytological dysplasia was higher than that in SSAs, whereas, no significant difference was observed between traditional serrated adenomas (TSAs) and TSAs with high-grade dysplasia. The frequency of miR-31, BRAF mutation CIMP-high and MLH1 methylation increased gradually from the rectum to cecum in serrated lesions. In conclusion, miR-31 expression was associated with CIMP-high status in serrated lesions with BRAF mutation. Our data also suggested that miR-31 plays an important role in SSA evolution and may be a molecule supporting the colorectal continuum. © 2014 UICC.

Artificial selection on brain-expressed genes during the domestication of dog.

PubMed

Li, Yan; Vonholdt, Bridgett M; Reynolds, Andy; Boyko, Adam R; Wayne, Robert K; Wu, Dong-Dong; Zhang, Ya-Ping

2013-08-01

Domesticated dogs have many unique behaviors not found in gray wolves that have augmented their interaction and communication with humans. The genetic basis of such unique behaviors in dogs remains poorly understood. We found that genes within regions highly differentiated between outbred Chinese native dogs (CNs) and wolves show high bias for expression localized to brain tissues, particularly the prefrontal cortex, a specific region responsible for complex cognitive behaviors. In contrast, candidate genes showing high population differentiation between CNs and German Shepherd dogs (GSs) did not demonstrate significant expression bias. These observations indicate that these candidate genes highly expressed in the brain have rapidly evolved. This rapid evolution was probably driven by artificial selection during the primary transition from wolves to ancient dogs and was consistent with the evolution of dog-specific characteristics, such as behavior transformation, for thousands of years.

High CD45 surface expression determines relapse risk in children with precursor B-cell and T-cell acute lymphoblastic leukemia treated according to the ALL-BFM 2000 protocol

PubMed Central

Cario, Gunnar; Rhein, Peter; Mitlöhner, Rita; Zimmermann, Martin; Bandapalli, Obul R.; Romey, Renja; Moericke, Anja; Ludwig, Wolf-Dieter; Ratei, Richard; Muckenthaler, Martina U.; Kulozik, Andreas E.; Schrappe, Martin; Stanulla, Martin; Karawajew, Leonid

2014-01-01

Further improvement of outcome in childhood acute lymphoblastic leukemia could be achieved by identifying additional high-risk patients who may benefit from intensified treatment. We earlier identified PTPRC (CD45) gene expression as a potential new stratification marker and now analyzed the prognostic relevance of CD45 protein expression. CD45 was measured by flow cytometry in 1065 patients treated according to the ALL-BFM-2000 protocol. The 75th percentile was used as cut-off to distinguish a CD45-high from a CD45-low group. As mean CD45 expression was significantly higher in T-cell acute lymphoblastic leukemia than in B-cell-precursor acute lymphoblastic leukemia (P<0.0001), the analysis was performed separately in both groups. In B-cell-precursor acute lymphoblastic leukemia we observed a significant association of a high CD45 expression with older age, high initial white blood cell count, ETV6/RUNX1 negativity, absence of high hyperdiploidy (P<0.0001), MLL/AF4 positivity (P=0.002), BCR/ABL1 positivity (P=0.007), prednisone poor response (P=0.002) and minimal residual disease (P<0.0001). In T-cell acute lymphoblastic leukemia we observed a significant association with initial white blood cell count (P=0.0003), prednisone poor response (P=0.01), and minimal residual disease (P=0.02). Compared to CD45-low patients, CD45-high patients had a lower event-free survival rate (B-cell-precursor acute lymphoblastic leukemia: 72±3% versus 86±1%, P<0.0001; T-cell acute lymphoblastic leukemia: 60±8% versus 78±4%, P=0.02), which was mainly attributable to a higher cumulative relapse incidence (B-cell-precursor acute lymphoblastic leukemia: 22±3% versus 11±1%, P<0.0001; T-cell acute lymphoblastic leukemia: 31±8% versus 11±3%, P=0.003) and kept its significance in multivariate analysis considering sex, age, initial white blood cell count, and minimal residual disease in B-cell-precursor- and T-cell acute lymphoblastic leukemia, and additionally presence of ETV6/RUNX1, MLL/AF4 and BCR/ABL1 rearrangements in B-cell-precursor acute lymphoblastic leukemia (P=0.002 and P=0.025, respectively). Consideration of CD45 expression may serve as an additional stratification tool in BFM-based protocols. (ClinicalTrials.gov identifier: NCT00430118) PMID:23911702

High CD45 surface expression determines relapse risk in children with precursor B-cell and T-cell acute lymphoblastic leukemia treated according to the ALL-BFM 2000 protocol.

PubMed

Cario, Gunnar; Rhein, Peter; Mitlöhner, Rita; Zimmermann, Martin; Bandapalli, Obul R; Romey, Renja; Moericke, Anja; Ludwig, Wolf-Dieter; Ratei, Richard; Muckenthaler, Martina U; Kulozik, Andreas E; Schrappe, Martin; Stanulla, Martin; Karawajew, Leonid

2014-01-01

Further improvement of outcome in childhood acute lymphoblastic leukemia could be achieved by identifying additional high-risk patients who may benefit from intensified treatment. We earlier identified PTPRC (CD45) gene expression as a potential new stratification marker and now analyzed the prognostic relevance of CD45 protein expression. CD45 was measured by flow cytometry in 1065 patients treated according to the ALL-BFM-2000 protocol. The 75(th) percentile was used as cut-off to distinguish a CD45-high from a CD45-low group. As mean CD45 expression was significantly higher in T-cell acute lymphoblastic leukemia than in B-cell-precursor acute lymphoblastic leukemia (P<0.0001), the analysis was performed separately in both groups. In B-cell-precursor acute lymphoblastic leukemia we observed a significant association of a high CD45 expression with older age, high initial white blood cell count, ETV6/RUNX1 negativity, absence of high hyperdiploidy (P<0.0001), MLL/AF4 positivity (P=0.002), BCR/ABL1 positivity (P=0.007), prednisone poor response (P=0.002) and minimal residual disease (P<0.0001). In T-cell acute lymphoblastic leukemia we observed a significant association with initial white blood cell count (P=0.0003), prednisone poor response (P=0.01), and minimal residual disease (P=0.02). Compared to CD45-low patients, CD45-high patients had a lower event-free survival rate (B-cell-precursor acute lymphoblastic leukemia: 72 ± 3% versus 86 ± 1%, P<0.0001; T-cell acute lymphoblastic leukemia: 60 ± 8% versus 78 ± 4%, P=0.02), which was mainly attributable to a higher cumulative relapse incidence (B-cell-precursor acute lymphoblastic leukemia: 22 ± 3% versus 11 ± 1%, P<0.0001; T-cell acute lymphoblastic leukemia: 31 ± 8% versus 11 ± 3%, P=0.003) and kept its significance in multivariate analysis considering sex, age, initial white blood cell count, and minimal residual disease in B-cell-precursor- and T-cell acute lymphoblastic leukemia, and additionally presence of ETV6/RUNX1, MLL/AF4 and BCR/ABL1 rearrangements in B-cell-precursor acute lymphoblastic leukemia (P=0.002 and P=0.025, respectively). Consideration of CD45 expression may serve as an additional stratification tool in BFM-based protocols. (ClinicalTrials.gov identifier: NCT00430118).

Different effects of low- and high-dose insulin on ROS production and VEGF expression in bovine retinal microvascular endothelial cells in the presence of high glucose.

PubMed

Wu, Haixiang; Jiang, Chunhui; Gan, Dekang; Liao, Yujie; Ren, Hui; Sun, Zhongcui; Zhang, Meng; Xu, Gezhi

2011-09-01

Clinical trials have demonstrated that acute intensive insulin therapy may cause transient worsening of retinopathy in type 1 and type 2 diabetes patients. However, the related mechanism still remains controversial. The purpose of the present study was to investigate the effect of insulin on the mitochondrial membrane potential (△Ψm), reactive oxygen species (ROS) production, UCP-2 and VEGF expression in bovine retinal microvascular endothelial cells (BRECs) in the presence of normal or high glucose and the related mechanisms. BRECs were isolated as primary cultures and identified by immunostaining. Passage BRECs were initially exposed to normal (5 mM) or high glucose (30 mM) for 3 days, with equimolar L: -glucose supplemented for osmotic equation. Then the cells were treated with 1 nM, 10 nM, or 100 nM insulin for 24 h: △Ψm and ROS production were determined by JC-1 and CM-H2DCFDA, respectively. Expression of UCP-2 and VEGF mRNA was determined by real-time RT-PCR; expression UCP-2 and VEGF protein was determined by Western-blotting analysis. A general ROS scavenger N-acetylcysteine (NAC, 10 mM) and an NADPH oxidase inhibitor apocynin (1 mmol/l) were added 1 h before treatment with 100 nM insulin. Insulin increased △Ψm, ROS production, and expression of UCP-2 and VEGF in BRECs at normal glucose (5 mM) in a dose-dependent manner. Low-dose insulin (1 nM) decreased △Ψm, ROS production, and UCP-2, VEGF expression in BRECs at high glucose (30 mM); and high-dose insulin (10 nM, 100nM) recovered △Ψm, ROS production, and UCP-2, VEGF expression. Pretreatment of cells with NADPH oxidase inhibitor apocynin significantly suppressed 100 nM insulin-induced ROS production (p < 0.01, one-way ANOVA). Pretreatment of cells with ROS scavenger N-acetylcysteine completely blocked insulin-induced UCP-2 expression (p < 0.01, one-way ANOVA) and significantly suppressed VEGF expression (p < 0.01, one-way ANOVA). High-dose insulin-induced ROS production and VEGF expression in BRECs in the presence of high glucose might be one of the reasons for the transient worsening of diabetic retinopathy during intensive insulin treatment.

Elevated Expression of IRS-1 Associates with p-Akt Expression and Predicts Poor Prognosis of Breast Invasive Ductal Carcinoma.

PubMed

Luo, Jiadi; Feng, Juan; Wen, Qiuyuan; Qoyawayma, Christopher; Wang, Weiyuan; Chen, Lingjiao; Lu, Junmi; Zhan, Yuting; Xu, Lina; Zang, Hongjing; Fan, Songqing; Chu, Shuzhou

2018-03-15

Overexpression of Insulin Receptor Substrate 1 (IRS-1) has been reported to promote cell growth, atypical hyperplasia, and carcinogenesis. And phosphorylated Akt (p-Akt) is certified to be involved in many types of cancers such as breast invasive ductal carcinoma (BIDC). However, the relationship between IRS-1 and Akt, as well as the role of expression of IRS-1 in BIDC, has never been reported. The purpose of this research is to investigate the association between expression of IRS-1 and p-Akt proteins and clinicopathological features of BIDC by immunohistochemistry, as well as the survival status. The results showed that the percentage of either elevated expression of IRS-1 or positive p-Akt expression in BIDC is significantly higher than that in control breast tissue from non-cancer patients (P<.001, P=.001, respectively). Overexpression of IRS-1 was evidently associated with positive expression of p-Akt (r=.337, P<.001). Also, positive percentage of p-Akt expression was statistically different among different molecular subtypes of BIDC (highest in luminal B BIDC, P=.009). Furthermore, significantly worse overall survival was in BIDC patients with high expression of IRS-1 and p-Akt than patients with low expression (P=.006, P=.004, respectively). The multivariate Cox proportional hazard regression analysis showed that high expression of IRS-1 and positive expression of p-Akt protein were independent poor prognostic factors for patients with BIDC (P=.022, P=.046, respectively). In conclusion, we report for the first time that overexpression of IRS-1 protein associates with expression of p-Akt, and overexpression of IRS-1 and positive expression of p-Akt might be independent biomarkers for poor prognosis in BIDC. Copyright © 2018. Published by Elsevier Inc.

miR-7 suppresses brain metastasis of breast cancer stem-like cells by modulating KLF4

PubMed Central

Okuda, Hiroshi; Xing, Fei; Pandey, Puspa R; Sharma, Sambad; Watabe, Misako; Pai, Sudha K.; Mo, Yin-Yuan; Iiizumi-Gairani, Megumi; Hirota, Shigeru; Liu, Yin; Wu, Kerui; Pochampally, Radhika; Watabe, Kounosuke

2012-01-01

Despite significant improvement in survival rates of breast cancer patients, prognosis of metastatic disease is still dismal. Cancer stem-like cells (CSCs) are considered to play a role in metastatic progression of breast cancer; however, the exact pathological role of CSCs is yet to be elucidated. In this report, we found that CSCs (CD24−/CD44+/ESA+) isolated from metastatic breast cell lines are significantly more metastatic than non-CSC populations in an organ specific manner. The results of our microRNA profile analysis for these cells revealed that CSCs that are highly metastatic to bone and brain expressed significantly lower level of miR-7 and that this microRNA was capable of modulating one of the essential genes for induced pluripotent stem cell, KLF4. Interestingly, high expression of KLF4 was significantly and inversely correlated to brain- but not bone-metastasis free survival of breast cancer patients, and we indeed found that the expression of miR-7 significantly suppressed the ability of CSCs to metastasize to brain but not to bone in our animal model. We also examined the expression of miR-7 and KLF4 in brain-metastatic lesions and found that these genes were significantly down- or up-regulated, respectively, in the tumor cells in brain. Furthermore, the results of our in vitro experiments indicate that miR-7 attenuates the abilities of invasion and self-renewal of CSCs by modulating KLF4 expression. These results suggest that miR-7 and KLF4 may serve as biomarkers or therapeutic targets for brain metastasis of breast cancer. PMID:23384942

Expression of lnterleukin-8 Correlates with Angiogenesis, Tumorigenicity, and Metastasis of Human Prostate Cancer Cells Implanted Orthotopically in Nude Mice1

PubMed Central

Sun, Jin Kim; Uehara, Hisanori; Karashima, Takashi; Mccarty, Marya; Shih, Nancy; Fidler, Isaiah J

2001-01-01

Abstract We determined whether the expression of interleukin-8 (IL-8) by human prostate cancer cells correlates with induction of angiogenesis, tumorigenicity, and production of metastasis. Low and high IL-8-producing clones were isolated from the heterogeneous PC-3 human prostate cancer cell line. The secretion of IL-8 protein correlated with transcriptional activity and levels of IL-8 mRNA. All PC-3 cells expressed both IL-8 receptors, CXCR1 and CXCR2. The low and high IL-8-producing clones were injected into the prostate of nude mice. Titration studies indicated that PC-3 cells expressing high levels of IL-8 were highly tumorigenic, producing rapidly growing, highly vascularized prostate tumors with and a 100% incidence of lymph node metastasis. Low IL-8-expressing PC-3 cells were less tumorigenic, producing slower growing and less vascularized primary tumors and a significantly lower incidence of metastasis. In situ hybridization (ISH) analysis of the tumors for expression of genes that regulate angiogenesis and metastasis showed that the expression level of IL-8, matrix metalloproteinases, vascular endothelial growth factor (VEGF), and E-cadherin corresponded with microvascular density and biological behavior of the prostate cancers in nude mice. Collectively, the data show that the expression level of IL-8 in human prostate cancer cells is associated with angiogenesis, tumorigenicity, and metastasis. PMID:11326314

EMMPRIN co-expressed with matrix metalloproteinases predicts poor prognosis in patients with osteosarcoma.

PubMed

Futamura, Naohisa; Nishida, Yoshihiro; Urakawa, Hiroshi; Kozawa, Eiji; Ikuta, Kunihiro; Hamada, Shunsuke; Ishiguro, Naoki

2014-06-01

Several studies have focused on the relationships between the expression of extracellular matrix metalloproteinase inducer (EMMPRIN) and the prognosis of patients with malignant tumors. However, few of these have investigated the expression of EMMPRIN in osteosarcoma. We examined expression levels of EMMPRIN immunohistochemically in 53 cases of high-grade osteosarcoma of the extremities and analyzed the correlation of its expression with patient prognosis. The correlation between matrix metalloproteinases (MMPs) and EMMPRIN expression and the prognostic value of co-expression were also analyzed. Staining positivity for EMMPRIN was negative in 7 cases, low in 17, moderate in 19, and strong in 10. The overall and disease-free survivals (OS and DFS) in patients with higher EMMPRIN expression (strong-moderate) were significantly lower than those in the lower (weak-negative) group (0.037 and 0.024, respectively). In multivariate analysis, age (P=0.004), location (P=0.046), and EMMPRIN expression (P=0.038) were significant prognostic factors for overall survival. EMMPRIN expression (P=0.024) was also a significant prognostic factor for disease-free survival. Co-expression analyses of EMMPRIN and MMPs revealed that strong co-expression of EMMPRIN and membrane-type 1 (MT1)-MMP had a poor prognostic value (P=0.056 for DFS, P=0.006 for OS). EMMPRIN expression and co-expression with MMPs well predict the prognosis of patients with extremity osteosarcoma, making EMMPRIN a possible therapeutic target in these patients.

HLA class I antigen processing machinery (APM) component expression and PD-1:PD-L1 pathway activation in HIV-infected head and neck cancers.

PubMed

Pai, Sara I; Jack Lee, J; Carey, Thomas E; Westra, William H; Ferrone, Soldano; Moore, Charles; Mosunjac, Marina B; Shin, Dong M; Ferris, Robert L

2018-02-01

Human immunodeficiency virus (HIV)-infected individuals are at increased risk for developing several non-AIDS related malignancies and are often excluded from cancer immunotherapy regimens. To evaluate the immune competence of this cancer patient population, we evaluated HLA class I antigen presenting machinery (APM) component expression and PD-1:PD-L1 pathway upregulation in HIV(+) and HIV(-) head and neck cancers (HNCs). Sixty-two HIV(+) and 44 matched HIV(-) controls diagnosed with HNC between 1991 and 2011 from five tertiary care referral centers in the United States were identified. HLA class I APM component, PD-1, and PD-L1 expression were analyzed by immunohistochemical staining with monoclonal antibodies (mAbs). Clinical data was abstracted from the medical records. There was no significant difference between the cases and controls in LMP2, TAP1, HLA-A and HLA-B/C, as well as PD-1 and PD-L1 expression. Overall, 62% of all subjects had high PD-1 expression and 82% of the subjects expressed PD-L1 within the tumor microenvironment. LMP2, HLA-A and HLA-B/C expression were significantly associated with moderate to high PD-1 expression in the HIV(+) HNC cases (p = .004, p = .026, and p = .006, respectively) but not in the HIV(-) controls. In addition, HLA-A expression was significantly associated with PD-L1 expression in the HIV(+) HNC cases only (p = .029). HIV-infected individuals diagnosed with HNC do not have any detectable defects in HLA class I APM component expression and in PD-1:PD-L1 pathway activation. Given the current successes of HAART therapy in maintaining immune cell counts, HIV(+) patients diagnosed with cancer may benefit from the recently FDA-approved immune checkpoint blockade therapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Prognostic significance of INF-induced transmembrane protein 1 in colorectal cancer.

PubMed

He, Jingdong; Li, Jin; Feng, Wanting; Chen, Longbang; Yang, Kangqun

2015-01-01

Interferon-induced transmembrane protein 1 (IFITM1) has recently been implicated in tumorigenesis. However, the prognostic value of IFITM1 in colorectal cancer remains unknown. The present study aimed to examine the expression and prognostic significance of IFITM1 in human colorectal cancer. IFITM1 expression was analyzed in 144 archived, paraffin-embedded colorectal cancer tissues and corresponding normal colorectal mucosa by immunohistochemistry. The correlation of IFITM1 with clinic-pathological features and overall survival of colorectal cancer patients was evaluated. IFITM1 was overexpressed in colonic cancer tissues but not in rectal cancer tissues, compared to control normal tissues. The expression of IFITM1 was significantly higher in patients with poor differentiation (P=0.031). The patients with higher IFITM1 expression had worse overall survival outcomes than those with lower IFITM1 expression in rectal cancer (P=0.037). Univariate Cox regression suggested that older age and poorly differentiation status predict shorter overall survival in colorectal cancer (P<0.05). However, IFITM1 expression was not a significant prognostic factor for survival by univariate or multivariate analyses. In conclusion, high expression of IFITM1 is associated with poor prognosis of rectal cancer. IFITM1 may serve as an independent prognostic biomarker for colorectal cancer.

Radotinib induces high cytotoxicity in c-KIT positive acute myeloid leukemia cells.

PubMed

Heo, Sook-Kyoung; Noh, Eui-Kyu; Kim, Jeong Yi; Jo, Jae-Cheol; Choi, Yunsuk; Koh, SuJin; Baek, Jin Ho; Min, Young Joo; Kim, Hawk

2017-06-05

Previously, we reported that radotinib, a BCR-ABL1 tyrosine kinase inhibitor, induced cytotoxicity in acute myeloid leukemia (AML) cells. However, the effects of radotinib in the subpopulation of c-KIT-positive AML cells were unclear. We observed that low-concentration radotinib had more potent cytotoxicity in c-KIT-positive cells than c-KIT-negative cells from AML patients. To address this issue, cell lines with high c-KIT expression, HEL92.1.7, and moderate c-KIT expression, H209, were selected. HEL92.1.7 cells were grouped into intermediate and high c-KIT expression populations. The cytotoxicity of radotinib against the HEL92.1.7 cell population with intermediate c-KIT expression was not different from that of the population with high c-KIT expression. When H209 cells were grouped into c-KIT expression-negative and c-KIT expression-positive populations, radotinib induced cytotoxicity in the c-KIT-positive population, but not the c-KIT-negative population. Thus, radotinib induces cytotoxicity in c-KIT-positive cells, regardless of the c-KIT expression intensity. Therefore, radotinib induces significant cytotoxicity in c-KIT-positive AML cells, suggesting that radotinib is a potential target agent for the treatment of c-KIT-positive malignancies including AML. Copyright © 2017 Elsevier B.V. All rights reserved.

Interferon gamma, an important marker of response to immune checkpoint blockade in non-small cell lung cancer and melanoma patients

PubMed Central

Karachaliou, Niki; Gonzalez-Cao, Maria; Crespo, Guillermo; Drozdowskyj, Ana; Aldeguer, Erika; Gimenez-Capitan, Ana; Teixido, Cristina; Molina-Vila, Miguel Angel; Viteri, Santiago; De Los Llanos Gil, Maria; Algarra, Salvador Martin; Perez-Ruiz, Elisabeth; Marquez-Rodas, Ivan; Rodriguez-Abreu, Delvys; Blanco, Remedios; Puertolas, Teresa; Royo, Maria Angeles; Rosell, Rafael

2018-01-01

Background: Programmed death-ligand 1 (PD-L1) may be induced by oncogenic signals or can be upregulated via interferon gamma (IFN-γ). We have explored whether the expression of IFNG, the gene encoding IFN-γ, is associated with clinical response to the immune checkpoint blockade in non-small cell lung cancer (NSCLC) and melanoma patients. The role of inflammation-associated transcription factors STAT3, IKBKE, STAT1 and other associated genes has also been examined. Methods: Total RNA from 17 NSCLC and 21 melanoma patients was analyzed by quantitative reverse transcription PCR. STAT3 and Rantes, YAP1 and CXCL5, DNMT1, RIG1 and TET1, EOMES, IFNG, PD-L1 and CTLA4, IKBKE and NFATC1 mRNA were examined. PD-L1 protein expression in tumor and immune cells and stromal infiltration of CD8+ T-cells were also evaluated. Progression-free survival and overall survival were estimated. Results: A total of 17 NSCLC patients received nivolumab and 21 melanoma patients received pembrolizumab. Progression-free survival with nivolumab was significantly longer in NSCLC patients with high versus low IFNG expression (5.1 months versus 2 months, p = 0.0124). Progression-free survival with pembrolizumab was significantly longer in melanoma patients with high versus low IFNG expression (5.0 months versus 1.9 months, p = 0.0099). Significantly longer overall survival was observed for melanoma patients with high versus low IFNG expression (not reached versus 10.2 months p = 0.0183). There was a trend for longer overall survival for NSCLC patients with high versus low IFNG expression. Conclusions: IFN-γ is an important marker for prediction of response to immune checkpoint blockade. Further research is warranted in order to validate whether IFNG is more accurate than PD-L1. PMID:29383037

Keratin 17 in premalignant and malignant squamous lesions of the cervix: proteomic discovery and immunohistochemical validation as a diagnostic and prognostic biomarker

PubMed Central

Escobar-Hoyos, Luisa F; Yang, Jie; Zhu, Jiawen; Cavallo, Julie-Ann; Zhai, Haiyan; Burke, Stephanie; Koller, Antonius; Chen, Emily I; Shroyer, Kenneth R

2014-01-01

Most previously described immunohistochemical markers of cervical high-grade squamous intraepithelial lesion (HSIL) and squamous cell carcinoma may help to improve diagnostic accuracy but have a minimal prognostic value. The goals of the current study were to identify and validate novel candidate biomarkers that could potentially improve diagnostic and prognostic accuracy for cervical HSIL and squamous cell carcinoma. Microdissected tissue sections from formalin-fixed paraffin-embedded normal ectocervical squamous mucosa, low-grade squamous intraepithelial lesion (LSIL), HSIL and squamous cell carcinoma sections were analyzed by mass spectrometry-based shotgun proteomics for biomarker discovery. The diagnostic specificity of candidate biomarkers was subsequently evaluated by immunohistochemical analysis of tissue microarrays. Among 1750 proteins identified by proteomic analyses, keratin 4 (KRT4) and keratin 17 (KRT17) showed reciprocal patterns of expression in the spectrum of cases ranging from normal ectocervical squamous mucosa to squamous cell carcinoma. Immunohistochemical studies confirmed that KRT4 expression was significantly decreased in squamous cell carcinoma compared with the other diagnostic categories. By contrast, KRT17 expression was significantly increased in HSIL and squamous cell carcinoma compared with normal ectocervical squamous mucosa and LSIL. KRT17 was also highly expressed in immature squamous metaplasia and in endocervical reserve cells but was generally not detected in mature squamous metaplasia. Furthermore, high levels of KRT17 expression were significantly associated with poor survival of squamous cell carcinoma patients (Hazard ratio = 14.76, P = 0.01). In summary, both KRT4 and KRT17 expressions are related to the histopathology of the cervical squamous mucosa; KRT17 is highly overexpressed in immature squamous metaplasia, in HSIL, and in squamous cell carcinoma and the level of KRT17 in squamous cell carcinoma may help to identify patients who are at greatest risk for cervical cancer mortality. PMID:24051697

Clinicopathological significance of chemokine receptor (CCR1, CCR3, CCR4, CCR5, CCR7 and CXCR4) expression in head and neck squamous cell carcinomas.

PubMed

González-Arriagada, Wilfredo A; Lozano-Burgos, Carlos; Zúñiga-Moreta, Rodrigo; González-Díaz, Paulina; Coletta, Ricardo D

2018-05-24

Head and neck squamous cell carcinoma shows high prevalence of lymph node metastasis at diagnosis, and despite the advances in treatment, the overall 5-year survival is still under 50%. Chemokine receptors have a role in the development and progression of cancer, but their effect in head and neck carcinoma remains poorly characterised. This study aimed to assess the prognostic value of CCR1, CCR3, CCR4, CCR5, CCR7 and CXCR4 in head and neck squamous cell carcinomas. Immunohistochemical expression of chemokine receptors was evaluated in a retrospective cohort of 76 cases of head and neck squamous cell carcinoma. Clinicopathological associations were analysed using the chi-square test, survival curves were analysed according to the Kaplan-Meier method, and the Cox proportional hazard model was applied for multivariate survival analysis. The chemokine receptors were highly expressed in primary carcinomas, except for CCR1 and CCR3. Significant associations were detected, including the associations between CCR5 expression and lymph node metastasis (N stage, P = .03), advanced clinical stage (P = .003), poor differentiation of tumours (P = .05) and recurrence (P = .01). The high expression of CCR5 was also associated with shortened disease-free survival (HR: 2.85, 95% CI: 1.09-8.14, P = .05), but the association did not withstand the Cox multivariate survival analysis. At univariate analysis, high expression of CCR7 was associated with disease-free survival and low levels of CXCR4 were significantly associated with both disease-specific and disease-free survival. These findings show that chemokine receptors may have an important role in head and neck squamous cell carcinoma progression, regional lymph node metastasis and recurrence. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Functional genomics of commercial baker's yeasts that have different abilities for sugar utilization and high-sucrose tolerance under different sugar conditions.

PubMed

Tanaka-Tsuno, Fumiko; Mizukami-Murata, Satomi; Murata, Yoshinori; Nakamura, Toshihide; Ando, Akira; Takagi, Hiroshi; Shima, Jun

2007-10-01

In the modern baking industry, high-sucrose-tolerant (HS) and maltose-utilizing (LS) yeast were developed using breeding techniques and are now used commercially. Sugar utilization and high-sucrose tolerance differ significantly between HS and LS yeasts. We analysed the gene expression profiles of HS and LS yeasts under different sucrose conditions in order to determine their basic physiology. Two-way hierarchical clustering was performed to obtain the overall patterns of gene expression. The clustering clearly showed that the gene expression patterns of LS yeast differed from those of HS yeast. Quality threshold clustering was used to identify the gene clusters containing upregulated genes (cluster 1) and downregulated genes (cluster 2) under high-sucrose conditions. Clusters 1 and 2 contained numerous genes involved in carbon and nitrogen metabolism, respectively. The expression level of the genes involved in the metabolism of glycerol and trehalose, which are known to be osmoprotectants, in LS yeast was higher than that in HS yeast under sucrose concentrations of 5-40%. No clear correlation was found between the expression level of the genes involved in the biosynthesis of the osmoprotectants and the intracellular contents of the osmoprotectants. The present gene expression data were compared with data previously reported in a comprehensive analysis of a gene deletion strain collection. Welch's t-test for this comparison showed that the relative growth rates of the deletion strains whose deletion occurred in genes belonging to cluster 1 were significantly higher than the average growth rates of all deletion strains. Copyright 2007 John Wiley & Sons, Ltd.

Pathway-based factor analysis of gene expression data produces highly heritable phenotypes that associate with age.

PubMed

Anand Brown, Andrew; Ding, Zhihao; Viñuela, Ana; Glass, Dan; Parts, Leopold; Spector, Tim; Winn, John; Durbin, Richard

2015-03-09

Statistical factor analysis methods have previously been used to remove noise components from high-dimensional data prior to genetic association mapping and, in a guided fashion, to summarize biologically relevant sources of variation. Here, we show how the derived factors summarizing pathway expression can be used to analyze the relationships between expression, heritability, and aging. We used skin gene expression data from 647 twins from the MuTHER Consortium and applied factor analysis to concisely summarize patterns of gene expression to remove broad confounding influences and to produce concise pathway-level phenotypes. We derived 930 "pathway phenotypes" that summarized patterns of variation across 186 KEGG pathways (five phenotypes per pathway). We identified 69 significant associations of age with phenotype from 57 distinct KEGG pathways at a stringent Bonferroni threshold ([Formula: see text]). These phenotypes are more heritable ([Formula: see text]) than gene expression levels. On average, expression levels of 16% of genes within these pathways are associated with age. Several significant pathways relate to metabolizing sugars and fatty acids; others relate to insulin signaling. We have demonstrated that factor analysis methods combined with biological knowledge can produce more reliable phenotypes with less stochastic noise than the individual gene expression levels, which increases our power to discover biologically relevant associations. These phenotypes could also be applied to discover associations with other environmental factors. Copyright © 2015 Brown et al.

Pathway-Based Factor Analysis of Gene Expression Data Produces Highly Heritable Phenotypes That Associate with Age

PubMed Central

Anand Brown, Andrew; Ding, Zhihao; Viñuela, Ana; Glass, Dan; Parts, Leopold; Spector, Tim; Winn, John; Durbin, Richard

2015-01-01

Statistical factor analysis methods have previously been used to remove noise components from high-dimensional data prior to genetic association mapping and, in a guided fashion, to summarize biologically relevant sources of variation. Here, we show how the derived factors summarizing pathway expression can be used to analyze the relationships between expression, heritability, and aging. We used skin gene expression data from 647 twins from the MuTHER Consortium and applied factor analysis to concisely summarize patterns of gene expression to remove broad confounding influences and to produce concise pathway-level phenotypes. We derived 930 “pathway phenotypes” that summarized patterns of variation across 186 KEGG pathways (five phenotypes per pathway). We identified 69 significant associations of age with phenotype from 57 distinct KEGG pathways at a stringent Bonferroni threshold (P<5.38×10−5). These phenotypes are more heritable (h2=0.32) than gene expression levels. On average, expression levels of 16% of genes within these pathways are associated with age. Several significant pathways relate to metabolizing sugars and fatty acids; others relate to insulin signaling. We have demonstrated that factor analysis methods combined with biological knowledge can produce more reliable phenotypes with less stochastic noise than the individual gene expression levels, which increases our power to discover biologically relevant associations. These phenotypes could also be applied to discover associations with other environmental factors. PMID:25758824

Altered sperm chromatin structure in mice exposed to sodium fluoride through drinking water.

PubMed

Sun, Zilong; Niu, Ruiyan; Wang, Bin; Wang, Jundong

2014-06-01

This study investigated the effects of sodium fluoride (NaF) on sperm abnormality, sperm chromatin structure, protamine 1 and protamine 2 (P1 and P2) mRNA expression, and histones expression in sperm in male mice. NaF was orally administrated to male mice at 30, 70, and 150 mg/l for 49 days (more than one spermatogenic cycle). Sperm head and tail abnormalities were significantly enhanced at middle and high doses. Similarly, sperm chromatin structure was also adversely affected by NaF exposure, indicating DNA integrity damage. Furthermore, middle and high NaF significantly reduced the mRNA expressions of P1 and P2, and P1/P2 ratio, whereas the sperm histones level was increased, suggesting the abnormal histone-protamine replacement. Therefore, we concluded that the mechanism by which F induced mice sperm abnormality and DNA integrity damage may involved in the alterations in P1, P2, and histones expression in sperm of mice. Copyright © 2012 Wiley Periodicals, Inc.

Overexpression of MTA1 and loss of KAI-1 and KiSS-1 expressions are associated with invasion, metastasis, and poor-prognosis of gallbladder adenocarcinoma.

PubMed

Wang, Wenjun; Yang, Zhu-lin; Liu, Jie-qiong; Yang, Le-ping; Yang, Xiao-jing; Fu, Xi

2014-01-01

Over 90% of patients with gallbladder cancer have invasion and/or metastasis when they are diagnosed at the clinic. Such patients usually have an extremely poor prognosis. The molecular mechanism responsible for the high prevalence of invasion and metastasis remains unknown. We investigated the expression of two metastasis-suppression genes--KAI-1 and KiSS-1--and a metastasis-associated gene--MTA1--in 108 adenocarcinomas, 15 gallbladder polyps, 35 chronic cholecystitis tissues, and 46 peritumoral tissues using in situ hybridization or immunohistochemistry. We demonstrated that positive MTA1 expression was significantly higher whereas positive expressions of KAI-1 and KiSS-1 genes were significantly lower in gallbladder adenocarcinoma than in peritumoral tissues, polyps, and chronic cholecystitis. Positive MTA1 expression was significantly lower, but positive KAI-1 and KiSS-1 expressions were significantly higher in cases with well-differentiated adenocarcinoma, smaller tumor mass, no metastasis of lymph node, and no invasion of regional tissues than in cases having poorly differentiated adenocarcinoma, larger tumor mass, metastasis and invasion. Univariate Kaplan-Meier analysis showed that increased expression of MTA1 and lowered expression of KAI-1 and KiSS-1 were significantly associated with decreased overall survival. Cox regression analysis showed that tumor mass, lymph node metastasis, invasion, and MTA1 expression levels negatively correlated with survival. Our study suggested that KAI-1, KiSS-1, and MTA1 might be important biological markers involved in the carcinogenesis, metastasis, and invasion of gallbladder adenocarcinoma, but MTA1 is an independent factor of prognosis.

[Antiapoptotic Effect of the Leukemia Associated Gene MLAA-34 in HeLa Cells].

PubMed

Zhang, Peng-Yu; Zhao, Xuan; Zhang, Wen-Juan; Zhang, Wang-Gang; Chen, Yin-Xia

2016-04-01

To study the antiapoptotic effect of leukemia-associated gene MLAA-34 in HeLa cells. The MLAA-34 recombinant lentiviral expression vector was constructed, and the stably transfected HeLa cell line with high expression of MLAA-34 was set up; As(2)O(3) was used to induce apoptosis; the MTT assay, colony formation test and flow cytometry were used to detect the ability of cell proliferation, colong formation, apoptosis and cell cycle changes respectively. After treatment with As(2)O(3), the survival rate of HeLa cells with MLAA-34 overexpression was significantly higher than that of the control cells, and the colony formation ability of MLAA-34 significantly increased, and the high expression of MLAA-34 gene significantly decreased the apoptosis rate of HeLa cells, and decreased the proportion of G(2)/M phase cells. The leukemia-associated gene MLAA-34 has been comfirmed to show antiapoptotic effect in HeLa cells which are induced by As(2)O(3).

Seasonal changes in gastric mucosal factors associated with peptic ulcer bleeding.

PubMed

Yuan, Xiao-Gang; Xie, Chuan; Chen, Jiang; Xie, Yong; Zhang, Kun-He; Lu, Nong-Hua

2015-01-01

A close association has been established between climate and peptic ulcer bleeding (PUB). The incidence of PUB in cold climates is significantly higher than that in hot climates. In this study, gastric mucosal damage and its barrier function (through associated barrier factors) in extreme climate conditions were examined to investigate the pathogenesis of PUB in extreme cold climates. Gastric juice and biopsy specimens were collected from 176 patients with peptic ulcer. Conventional hematoxylin and eosin staining was used to exclude malignant ulcers. Helicobacter pylori infections were detected by modified Giemsa staining. pH values of the gastric juice samples were obtained on-site by precise pH dipstick readings. The protein expression levels of heat shock protein (HSP) 70, occludin, nitric oxide synthase (NOS), epidermal growth factor (EGF) and EGF receptor (EGFR) in the gastric mucosa were detected by immunohistochemistry. No significant differences were identified between the high and low bleeding risk groups in the rates of H. pylori infection and the pH values of the gastric juices in the extreme hot or cold climates. Furthermore, no statistically significant differences were identified in the protein expression levels of occludin, NOS, EGF and EGFR between the high and low bleeding risk groups. In the extreme cold climate, the expression of HSP70 and the mucus thickness of the gastric antrum in the high bleeding risk group were significantly lower than those in the low bleeding risk group. The protein expression levels of occludin, HSP70, NOS and EGFR in the extreme cold climate were significantly lower than those in the extreme hot climate, whereas the gastric acid secretion was significantly higher in the extreme cold climate than that in the extreme hot climate. In conclusion, low expression of HSP70 in the gastric mucosa and reduced gastric mucus thickness may play key roles in the mechanism of PUB in extreme cold climates. The significant decrease in barrier factors and increase in damage in extreme cold climates may be associated with the seasonal pattern of peptic ulcers.

Seasonal changes in gastric mucosal factors associated with peptic ulcer bleeding

PubMed Central

YUAN, XIAO-GANG; XIE, CHUAN; CHEN, JIANG; XIE, YONG; ZHANG, KUN-HE; LU, NONG-HUA

2015-01-01

A close association has been established between climate and peptic ulcer bleeding (PUB). The incidence of PUB in cold climates is significantly higher than that in hot climates. In this study, gastric mucosal damage and its barrier function (through associated barrier factors) in extreme climate conditions were examined to investigate the pathogenesis of PUB in extreme cold climates. Gastric juice and biopsy specimens were collected from 176 patients with peptic ulcer. Conventional hematoxylin and eosin staining was used to exclude malignant ulcers. Helicobacter pylori infections were detected by modified Giemsa staining. pH values of the gastric juice samples were obtained on-site by precise pH dipstick readings. The protein expression levels of heat shock protein (HSP) 70, occludin, nitric oxide synthase (NOS), epidermal growth factor (EGF) and EGF receptor (EGFR) in the gastric mucosa were detected by immunohistochemistry. No significant differences were identified between the high and low bleeding risk groups in the rates of H. pylori infection and the pH values of the gastric juices in the extreme hot or cold climates. Furthermore, no statistically significant differences were identified in the protein expression levels of occludin, NOS, EGF and EGFR between the high and low bleeding risk groups. In the extreme cold climate, the expression of HSP70 and the mucus thickness of the gastric antrum in the high bleeding risk group were significantly lower than those in the low bleeding risk group. The protein expression levels of occludin, HSP70, NOS and EGFR in the extreme cold climate were significantly lower than those in the extreme hot climate, whereas the gastric acid secretion was significantly higher in the extreme cold climate than that in the extreme hot climate. In conclusion, low expression of HSP70 in the gastric mucosa and reduced gastric mucus thickness may play key roles in the mechanism of PUB in extreme cold climates. The significant decrease in barrier factors and increase in damage in extreme cold climates may be associated with the seasonal pattern of peptic ulcers. PMID:25452787

Expression of MUC1, MUC2, MUC3 and MUC4 mucin mRNAs in human pancreatic and intestinal tumor cell lines.

PubMed

Hollingsworth, M A; Strawhecker, J M; Caffrey, T C; Mack, D R

1994-04-15

We examined the steady-state expression levels of mRNA for the MUC1, MUC2, MUC3 and MUC4 gene products in 12 pancreatic tumor cell lines, 6 colon tumor cell lines, and one ileocecal tumor cell line. The results showed that 10 of 12 pancreatic tumor cell lines expressed MUC1 mRNA and that 7 of these 12 lines also expressed relatively high levels of MUC4 mRNA. In contrast, MUC2 mRNA was expressed at only low levels and MUC3 was not detected in the pancreatic tumor cell lines. All 7 intestinal tumor cell lines examined expressed MUC2, and 5 of 7 expressed MUC3; however only one expressed significant levels of MUC1 and 2 expressed low levels of MUC4 mRNA. This report of high levels of MUC4 mRNA expression by pancreatic tumor cells raises the possibility that mucin carbohydrate epitopes defined by antibodies such as DuPan 2 may be expressed on a second mucin core protein produced by pancreatic tumor cells.

Biological significance of long non-coding RNA FTX expression in human colorectal cancer

PubMed Central

Guo, Xiao-Bo; Hua, Zhu; Li, Chen; Peng, Li-Pan; Wang, Jing-Shen; Wang, Bo; Zhi, Qiao-Ming

2015-01-01

The purpose of this study was to determine the expression of long non-coding RNA (lncRNA) FTX and analyze its prognostic and biological significance in colorectal cancer (CRC). A quantitative reverse transcription PCR was performed to detect the expression of long non-coding RNA FTX in 35 pairs of colorectal cancer and corresponding noncancerous tissues. The expression of long non-coding RNA FTX was detected in 187 colorectal cancer tissues and its correlations with clinicopathological factors of patients were examined. Univariate and multivariate analyses were performed to analyze the prognostic significance of Long Non-coding RNA FTX expression. The effects of long non-coding RNA FTX expression on malignant phenotypes of colorectal cancer cells and its possible biological significances were further determined. Long non-coding RNA FTX was significantly upregulated in colorectal cancer tissues, and low long non-coding RNA FTX expression was significantly correlated with differentiation grade, lymph vascular invasion, and clinical stage. Patients with high long non-coding RNA FTX showed poorer overall survival than those with low long non-coding RNA FTX. Multivariate analyses indicated that status of long non-coding RNA FTX was an independent prognostic factor for patients. Functional analyses showed that upregulation of long non-coding RNA FTX significantly promoted growth, migration, invasion, and increased colony formation in colorectal cancer cells. Therefore, long non-coding RNA FTX may be a potential biomarker for predicting the survival of colorectal cancer patients and might be a molecular target for treatment of human colorectal cancer. PMID:26629053

T-LAK Cell-Originated Protein Kinase (TOPK) as a Prognostic Factor and a Potential Therapeutic Target in Ovarian Cancer.

PubMed

Ikeda, Yuji; Park, Jae-Hyun; Miyamoto, Takashi; Takamatsu, Naofumi; Kato, Taigo; Iwasa, Akiko; Okabe, Shuhei; Imai, Yuichi; Fujiwara, Keiichi; Nakamura, Yusuke; Hasegawa, Kosei

2016-12-15

We aimed to clarify the clinical significance of TOPK (T-lymphokine-activated killer cell-originated protein kinase) expression in ovarian cancer and evaluate the possible effect of TOPK inhibitors, OTS514 and OTS964, on ovarian cancer cells. TOPK expression was examined by immunohistochemistry using 163 samples with epithelial ovarian cancer (EOC). TOPK protein level and FOXM1 transcriptional level in ovarian cancer cell lines were examined by Western blot and RT-PCR, respectively. Half-maximum inhibitory concentration (IC 50 ) values against TOPK inhibitors were examined by the MTT assay. Using the peritoneal dissemination model of ES-2 ovarian cancer cells, we examined the in vivo efficacy of OTS514. In addition, the cytotoxic effect of OTS514 and OTS964 on 31 patient-derived primary ovarian cancer cells was examined. TOPK was expressed very highly in 84 (52%) of 163 EOC tissues, and high TOPK expression was significantly associated with poor progression-free survival and overall survival in early-stage cases of EOC (P = 0.008 and 0.006, respectively). Both OTS514 and OTS964 showed significant growth-inhibitory effect on ovarian cancer cell lines with IC 50 values of 3.0 to 46 nmol/L and 14 to 110 nmol/L, respectively. TOPK protein and transcriptional levels of FOXM1 were reduced by TOPK inhibitor treatment. Oral administration of OTS514 significantly elongated overall survival in the ES-2 abdominal dissemination xenograft model, compared with vehicle control (P < 0.001). Two drugs showed strong growth-inhibitory effect on primary ovarian cancer cells regardless of tumor sites or histological subtypes. Our results demonstrated the clinical significance of high TOPK expression and potential of TOPK inhibitors to treat ovarian cancer. Clin Cancer Res; 22(24); 6110-7. ©2016 AACR. ©2016 American Association for Cancer Research.

Correlation of P16 (Ink4a) and CK17 to HPV (16E6+18E6) in Premalignant and Malignant Lesions of Uterine Cervix: A Clinicopathologic Study

PubMed Central

Chaloob, Mohammed K.; Hussein, Alaa G.; Qasim, Ban J.

2016-01-01

Background: This research was accomplished to evaluate the IHC expression of p16 (ink4a) and CK17 in low grade cervical intraepithelial lesions (LSIL), high grade cervical intraepithelial lesions (HSIL) and invasive cervical carcinomas and to assess their correlation to HPV (16E6+18E6). Methods: The study included (127) formalin-fixed paraffin-embedded cervical biopsies; of which 22 cases were chronic cervicitis, 24 cases were LSIL, 28 cases were HSIL and 53 cases were invasive cervical carcinomas. Sections were immunohistochemically stained for p16 (ink4a), CK17 and HPV (16E6+18E6). Results: The study established a highly significant increase in IHC of expression of p16 (ink4a), CK17 and HPV (16E6+18E6) from LSIL through HSIL to invasive carcinomas (P-value˂0.001). There was non-significant association between IHC expression of all makers with age of patients; types, grade and stage of cervical carcinomas (P-value˃0.05). HPV (16E6+18E6) revealed a significantly positive correlation with p16 (ink4a) (P-value˂0.05) and a non- significant correlation with CK17 (P-value˃0.05); in LSIL, HSIL and invasive carcinoma cases. Conclusion: p16 (ink4a) expression directly reflects infection with high risk HPV in cervical lesions and can add a significant diagnostic accuracy in the evaluation of CIN. CK 17 is a good marker of malignant transformation, with increasing in its expression according to the severity of cervical lesions; however, it is not related to HPV infection. Both markers are not related to prognostic variables of patients with cervical carcinoma. PMID:28855930

Multi-institutional evaluation of the prognostic significance of EZH2 expression in high-grade upper tract urothelial carcinoma.

PubMed

Singla, Nirmish; Krabbe, Laura-Maria; Aydin, Ahmet M; Panwar, Vandana; Woldu, Solomon L; Freifeld, Yuval; Wood, Christopher G; Karam, Jose A; Weizer, Alon Z; Raman, Jay D; Remzi, Mesut; Rioux-Leclercq, Nathalie; Haitel, Andrea; Roscigno, Marco; Bolenz, Christian; Bensalah, Karim; Sagalowsky, Arthur I; Shariat, Shahrokh F; Lotan, Yair; Bagrodia, Aditya; Kapur, Payal; Margulis, Vitaly

2018-07-01

Enhancer of zeste homolog 2 is a methyltransferase encoded by the EZH2 gene, whose role in upper tract urothelial carcinoma (UTUC) is poorly understood. We sought to evaluate the prognostic value of EZH2 expression in UTUC. We reviewed a multi-institutional cohort of patients who underwent radical nephroureterectomy for high-grade UTUC from 1990 to 2008. Immunohistochemistry for EZH2 was performed on tissue microarrays. Percentage of staining was evaluated, and the discriminative value of EZH2 was tested, with EZH2 positivity defined as>20% staining present. Clinicopathologic characteristics and oncologic outcomes (recurrence-free (RFS), cancer-specific (CSS), and overall survival (OS)) were compared, stratified by EZH2 positivity. The prognostic role of EZH2 was assessed using Kaplan-Meier, univariate (UVA), and multivariate (MVA) Cox regression analyses. Significance was defined for P<0.05. A total of 376 patients were included for analysis, with median follow-up 36.0 months. Overall, 78 (20.7%) were EZH2-positive. EZH2 expression was more often associated with ureteral location, lymphovascular invasion, sessile architecture, necrosis, and concomitant carcinoma in situ. On UVA, increased EZH2 expression was a significant predictor for inferior RFS (HR 1.63, P = 0.033), CSS (HR 2.03, P = 0.003), and OS (HR 2.11, P<0.001). On MVA EZH2 remained a significant predictor of worse CSS (HR 1.99 [95% CI: 1.21-3.27], P = 0.007) and OS (HR 1.54 [95% CI: 1.06-2.24], P = 0.024), while significance was lost for RFS. Increased EZH2 expression is associated with adverse pathologic features and inferior oncologic outcomes in patients with high-grade UTUC. The role of EZH2 biology in UTUC pathogenesis remains to be further elucidated. Copyright © 2018 Elsevier Inc. All rights reserved.

Dietary Lipid Levels Influence Lipid Deposition in the Liver of Large Yellow Croaker (Larimichthys crocea) by Regulating Lipoprotein Receptors, Fatty Acid Uptake and Triacylglycerol Synthesis and Catabolism at the Transcriptional Level.

PubMed

Yan, Jing; Liao, Kai; Wang, Tianjiao; Mai, Kangsen; Xu, Wei; Ai, Qinghui

2015-01-01

Ectopic lipid accumulation has been observed in fish fed a high-lipid diet. However, no information is available on the mechanism by which dietary lipid levels comprehensively regulate lipid transport, uptake, synthesis and catabolism in fish. Therefore, the present study aimed to gain further insight into how dietary lipids affect lipid deposition in the liver of large yellow croaker(Larimichthys crocea). Fish (150.00±4.95 g) were fed a diet with a low (6%), moderate (12%, the control diet) or high (18%) crude lipid content for 10 weeks. Growth performance, plasma biochemical indexes, lipid contents and gene expression related to lipid deposition, including lipoprotein assembly and clearance, fatty acid uptake and triacylglycerol synthesis and catabolism, were assessed. Growth performance was not significantly affected. However, the hepato-somatic and viscera-somatic indexes as well as plasma triacylglycerol, non-esterified fatty acids and LDL-cholesterol levels were significantly increased in fish fed the high-lipid diet. In the livers of fish fed the high-lipid diet, the expression of genes related to lipoprotein clearance (LDLR) and fatty acid uptake (FABP11) was significantly up-regulated, whereas the expression of genes involved in lipoprotein assembly (apoB100), triacylglycerol synthesis and catabolism (DGAT2, CPT I) was significantly down-regulated compared with fish fed the control diet, and hepatic lipid deposition increased. In fish fed the low-lipid diet, the expression of genes associated with lipoprotein assembly and clearance (apoB100, LDLR, LRP-1), fatty acid uptake (CD36, FATP1, FABP3) and triacylglycerol synthesis (FAS) was significantly increased, whereas the expression of triacylglycerol catabolism related genes (ATGL, CPT I) was reduced compared with fish fed the control diet. However, hepatic lipid content in fish fed the low-lipid diet decreased mainly due to low dietary lipid intake. In summary, findings of this study provide molecular insight into the role of lipid deposition in the liver in response to different dietary lipid contents.

Dietary Lipid Levels Influence Lipid Deposition in the Liver of Large Yellow Croaker (Larimichthys crocea) by Regulating Lipoprotein Receptors, Fatty Acid Uptake and Triacylglycerol Synthesis and Catabolism at the Transcriptional Level

PubMed Central

Yan, Jing; Liao, Kai; Wang, Tianjiao; Mai, Kangsen; Xu, Wei; Ai, Qinghui

2015-01-01

Ectopic lipid accumulation has been observed in fish fed a high-lipid diet. However, no information is available on the mechanism by which dietary lipid levels comprehensively regulate lipid transport, uptake, synthesis and catabolism in fish. Therefore, the present study aimed to gain further insight into how dietary lipids affect lipid deposition in the liver of large yellow croaker(Larimichthys crocea). Fish (150.00±4.95 g) were fed a diet with a low (6%), moderate (12%, the control diet) or high (18%) crude lipid content for 10 weeks. Growth performance, plasma biochemical indexes, lipid contents and gene expression related to lipid deposition, including lipoprotein assembly and clearance, fatty acid uptake and triacylglycerol synthesis and catabolism, were assessed. Growth performance was not significantly affected. However, the hepato-somatic and viscera-somatic indexes as well as plasma triacylglycerol, non-esterified fatty acids and LDL-cholesterol levels were significantly increased in fish fed the high-lipid diet. In the livers of fish fed the high-lipid diet, the expression of genes related to lipoprotein clearance (LDLR) and fatty acid uptake (FABP11) was significantly up-regulated, whereas the expression of genes involved in lipoprotein assembly (apoB100), triacylglycerol synthesis and catabolism (DGAT2, CPT I) was significantly down-regulated compared with fish fed the control diet, and hepatic lipid deposition increased. In fish fed the low-lipid diet, the expression of genes associated with lipoprotein assembly and clearance (apoB100, LDLR, LRP-1), fatty acid uptake (CD36, FATP1, FABP3) and triacylglycerol synthesis (FAS) was significantly increased, whereas the expression of triacylglycerol catabolism related genes (ATGL, CPT I) was reduced compared with fish fed the control diet. However, hepatic lipid content in fish fed the low-lipid diet decreased mainly due to low dietary lipid intake. In summary, findings of this study provide molecular insight into the role of lipid deposition in the liver in response to different dietary lipid contents. PMID:26114429

Interleukin-8 is a prognostic indicator in human hilar cholangiocarcinoma

PubMed Central

Sun, Qi; Li, Fanni; Sun, Fengkai; Niu, Jun

2015-01-01

Interleukin-8 (IL-8), matrix metalloproteinase-9 (MMP-9) and neovascularization have been implicated to be associated with biological processes, especially cancer progression. However, few studies have investigated the role of IL-8 in human hilar cholangiocarcinoma. In this study we detected the expression of IL-8 combined with MMP-9 and microvessel density (MVD) in hilar cholangiocarcinoma to evaluate their clinicopathological significance and prognostic value. A total of 62 patients with hilar cholangiocarcinoma who underwent curative surgery were enrolled in this study. The expression of IL-8, MMP-9 and MVD were examined immunohistochemically. The correlation of IL-8 with MMP-9 expression, MVD, clinicopathological features and survival time of patients were then analyzed. Expression of IL-8 was observed in 56.5% tumors, which was related to advanced TNM stage (P = 0.026) and tumor recurrence (P = 0.018). IL-8 had a positive correlation with MMP-9 expression and MVD. Furthermore, patients with high IL-8 expression had a significantly shorter overall survival than those with low IL-8 expression (P = 0.01). Multivariate analysis confirmed IL-8 as an independent prognostic factor (P = 0.005). In conclusion, IL-8 expression significantly correlated with MMP-9 expression and MVD, and IL-8 was a valuable prognostic factor for human hilar cholangiocarcinoma. PMID:26339407

CXCL7 promotes proliferation and invasion of cholangiocarcinoma cells.

PubMed

Guo, Qian; Jian, Zhixiang; Jia, Baoqing; Chang, Liang

2017-02-01

CXCL7 is an important chemoattractant cytokine, which signals through binding to its receptor CXCR2. Recent studies have demonstrated that the CXCL7/CXCR2 signaling plays a promoting role in several common malignancies, including lung, renal, colon, and breast cancer. However, the regulatory role of CXCL7, in cholangiocarcinoma, as well as the underlying mechanism, has not been previously reported. Herein, we found more positive expression of CXCL7 in cholangiocarcinoma tissues compared to adjacent non-tumor tissues. High CXCL7 expression was significantly correlated with poor differentiation, lymph node metastasis, vascular invasion and advanced clinical stage, but was not associated with age, gender, or tumor size. Besides, the expression of CXCL7 was significantly associated with the Ki67 expression, but not associated with CA199, AFP, or P53 expression in cholangiocarcinoma. Moreover, the overall survival of cholangiocarcinoma patients with high CXCL7 expression was significantly shorter than those with low CXCL7 expression. In vitro study indicated that CXCL7 and CXCR2 were also positively expressed in several common cholangiocarcinoma cell lines, including HuCCT1, HuH28, QBC939, EGI-1, OZ and WITT. SiRNA-induced inhibition of CXCL7 significantly reduced the proliferation and invasion of QBC939 cells. On the contrary, overexpression of CXCL7 markedly promoted these malignant phenotypes of QBC939 cells. Of note, the conditioned medium of CXCL7-overexpresing human hepatic stellate cells could also promote the proliferation and invasion of QBC939 cells, suggesting that CXCL7 may also play an oncogenic role in cholangiocarcinoma in a paracrine-dependent manner, not only in an autocrine-dependent manner. Molecular assay data suggested that the AKT signaling pathway was involved in the CXCL7-mediated malignant phenotypes of QBC939 cells. In summary, our study suggests that CXCL7 plays a promoting role in regulating the growth and metastasis of cholangiocarcinoma.

Dietary arachidonic acid and docosahexaenoic acid regulate liver fatty acid desaturase (FADS) alternative transcript expression in suckling piglets.

PubMed

Wijendran, Vasuki; Downs, Ian; Srigley, Cynthia Tyburczy; Kothapalli, Kumar S D; Park, Woo Jung; Blank, Bryant S; Zimmer, J Paul; Butt, C M; Salem, Norman; Brenna, J Thomas

2013-10-01

Molecular regulation of fatty acid desaturase (Fads) gene expression by dietary arachidonic acid (ARA) and docosahexaenoic acid (DHA) during early post-natal period, when the demand for long chain polyunsaturated fatty acids (LC-PUFA) is very high, has not been well defined. The objective of the current study was to determine regulation of liver Fads1, Fads2 and Fads3 classical (CS) and alternative transcripts (AT) expression by dietary ARA and DHA, within the physiological range present in human breast milk, in suckling piglets. Piglets were fed one of six milk replacer formula diets (formula-reared groups, FR) with varying ARA and DHA content from days 3-28 of age. The ARA/DHA levels of the six formula diets were as follows (% total fatty acid, FA/FA): (A1) 0.1/1.0; (A2) 0.53/1.0; (A3-D3) 0.69/1.0; (A4) 1.1/1.0; (D2) 0.67/0.62; and (D1) 0.66/0.33. The control maternal-reared (MR) group remained with the dam. Fads1 expression was not significantly different between FR and MR groups. Fads2 expression was down-regulated significantly in diets with 1:1 ratio of ARA:DHA, compared to MR. Fads2 AT1 expression was highly correlated to Fads2 expression. Fads3 AT7 was the only Fads3 transcript sensitive to dietary LC-PUFA intake and was up-regulated in the formula diets with lowest ARA and DHA contents compared to MR. Thus, the present study provides evidence that the proportion of dietary ARA:DHA is a significant determinant of Fads2 expression and LC-PUFA metabolism during the early postnatal period. Further, the data suggest that Fads3 AT7 may have functional significance when dietary supply of ARA and DHA are low during early development. © 2013 Elsevier Ltd. All rights reserved.

[Expression of Ki-67 and P53 protein in oral squamous cell carcinoma and its clinical significance].

PubMed

He, Wei; Xiao, Yan; Chen, Wei-min

2015-04-01

To investigate the clinical and pathological features and its relationship with the expression of Ki-67 and p53 protein in oral squamous cell carcinoma. Immunohistochemical SP staining method was used to quantify the protein expression levels of Ki-67 and p53 protein in 10 cases of normal oral mucosa, 16 cases of oral leukoplakia (OLK) tissue, and 48 cases of oral squamous cell carcinoma. The relationship of the expression of Ki-67 and p53 protein to clinical and pathological data was analyzed, and SPSS17.0 software package was used for statistical analysis. The positive expression rate of Ki-67 protein in normal oral mucosa, oral leukoplakia and oral squamous cell carcinoma was 30%, 56.3% and 79.2%, respectively; The positive expression rate of p53 was 0%, 43.8%, and 70.8%, respectively; Ki-67 and p53 expression had significant difference among normal oral mucosa, oral leukoplakia and oral squamous cell carcinoma (P<0.05); The expression of Ki-67 protein was significantly elevated with tumor stage, differentiation and cervical lymph node metastasis (P<0.05); The expression of p53 protein was significantly related to the degree of tumor differentiation (P<0.05); The expression of Ki-67 and p53 was positively correlated in oral squamous cell carcinoma (P<0.05). The high expression of Ki-67 and p53 protein in oral squamous cell carcinoma tissues may play an important role in the development of oral squamous cell carcinoma.

High expression of Y-box-binding protein 1 is associated with local recurrence and predicts poor outcome in patients with colorectal cancer

PubMed Central

Yan, Xuebing; Yan, Leilei; zhou, Jia; Liu, Sihong; Shan, Zezhi; Jiang, Chunyu; Tian, Yuan; Jin, Zhiming

2014-01-01

Colorectal cancer (CRC) is one of the most common and fatal malignancies worldwide. Novel prognostic biomarkers are urgently warranted to help improve the treatment of CRC. Y-box-binding protein 1 (YB-1) has been identified as a multifunctional oncoprotein in various malignancies. Our previous study has suggested that YB-1 may promote malignant progression of CRC cells in vitro. However, its clinical and prognostic significance in CRC patients remains unclear. In this study, the expression of YB-1 was examined in 32 fresh CRC tissues using quantitative real-time polymerase chain reaction (qRT-PCR) and in 170 paraffin-embedded CRC tissues using immunohistochemistry. The result of qRT-PCR demonstrated mRNA expression of YB-1 was increased in 26 of 32 (81.25%) of CRC patients. The statistical analysis based on immunohistochemical staining suggested that YB-1 expression was significantly correlated with tumor differentiation, tumor invasion, lymph node metastasis and Dukes’ classification (all P<0.05). Furthermore, we found that patients with high YB-1 expression had a poorer prognosis and were more likely to undergo local recurrence, compared to those with low YB-1 expression. We also identified that YB-1 expression, together with lymph node metastasis and Dukes’ classification were independent prognostic factors for CRC patients. In conclusion, our study for the first time demonstrated the clinical and prognostic significance of YB-1 in CRC and suggested that YB-1 is of great potential to be an attractive therapeutic target as well as prognostic biomarker for CRC patients. PMID:25674237

The Impact of Significant Other Expressed Emotion on Patient Outcomes in Chronic Fatigue Syndrome

PubMed Central

2014-01-01

Objective: Previous literature has identified the importance of interpersonal processes for patient outcomes in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), particularly in the context of significant other relationships. The current study investigated expressed emotion (EE), examining the independent effects of critical comments and emotional overinvolvement (EOI) in association with patient outcomes. Method: Fifty-five patients with CFS/ME and their significant others were recruited from specialist CFS/ME services. Significant other EE status was coded from a modified Camberwell Family Interview. Patient outcomes (fatigue severity, disability, and depression) were derived from questionnaire measures. Forty-four patients (80%) completed follow-up questionnaires 6-months after recruitment. Results: Significant other high-EE categorized by both high levels of critical comments and high EOI was predictive of worse fatigue severity at follow-up. High-critical EE was associated with higher levels of patient depressive symptoms longitudinally; depressive symptoms were observed to mediate the relationship between high critical comments and fatigue severity reported at follow-up. There were higher rates of high-EE in parents than in partners, and this was because of higher rates of EOI in parents. Conclusions: Patients with high-EE significant others demonstrated poorer outcomes at follow-up compared with patients in low-EE dyads. One mechanism for this appears to be as a result of increased patient depression. Future research should seek to further clarify whether the role of interpersonal processes in CFS/ME differs across different patient-significant other relationships. The development of significant other-focused treatment interventions may be particularly beneficial for both patients and significant others. PMID:25180548

Expression of CD10 predicts tumor progression and unfavorable prognosis in malignant melanoma.

PubMed

Oba, Junna; Nakahara, Takeshi; Hayashida, Sayaka; Kido, Makiko; Xie, Lining; Takahara, Masakazu; Uchi, Hiroshi; Miyazaki, Shogo; Abe, Takeru; Hagihara, Akihito; Moroi, Yoichi; Furue, Masutaka

2011-12-01

CD10 expression in malignant melanoma (MM) has been reported to increase according to tumor progression and metastasis; however, its association with patient outcome has not been clarified. We examined the immunohistochemical expression of CD10 in MM to determine whether or not it could serve as a marker for tumor progression and prognosis. A total of 64 formalin-fixed, paraffin-embedded samples of primary MM were immunostained for CD10. Similarly, 40 samples of melanocytic nevus and 20 of metastatic MM were analyzed for comparison. The following clinicopathologic variables were evaluated: age, gender, histologic type, tumor site, Breslow thickness, Clark level, the presence or absence of ulceration and tumor-infiltrating lymphocytes, and survival. Statistical analyses were performed to assess for associations. Several parameters were analyzed for survival using the Kaplan-Meier method and Cox proportional hazards model. Immunohistochemical analysis revealed that 34 of 64 cases (53%) of primary MM expressed CD10, compared with 15 of 20 cases (75%) of metastatic MM and only 4 of 40 cases (10%) of nevus. There was a significant positive relationship between CD10 expression and Breslow thickness, Clark level, and ulceration. Univariate analysis revealed 4 significant factors for shorter survival periods: CD10 expression, high Breslow thickness, high Clark level, and the presence of ulceration (P < .01 each). In multivariate analysis, CD10 expression was revealed to be a statistically significant and independent prognostic factor. The major limitation was the small sample size. CD10 expression may serve as a progression marker and can predict unfavorable prognosis in patients with MM. Copyright © 2010 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

HSPB8 and the Cochaperone BAG3 Are Highly Expressed During the Synthetic Phase of Rat Myometrium Programming During Pregnancy.

PubMed

Marsh, Noelle M; Wareham, Angela; White, Bryan G; Miskiewicz, Ewa I; Landry, Jacques; MacPhee, Daniel J

2015-05-01

The small heat shock protein (HSP) B family of proteins are a group of molecular chaperones that enable tissues to adapt to changes in their local environments during differentiation, stress, or disease conditions. The objective of this research was to characterize the expression of HSPB8 and its cochaperone Bcl2-associated athanogene 3 (BAG3) in nonpregnant (NP) and pregnant rat myometrium during myometrial programming. Rat myometrium was collected from NP and pregnant rats as well as 1 day postpartum (PP) and samples prepared for immunoblot and immunofluorescence analysis. Immunoblot analysis determined that HSPB8 protein expression was significantly elevated at Day (D) 15, D17, and D19 compared to expression at NP and D6, while BAG3 expression was significantly elevated at D15 compared to NP, and D17 compared to NP, D6, D23, and PP time points (P < 0.05). In situ, HSPB8 and BAG3 were predominantly localized to myometrial cells throughout pregnancy, with intense cytoplasmic HSPB8 and BAG3 detection on D15 and D17 in both longitudinal and circular muscle layers. Immunoblot analysis of HSPB8 and BAG3 protein expression in myometrium from unilateral pregnancies also revealed that expression of both proteins was significantly increased at D15 in gravid compared to nongravid horns. Thus, HSPB8 and BAG3 are highly expressed during the synthetic phase of myometrial differentiation marked by initiation of uterine distension and myometrial hypertrophy. HSPB8 and BAG3 could be regulators of the protein quality control required for this process. © 2015 by the Society for the Study of Reproduction, Inc.

Disruption of thyroid hormone (TH) levels and TH-regulated gene expression by polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs), and hydroxylated PCBs in e-waste recycling workers.

PubMed

Zheng, Jing; He, Chun-Tao; Chen, She-Jun; Yan, Xiao; Guo, Mi-Na; Wang, Mei-Huan; Yu, Yun-Jiang; Yang, Zhong-Yi; Mai, Bi-Xian

2017-05-01

Polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) are the primary toxicants released by electronic waste (e-waste) recycling, but their adverse effects on people working in e-waste recycling or living near e-waste sites have not been studied well. In the present study, the serum concentrations of PBDEs, PCBs, and hydroxylated PCBs, the circulating levels of thyroid hormones (THs), and the mRNA levels of seven TH-regulated genes in peripheral blood leukocytes of e-waste recycling workers were analyzed. The associations of the hormone levels and gene expression with the exposure to these contaminants were examined using multiple linear regression models. There were nearly no associations of the TH levels with PCBs and hydroxylated PCBs, whereas elevated hormone (T 4 and T 3 ) levels were associated with certain lower-brominated BDEs. While not statistically significant, we did observe a negative association between highly brominated PBDE congeners and thyroid-stimulating hormone (TSH) levels in the e-waste workers. The TH-regulated gene expression was more significantly associated with the organohalogen compounds (OHCs) than the TH levels in these workers. The TH-regulated gene expression was significantly associated with certain PCB and hydroxylated PCB congeners. However, the expression of most target genes was suppressed by PBDEs (mostly highly brominated congeners). This is the first evidence of alterations in TH-regulated gene expression in humans exposed to OHCs. Our findings indicated that OHCs may interfere with TH signaling and/or exert TH-like effects, leading to alterations in related gene expression in humans. Further research is needed to investigate the mechanisms of action and associated biological consequences of the gene expression disruption by OHCs. Copyright © 2017 Elsevier Ltd. All rights reserved.

Long non-coding RNA FEZF1-AS1 is up-regulated and associated with poor prognosis in patients with cervical cancer.

PubMed

Zhang, H-H; Li, A-H

2018-06-01

Long noncoding RNA FEZF1-AS1 (FEZF1-AS1) has been showed to involve in a variety of cancers. However, its function and clinical significance in cervical cancer (CC) have not been investigated. The aim of this study was to explore the prognostic value of FEZF1-AS1 in CC patients. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to determine the expression level of FEZF1-AS1 in CC specimens and adjacent normal cervical tissues. Association between FEZF1-AS1 expression and clinicopathological characteristics was analyzed x2-test. The Kaplan-Meier method was used to estimate survival curves, and the log-rank statistic was used to test the role of FEZF1-AS1 expression. The possibility of FEZF1-AS1 as a prognostic biomarker for CC was examined by Cox proportional hazard regression model. We found that FEZF1-AS1 expression levels were significantly higher in CC tissues compared with adjacent non-cancerous tissues (p < 0.01). High expressions of FEZF1-AS1 were significantly association with poorer histological grade (p = 0.004), positive distant metastasis (p = 0.002) and advanced FIGO stage (p = 0.001). Furthermore, patients with low FEZF1-AS1 expression lived shorter than those with high FEZF1-AS1 expression (Log-rank test, p < 0.0034). Cox regression analysis demonstrated that FEZF1-AS1 expression level was an independent prognostic factor for CC overall survival rates (p = 0.008). We firstly provided clinical evidence that FEZF1-AS1 may be a possible biomarker of poor prognosis in CC.

Predictive value of the combination of SMAD4 expression and lymphocyte infiltration in malignant transformation of oral leukoplakia.

PubMed

Sakata, Junki; Yoshida, Ryoji; Matsuoka, Yuichiro; Nagata, Masashi; Hirosue, Akiyuki; Kawahara, Kenta; Nakamura, Takuya; Nakamoto, Masafumi; Hirayama, Masatoshi; Takahashi, Nozomu; Nakashima, Hikaru; Arita, Hidetaka; Ogi, Hidenao; Hiraki, Akimitsu; Shinohara, Masanori; Nakayama, Hideki

2017-04-01

Oral leukoplakia (OL) is a common, potentially malignant disorder of the oral cavity. SMAD4 was initially identified as a tumor suppressor and central mediator of transforming growth factor (TGF)-β signaling. In this study, we aimed to determine the expression patterns of SMAD4 in OL, its relationship with the degree of inflammation, and its clinical implications as a biomarker for OL malignant transformation. A total of 150 patients with OL were enrolled in this study. Paraffin-embedded sections obtained from biopsy or resection specimens were subjected to immunohistochemical analysis. Associations among the status of epithelial SMAD4 expression, stromal lymphocyte infiltration, and malignant transformation of OL were examined. Malignant transformation was significantly associated with the status of SMAD4 expression (P = 0.0017) and lymphocyte infiltration status (P = 0.0054). Cox regression analysis, based on the event-free survival (EFS), revealed that a low SMAD4 expression was a significant prognostic factor in OL patients (hazard ratio, 2.632; P = 0.043). In addition, a low SMAD4 expression was closely correlated with high lymphocyte infiltration (P = 0.00035), resulting in a significant correlation between the combination of low SMAD4 expression and high lymphocyte infiltration with malignant transformation of OL (P = 0.00027). The combination of the status of epithelial SMAD4 expression and stromal lymphocyte infiltration may be a useful biomarker for predicting malignant transformation in OL patients. These results suggest that not only epithelial SMAD4 loss, but also stromal features, may regulate the risk of malignant transformation of OL. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

HER2 over-expressing high grade endometrial cancer expresses high levels of p95HER2 variant.

PubMed

Growdon, Whitfield B; Groeneweg, Jolijn; Byron, Virginia; DiGloria, Celeste; Borger, Darrell R; Tambouret, Rosemary; Foster, Rosemary; Chenna, Ahmed; Sperinde, Jeff; Winslow, John; Rueda, Bo R

2015-04-01

Subsets of high grade endometrial cancer (EnCa) over-express HER2 (ERBB2), yet clinical trials have failed to demonstrate any anti-tumor activity utilizing trastuzumab, an approved platform for HER2 positive breast cancer (BrCa). A truncated p95HER2 variant lacking the trastuzumab binding site may confer resistance. The objective of this investigation was to characterize the expression of the p95HER2 truncated variant in EnCa. With institutional approval, 86 high grade EnCa tumors were identified with tumor specimens from surgeries performed between 2000 and 2011. Clinical data were collected and all specimens underwent tumor genotyping, HER2 immunohistochemistry (IHC, HercepTest®), HER2 fluorescent in situ hybridization (FISH), along with total HER2 (H2T) and p95HER2 assessment with VeraTag® testing. Regression models were used to compare a cohort of 86 breast tumors selected for equivalent HER2 protein expression. We identified 44 high grade endometrioid and 42 uterine serous carcinomas (USC). IHC identified high HER2 expression (2+ or 3+) in 59% of the tumors. HER2 gene amplification was observed in 16 tumors (12 USC, 4 endometrioid). Both HER2 gene amplification and protein expression correlated with H2T values. High p95HER2 expression above 2.8RF/mm2 was observed in 53% (n=54) with significant correlation with H2T levels. When matched to a cohort of 107 breast tumors based on HercepTest HER2 expression, high grade EnCa presented with higher p95 levels (p<0.001). These data demonstrate that compared to BrCa, high grade EnCa expresses higher levels of p95HER2 possibly providing rationale for the trastuzumab resistance observed in EnCa. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

[Impact of high-fat diet induced obesity on glucose absorption in small intestinal mucose in rats].

PubMed

Huang, Wei; Liu, Rui; Guo, Wei; Wei, Na; Qiang, Ou; Li, Xian; Ou, Yan; Tang, Chengwei

2012-11-01

To investigate whether high-fat diet induced obesity was associated with variation of glucose absorption in small intestinal mucosa of rats. 46 male SD rats were randomly divided into high-fat diet group (n = 31) and control group (n = 15), fed with high-fat diet and normal diet for 24 weeks, respectively. After 24 weeks, the rats were divided into obese (n = 16) and obesity-resistant group (n = 10) according to their body weight. Rats' body weight, abdominal fat weight, plasma glucose level, maltase, sucrase activity in small intestinal mucosa were measured. SGLT-1 expression in intestinal mucosa was detected by immunohistochemistry, RT-PCR and Western blot. Mean body weight, abdominal fat weight, fast plasma glucose levels, maltase activities and SGLT-1 protein expression in intestinal mucosa of obese rats were significantly higher than those in the control and obesity-resistant rats (P < 0.05). Sucrase activities in intestinal mucosa showed no statistical difference among the three groups (P > 0.05). The SGLT-1 mRNA expression in obese group was increased by 12.5% and 23% when compare with the control and obesity-resistant group, respectively. But the difference was not statistical significant (P > 0.05). High-fat diet induced obesity was associated with the increased intestinal maltase activity and expression of SGLT-1 in rats, the key molecule in glucose absorption.

Identification of Rubisco rbcL and rbcS in Camellia oleifera and their potential as molecular markers for selection of high tea oil cultivars

PubMed Central

Chen, Yongzhong; Wang, Baoming; Chen, Jianjun; Wang, Xiangnan; Wang, Rui; Peng, Shaofeng; Chen, Longsheng; Ma, Li; Luo, Jian

2015-01-01

Tea oil derived from seeds of Camellia oleifera Abel. is high-quality edible oil in China. This study isolated full-length cDNAs of Rubisco subunits rbcL and rbcS from C. oleifera. The rbcL has 1,522 bp with a 1,425 bp coding region, encoding 475 amino acids; and the rbcS has 615 bp containing a 528 bp coding region, encoding 176 amino acids. The expression level of the two genes, designated as Co-rbcL and Co-rbcS, was determined in three C. oleifera cultivars: Hengchong 89, Xianglin 1, and Xianglin 14 whose annual oil yields were 546.9, 591.4, and 657.7 kg ha-1, respectively. The Co-rbcL expression in ‘Xianglin 14’ was significantly higher than ‘Xianglin 1’, and ‘Xianglin 1’ was greater than ‘Hengchong 89’. The expression levels of Co-rbcS in ‘Xianglin 1’ and ‘Xianglin 14’ were similar but were significantly greater than in ‘Hengchong 89’. The net photosynthetic rate of ‘Xianglin 14’ was significantly higher than ‘Xianglin 1’, and ‘Xianglin 1’ was higher than ‘Hengchong 89’. Pearson’s correlation analysis showed that seed yields and oil yields were highly correlated with the expression level of Co-rbcL at P < 0.001 level; and the expression of Co-rbcS was correlated with oil yield at P < 0.01 level. Net photosynthetic rate was also correlated with oil yields and seed yields at P < 0.001 and P < 0.01 levels, respectively. Our results suggest that Co-rbcS and Co-rbcL in particular could potentially be molecular markers for early selection of high oil yield cultivars. In combination with the measurement of net photosynthetic rates, the early identification of potential high oil production cultivars would significantly shorten plant breeding time and increase breeding efficiency. PMID:25873921

Human papillomavirus infection and immunohistochemical p16(INK4a) expression as predictors of outcome in penile squamous cell carcinomas.

PubMed

Bezerra, Stephania M; Chaux, Alcides; Ball, Mark W; Faraj, Sheila F; Munari, Enrico; Gonzalez-Roibon, Nilda; Sharma, Rajni; Bivalacqua, Trinity J; Burnett, Arthur L; Netto, George J

2015-04-01

Approximately 50% of penile squamous cell carcinomas (SCC) are associated with high-risk human papillomavirus (HR-HPV) infection. We evaluated the correlation of p16(INK4a) expression and HR-HPV with clinicopathological features and outcome in a cohort of patients with penile SCC. Two tissue microarrays were constructed from 53 invasive penile SCC at our hospital. p16(INK4a) expression was assessed by immunohistochemistry (CINtec Kit). High-risk human papillomavirus status was assessed by in situ hybridization (INFORM HPV III family 16 probe B cocktail). High-risk human papillomavirus was detected in 8 cases (15%), and p16(INK4a) overexpression was found in 23 cases (44%). Both markers showed a significant association with histologic subtype (P = .017 and P = .01, respectively) and lymphovascular invasion (P = .015 and P = .015, respectively). Regarding outcome analyses, neither HPV infection nor p16(INK4a) overexpression significantly predicted overall survival or cancer-specific survival using Cox proportional hazards regression model. High-risk human papillomavirus positivity and p16(INK4a) overexpression were significantly associated with histologic subtype and presence of lymphovascular invasion. Human papillomavirus status was not predictive of outcome in our cohort. Copyright © 2015 Elsevier Inc. All rights reserved.

Regulatory Efficacy of Brown Seaweed Lessonia nigrescens Extract on the Gene Expression Profile and Intestinal Microflora in Type 2 Diabetic Mice.

PubMed

Zhao, Chao; Yang, Chengfeng; Chen, Mingjun; Lv, Xucong; Liu, Bin; Yi, Lunzhao; Cornara, Laura; Wei, Ming-Chi; Yang, Yu-Chiao; Tundis, Rosa; Xiao, Jianbo

2018-02-01

In this study, the antidiabetic activity of Lessonia nigrescens ethanolic extract (LNE) is investigated in streptozotocin (SZT)-induced type 2 diabetic mice fed with a high-sucrose/high-fat diet. Ultra high performance liquid chromatography coupled with photo-DAD and electospray ionization-mass spectrometry (ESI-MS) is employed to analyze the major compounds in LNE. The components of the intestinal microflora in type 2 diabetic mice are analyzed by high-throughput next-generation 16S rRNA gene sequencing. Fasting blood glucose levels in diabetic mice are significantly decreased after LNE administration. The histology reveals that LNE could protect the cellular architecture of liver and kidney. LNE treatment significantly increases Bacteroidetes and decreases Firmicutes populations in intestinal microflora. Specifically, It could selectively enrich the amounts of beneficial bacteria, Barnesiella, as well as reduce the abundances of Clostridium and Alistipes. The increased gene and protein expression levels of phosphatidylinositol 3-kinase (PI3K) in the liver are observed in LNE treatment groups, while the expressions of c-Jun N-terminal kinase (JNK) are significantly downregulated. The above findings suggest that LNE could be considered as a functional food for reducing blood glucose and regulating intestinal microflora. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Preparation of a Nanoscaled Poly(vinyl alcohol)/Hydroxyapatite/DNA Complex Using High Hydrostatic Pressure Technology for In Vitro and In Vivo Gene Delivery.

PubMed

Kimura, Tsuyoshi; Nibe, Yoichi; Funamoto, Seiichi; Okada, Masahiro; Furuzono, Tsutomu; Ono, Tsutomu; Yoshizawa, Hidekazu; Fujisato, Toshiya; Nam, Kwangwoo; Kishida, Akio

2011-01-01

Our previous research showed that poly(vinyl alcohol) (PVA) nanoparticles incorporating DNA with hydrogen bonds obtained by high hydrostatic pressurization are able to deliver DNA without any significant cytotoxicity. To enhance transfection efficiency of PVA/DNA nanoparticles, we describe a novel method to prepare PVA/DNA nanoparticles encapsulating nanoscaled hydroxyapatites (HAps) prepared by high hydrostatic pressurization (980 MPa), which is designed to facilitate endosomal escape induced by dissolving HAps in an endosome. Scanning electron microscopic observation and dynamic light scattering measurement revealed that HAps were significantly encapsulated in PVA/HAp/DNA nanoparticles. The cytotoxicity, cellular uptake, and transgene expression of PVA/HAp/DNA nanoparticles were investigated using COS-7 cells. It was found that, in contrast to PVA/DNA nanoparticles, their internalization and transgene expression increased without cytotoxicity occurring. Furthermore, a similar level of transgene expression between plasmid DNA and PVA/HAp/DNA nanoparticles was achieved using in vivo hydrodynamic injection. Our results show a novel method of preparing PVA/DNA nanoparticles encapsulating HAp nano-crystals by using high hydrostatic pressure technology and the potential use of HAps as an enhancer of the transfection efficiency of PVA/DNA nanoparticles without significant cytotoxicity.

Hepatocyte growth factor (HGF) upregulates heparanase expression via the PI3K/Akt/NF-κB signaling pathway for gastric cancer metastasis.

PubMed

Hao, Ning-Bo; Tang, Bo; Wang, Guo-Zheng; Xie, Rui; Hu, Chang-Jiang; Wang, Su-Min; Wu, Yu-Yun; Liu, En; Xie, Xia; Yang, Shi-Ming

2015-05-28

Heparanase (HPA) is an endoglucuronidase that can promote the shedding of associated cytokines in several types of tumors. However, little is known about what controls the expression of HPA or its role in gastric cancer. In this study, we report for the first time that HGF regulates HPA expression to promote gastric cancer metastasis. In this study, HGF and HPA were found to be significantly expressed in 58 gastric cancer patients. High expression of both HGF and HPA was positively associated with TNM stage, invasion depth and poor prognosis. In MKN74 cells, exogenous HGF significantly increased HPA expression at both the mRNA and protein levels. Further study revealed that HGF first activated PI3K/Akt signaling. NF-κB signaling was activated downstream of PI3K/Akt and promoted HPA expression. However, when c-met, PI3K/Akt or NF-κB signal inhibitors were used, HPA expression was significantly decreased. All of these results indicate that HGF regulates HPA expression by PI3K/Akt and downstream NF-κB signaling. Using bioinformatics and the ChIP assay, p65 was observed to bind to the HPA promoter. Furthermore, HGF significantly induced tumor cell migration, whereas treatment with an NF-κB inhibitor decreased migration. Moreover, when HPA was overexpressed in MKN74 cells, migration was significantly enhanced, and the HGF concentration was increased. However, when HPA was down-regulated in MKN45 cells, migration and HGF levels decreased. Together, these results demonstrate that HGF/c-met can activate PI3K/Akt and downstream NF-κB signaling to promote HPA expression and subsequent tumor metastasis. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Analyzing gene expression from relative codon usage bias in Yeast genome: a statistical significance and biological relevance.

PubMed

Das, Shibsankar; Roymondal, Uttam; Sahoo, Satyabrata

2009-08-15

Based on the hypothesis that highly expressed genes are often characterized by strong compositional bias in terms of codon usage, there are a number of measures currently in use that quantify codon usage bias in genes, and hence provide numerical indices to predict the expression levels of genes. With the recent advent of expression measure from the score of the relative codon usage bias (RCBS), we have explicitly tested the performance of this numerical measure to predict the gene expression level and illustrate this with an analysis of Yeast genomes. In contradiction with previous other studies, we observe a weak correlations between GC content and RCBS, but a selective pressure on the codon preferences in highly expressed genes. The assertion that the expression of a given gene depends on the score of relative codon usage bias (RCBS) is supported by the data. We further observe a strong correlation between RCBS and protein length indicating natural selection in favour of shorter genes to be expressed at higher level. We also attempt a statistical analysis to assess the strength of relative codon bias in genes as a guide to their likely expression level, suggesting a decrease of the informational entropy in the highly expressed genes.

Technical variations in low-input RNA-seq methodologies.

PubMed

Bhargava, Vipul; Head, Steven R; Ordoukhanian, Phillip; Mercola, Mark; Subramaniam, Shankar

2014-01-14

Recent advances in RNA-seq methodologies from limiting amounts of mRNA have facilitated the characterization of rare cell-types in various biological systems. So far, however, technical variations in these methods have not been adequately characterized, vis-à-vis sensitivity, starting with reduced levels of mRNA. Here, we generated sequencing libraries from limiting amounts of mRNA using three amplification-based methods, viz. Smart-seq, DP-seq and CEL-seq, and demonstrated significant technical variations in these libraries. Reduction in mRNA levels led to inefficient amplification of the majority of low to moderately expressed transcripts. Furthermore, noise in primer hybridization and/or enzyme incorporation was magnified during the amplification step resulting in significant distortions in fold changes of the transcripts. Consequently, the majority of the differentially expressed transcripts identified were either high-expressed and/or exhibited high fold changes. High technical variations ultimately masked subtle biological differences mandating the development of improved amplification-based strategies for quantitative transcriptomics from limiting amounts of mRNA.

IKZF1 expression is a prognostic marker in newly diagnosed standard-risk multiple myeloma treated with lenalidomide and intensive chemotherapy: a study of the German Myeloma Study Group (DSMM).

PubMed

Krönke, J; Kuchenbauer, F; Kull, M; Teleanu, V; Bullinger, L; Bunjes, D; Greiner, A; Kolmus, S; Köpff, S; Schreder, M; Mügge, L-O; Straka, C; Engelhardt, M; Döhner, H; Einsele, H; Bassermann, F; Bargou, R; Knop, S; Langer, C

2017-06-01

Lenalidomide is an immunomodulatory compound with high clinical activity in multiple myeloma. Lenalidomide binding to the Cereblon (CRBN) E3 ubiquitin ligase results in targeted ubiquitination and degradation of the lymphoid transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) leading to growth inhibition of multiple myeloma cells. Recently, Basigin (BSG) was identified as another protein regulated by CRBN that is involved in the activity of lenalidomide. Here, we analyzed the prognostic value of IKZF1, IKZF3, CRBN and BSG mRNA expression levels in pretreatment plasma cells from 60 patients with newly diagnosed multiple myeloma uniformly treated with lenalidomide in combination with intensive chemotherapy within a clinical trial. We found that IKZF1 mRNA expression levels are significantly associated with progression-free survival (PFS). Patients in the lowest quartile (Q1) of IKZF1 expression had a superior PFS compared with patients in the remaining quartiles (Q2-Q4; 3-year PFS of 86 vs 51%, P=0.01). This translated into a significant better overall survival (100 vs 74%, P=0.03). Subgroup analysis revealed a significant impact of IKZF1, IKZF3 and BSG expression levels on PFS in cytogenetically defined standard-risk but not high-risk patients. Our data suggest a prognostic role of IKZF1, IKZF3 and BSG expression levels in lenalidomide-treated multiple myeloma.

[Expression and clinical significance of CD147 in parathyroid carcinoma].

PubMed

Du, X M; Wang, L L; Chang, H; Meng, W; Zhang, J Y; Shen, B

2016-06-08

To study the expression and clinical significance of CD147 in the patients of parathyroid carcinoma. Fourteen cases of parathyroid carcinoma encountered during the period from 2012 to 2015 were enrolled. Thirty three cases of parathyroid adenoma encountered during the same period were enrolled. The expression of CD147 in parathyroid carcinoma and parathyroid adenoma was studied by means of immunohistochemistry (EnVision method). CD147 positive color was brown and yellow, and positive position was located mainly in the cytomembrane, and a small amount of cytoplasm was appeared. Among 14 cases of parathyroid carcinoma, 11 cases of CD147 positive score was 3+ , 3 cases of CD147 positive score was 2+ ; Among 33 cases of parathyroid adenoma , 8 cases of CD147 positive score was 2+ , 15 cases of it was 1+ , 10 cases of it was negative. CD147 was highly expressed in parathyroid carcinoma tissues, and the expression of CD147 was significantly different from the expression of parathyroid adenoma(P<0.05). CD147 immunohistochemical staining can help to diagnose parathyroid carcinoma.

Withaferin A (WFA) inhibits tumor growth and metastasis by targeting ovarian cancer stem cells.

PubMed

Kakar, Sham S; Parte, Seema; Carter, Kelsey; Joshua, Irving G; Worth, Christopher; Rameshwar, Pranela; Ratajczak, Mariusz Z

2017-09-26

Ovarian cancer is the fifth leading cause of deaths due to cancer among women in the United States. In 2017, 22,440 women are expected to be diagnosed with ovarian cancer and 14,080 women will die with it. Currently used chemotherapies (Cisplatin or platinum/taxane combination) targets cancer cells, but spares cancer stem cells (CSCs), which are responsible for tumor relapse leading to recurrence of cancer. Aldehyde dehydrogenase I (ALDH1) positive cancer stem cells are one of the major populations in ovarian tumor and have been related to tumor progression and metastasis. In our studies, we observed expression of ALDH1 in both ovarian surface epithelium (OSE) and cortex with high levels of expression in OSE in normal ovary and benign (BN) tumor, compared to borderline (BL) and high grade (HG) ovarian tumors. In contrast, high levels of expression of ALDH1 were observed in cortex in BL and HG tumors compared to normal ovary and BN tumor. Withaferin A (WFA) alone or in combination with cisplatin (CIS) significantly inhibited the spheroid formation (tumorigenic potential) of isolated ALDH1 CSCs in vitro and significantly reduced its expression in tumors collected from mice bearing orthotopic ovarian tumor compared to control. Treatment of animals with CIS alone significantly increased the ALDH1 CSC population in tumors, suggesting that CIS targets cancer cells but spares cancer stem cells, which undergo amplification. WFA and CIS combination suppresses the expression of securin an "oncogene", suggesting that securin may serve as a downstream signaling gene to mediate the antitumor effects of WFA.

GPER and ERα expression in abnormal endometrial proliferations.

PubMed

Tica, Andrei Adrian; Tica, Oana Sorina; Georgescu, Claudia Valentina; Pirici, Daniel; Bogdan, Maria; Ciurea, Tudorel; Mogoantă, Stelian ŞtefăniŢă; Georgescu, Corneliu Cristian; Comănescu, Alexandru Cristian; Bălşeanu, Tudor Adrian; Ciurea, Raluca Niculina; Osiac, Eugen; Buga, Ana Maria; Ciurea, Marius Eugen

2016-01-01

G-protein coupled estrogen receptor 1 (GPER), a particular extranuclear estrogen receptor (ER), seems not to be significantly involved in normal female phenotype development but especially associated with severe genital malignancies. This study investigated the GPER expression in different types of normal and abnormal proliferative endometrium, and the correlation with the presence of ERα. GPER was much highly expressed in cytoplasm (than onto cell membrane), contrary to ERα, which was almost exclusively located in the nucleus. Both ERs' densities were higher in columnar epithelial then in stromal cells, according with higher estrogen-sensitivity of epithelial cells. GPER and ERα density decreased as follows: complex endometrial hyperplasia (CEH) > simple endometrial hyperplasia (SHE) > normal proliferative endometrium (NPE) > atypical endometrial hyperplasia (AEH), ERα' density being constantly higher. In endometrial adenocarcinomas, both ERs were significant lower expressed, and widely varied, but GPER÷ERα ratio was significantly increased in high-grade lesions. The nuclear ERα is responsible for the genomic (the most important) mechanism of action of estrogens, involved in cell growth and multiplication. In normal and benign proliferations, ERα expression is increased as an evidence of its effects on cells with conserved architecture, in atypical and especially in malignant cells ERα's (and GPER's) density being much lower. Cytoplasmic GPER probably interfere with different tyrosine÷protein kinases signaling pathways, also involved in cell growth and proliferation. In benign endometrial lesions, GPER's presence is, at least partially, the result of an inductor effect of ERα on GPER gene transcription. In high-grade lesions, GPER÷ERα ratio was increased, demonstrating that GPER is involved per se in malignant endometrial proliferations.

Transcript expression and genetic variability analysis of caspases in breast carcinomas suggests CASP9 as the most interesting target.

PubMed

Brynychova, Veronika; Hlavac, Viktor; Ehrlichova, Marie; Vaclavikova, Radka; Nemcova-Furstova, Vlasta; Pecha, Vaclav; Trnkova, Marketa; Mrhalova, Marcela; Kodet, Roman; Vrana, David; Gatek, Jiri; Bendova, Marie; Vernerova, Zdenka; Kovar, Jan; Soucek, Pavel

2017-01-01

Apoptosis plays a critical role in cancer cell survival and tumor development. We provide a hypothesis-generating screen for further research by exploring the expression profile and genetic variability of caspases (2, 3, 7, 8, 9, and 10) in breast carcinoma patients. This study addressed isoform-specific caspase transcript expression and genetic variability in regulatory sequences of caspases 2 and 9. Gene expression profiling was performed by quantitative real-time PCR in tumor and paired non-malignant tissues of two independent groups of patients. Genetic variability was determined by high resolution melting, allelic discrimination, and sequencing analysis in tumor and peripheral blood lymphocyte DNA of the patients. CASP3 A+B and S isoforms were over-expressed in tumors of both patient groups. The CASP9 transcript was down-regulated in tumors of both groups of patients and significantly associated with expression of hormonal receptors and with the presence of rs4645978-rs2020903-rs4646034 haplotype in the CASP9 gene. Patients with a low intratumoral CASP9A/B isoform expression ratio (predicted to shift equilibrium towards anti-apoptotic isoform) subsequently treated with adjuvant chemotherapy had a significantly shorter disease-free survival than those with the high ratio (p=0.04). Inheritance of CC genotype of rs2020903 in CASP9 was associated with progesterone receptor expression in tumors (p=0.003). Genetic variability in CASP9 and expression of its splicing variants present targets for further study.

A comparative study of P450 gene expression in field and laboratory Musca domestica L. strains.

PubMed

Højland, Dorte H; Vagn Jensen, Karl-Martin; Kristensen, Michael

2014-08-01

The housefly is a global pest that has developed resistance to most insecticides applied for its control. Resistance has been associated with cytochrome P450 monooxygenases (P450s). The authors compare the expression of six genes possibly associated with insecticide resistance in three unselected strains: a multiresistant strain (791a), a neonicotinoid-resistant strain (766b) and a new field strain (845b). CYP4G2 was highly expressed throughout the range of strains and proved to be the one of the most interesting expression profiles of all P450s analysed. CYP6G4 was expressed up to 11-fold higher in 766b than in WHO-SRS. Significant differences between expression of P450 genes between F1 flies from 845b and established laboratory strains were shown. In general, P450 gene expression in 845b was 2-14-fold higher than in the reference strain (P < 0.0101) and 2-23-fold higher than in the multiresistant strain (P < 0.0110). The newly collected field strain 845b had significantly higher constitutive gene expression than both WHO-SRS and 791a. High constitutive expression of CYP4G2 in houseflies indicates a possible role of this gene in metabolic resistance. There is a strong indication that CYP6G4 is a major insecticide resistance gene involved in neonicotinoid resistance. © 2013 Society of Chemical Industry.

Bacterium-Induced CXCL10 Secretion by Osteoblasts Can Be Mediated in Part through Toll-Like Receptor 4

PubMed Central

Gasper, Nancy A.; Petty, Cynthia C.; Schrum, Laura W.; Marriott, Ian; Bost, Kenneth L.

2002-01-01

Two common pathogens known to cause bone infection, Salmonella and Staphylococcus aureus, were investigated to determine their abilities to induce chemokine expression in cultured mouse and human osteoblasts. While these cells are responsible for bone formation, we were surprised to find that they could respond to bacterial infection by upregulating expression of the chemokine CXCL10 (IP-10). However, there were significant differences in the abilities of the gram-negative bacterium Salmonella and the gram-positive bacterium S. aureus to induce expression of CXCL10. Reverse transcription-PCR and enzyme-linked immunosorbent assay analyses showed high levels of Salmonella-induced CXCL10 mRNA and protein expression, respectively, whereas the osteoblast response to S. aureus was significantly less. Consistent with these findings, Salmonella-derived lipopolysaccharide (LPS), but not S. aureus-derived peptidoglycan, could induce expression of CXCL10. An antibody against toll-like receptor 4 (TLR4) could block the LPS-induced CXCL10 production, demonstrating the functional expression of TLR4 by osteoblasts. Despite the inducible nature of TLR2 mRNA expression by bacterium-infected osteoblasts, peptidoglycan failed to stimulate CXCL10 secretion. Immunofluorescent staining of bacterium-infected calvaria (i.e., skull bone) demonstrated the presence of CXCL10 in osteoblasts. The fact that osteoblasts did not express CXCR3 mRNA, whereas T lymphocytes can express high levels of this receptor, suggests that osteoblast-derived CXCL10 may recruit T lymphocytes to the sites of bone infections. PMID:12117914

Supplementation of chitosan alleviates high-fat diet-enhanced lipogenesis in rats via adenosine monophosphate (AMP)-activated protein kinase activation and inhibition of lipogenesis-associated genes.

PubMed

Chiu, Chen-Yuan; Chan, Im-Lam; Yang, Tsung-Han; Liu, Shing-Hwa; Chiang, Meng-Tsan

2015-03-25

This study investigated the role of chitosan in lipogenesis in high-fat diet-induced obese rats. The lipogenesis-associated genes and their upstream regulatory proteins were explored. Diet supplementation of chitosan efficiently decreased the increased weights in body, livers, and adipose tissues in high-fat diet-fed rats. Chitosan supplementation significantly raised the lipolysis rate; attenuated the adipocyte hypertrophy, triglyceride accumulation, and lipoprotein lipase activity in epididymal adipose tissues; and decreased hepatic enzyme activities of lipid biosynthesis. Chitosan supplementation significantly activated adenosine monophosphate (AMP)-activated protein kinase (AMPK) phosphorylation and attenuated high-fat diet-induced protein expressions of lipogenic transcription factors (PPAR-γ and SREBP1c) in livers and adipose tissues. Moreover, chitosan supplementation significantly inhibited the expressions of downstream lipogenic genes (FAS, HMGCR, FATP1, and FABP4) in livers and adipose tissues of high-fat diet-fed rats. These results demonstrate for the first time that chitosan supplementation alleviates high-fat diet-enhanced lipogenesis in rats via AMPK activation and lipogenesis-associated gene inhibition.

Prognostic value of the chemokine receptor CXCR4 and epithelial-to-mesenchymal transition in patients with squamous cell carcinoma of the mobile tongue.

PubMed

Albert, Sébastien; Hourseau, Muriel; Halimi, Caroline; Serova, Maria; Descatoire, Véronique; Barry, Béatrix; Couvelard, Anne; Riveiro, Maria Eugenia; Tijeras-Raballand, Annemilaï; de Gramont, Armand; Raymond, Eric; Faivre, Sandrine

2012-12-01

The aim of this study was to evaluate the expression and the prognostic value of chemokine receptor 4 (CXCR4), its cognate ligand the CXCL12, and markers of epithelial-to-mesenchymal transition (EMT) in squamous cell carcinoma (SCC) of the mobile tongue. Patients with primary SCC of the mobile tongue who underwent surgery in our center were screened retrospectively. Patients without prior treatment, who had pre-surgery TNM staging and available tumor samples, were eligible. Protein expression of CXCL12, CXCR4, CA9, E-cadherin, and vimentin was determined by immunohistochemical staining, scored, and correlated with clinical and pathological parameters and overall survival. Multivariate and Cox proportional hazards analyses were performed. Among 160 patients treated and screened, 47 were analyzed. CXCR4 and CXCL12 expression was high in tumor cells. CXCR4 expression in primary tumor samples was significantly higher in patients with high-grade tumors, lymph node metastases, and microscopic nerve invasion (p ≤ 0.05). There was a non-significant trend towards a correlation between high CXCL12 expression and pathologic tumor stage (p=0.07). Tumors with high CXCR4 expression correlated with poor overall survival (hazard ratio=3.6, 95% confidence interval 1.3-9.7; p=0.011), notably in the CXCR4(high)/vimentin-positive subgroup. Vimentin-positive tumors, characterizing EMT, were associated with lower survival (hazard ratio=4.5, 95% confidence interval 1.6-12.3; p=0.0086). Multivariate analysis confirmed vimentin (but not CXCR4) expression as an independent prognostic factor of poor overall survival (p=0.016). Our results suggest that CXCR4 is a marker of tumor aggressiveness and vimentin is an important and independent prognostic factor in patients with SCC of the mobile tongue. Copyright © 2012 Elsevier Ltd. All rights reserved.

Oligonucleotide Microarray Analysis of Dietary-Induced Hyperlipidemia Gene Expression Profiles in Miniature Pigs

PubMed Central

Takahashi, Junko; Waki, Shiori; Matsumoto, Rena; Odake, Junji; Miyaji, Takayuki; Tottori, Junichi; Iwanaga, Takehiro; Iwahashi, Hitoshi

2012-01-01

Background Hyperlipidemia animal models have been established, but complete gene expression profiles of the transition from normal lipid levels have not been obtained. Miniature pigs are useful model animals for gene expression studies on dietary-induced hyperlipidemia because they have a similar anatomy and digestive physiology to humans, and blood samples can be obtained from them repeatedly. Methodology Two typical dietary treatments were used for dietary-induced hyperlipidemia models, by using specific pathogen-free (SPF) Clawn miniature pigs. One was a high-fat and high-cholesterol diet (HFCD) and the other was a high-fat, high-cholesterol, and high-sucrose diet (HFCSD). Microarray analyses were conducted from whole blood samples during the dietary period and from white blood cells at the end of the dietary period to evaluate the transition of expression profiles of the two dietary models. Principal Findings Variations in whole blood gene expression intensity within the HFCD or the HFCSD group were in the same range as the controls provide with normal diet at all periods. This indicates uniformity of dietary-induced hyperlipidemia for our dietary protocols. Gene ontology- (GO) based functional analyses revealed that characteristics of the common changes between HFCD and HFCSD were involved in inflammatory responses and reproduction. The correlation coefficient between whole blood and white blood cell expression profiles at 27 weeks with the HFCSD diet was significantly lower than that of the control and HFCD diet groups. This may be due to the effects of RNA originating from the tissues and/or organs. Conclusions No statistically significant differences in fasting plasma lipids and glucose levels between the HFCD and HFCSD groups were observed. However, blood RNA analyses revealed different characteristics corresponding to the dietary protocols. In this study, whole blood RNA analyses proved to be a useful tool to evaluate transitions in dietary-induced hyperlipidemia gene expression profiles in miniature pigs. PMID:22662175

Trehalose prevents adipocyte hypertrophy and mitigates insulin resistance.

PubMed

Arai, Chikako; Arai, Norie; Mizote, Akiko; Kohno, Keizo; Iwaki, Kanso; Hanaya, Toshiharu; Arai, Shigeyuki; Ushio, Simpei; Fukuda, Shigeharu

2010-12-01

Trehalose has been shown to evoke lower insulin secretion than glucose in oral saccharide tolerance tests in humans. Given this hypoinsulinemic effect of trehalose, we hypothesized that trehalose suppresses adipocyte hypertrophy by reducing storage of triglyceride and mitigates insulin resistance in mice fed a high-fat diet (HFD). Mice were fed an HFD and given drinking water containing 2.5% saccharide (glucose [Glc], trehalose [Tre], maltose [Mal], high-fructose corn syrup, or fructose [Fru]) ad libitum. After 7 weeks of HFD and saccharide intake, fasting serum insulin levels in the Tre/HFD group were significantly lower than in the Mal/HFD and Glc/HFD groups (P < .05). Furthermore, the Tre/HFD group showed a significantly suppressed elevation of homeostasis model assessment-insulin resistance compared with the Mal/HFD group (P < .05) and showed a trend toward lower homeostasis model assessment-insulin resistance than the Glc/HFD group. After 8 weeks of feeding, mesenteric adipocyte size in the Tre/HFD group showed significantly less hypertrophy than the Glc/HFD, Mal/HFD, high-fructose corn syrup/HFD, or Fru/HFD group. Analysis of gene expression in mesenteric adipocytes showed that no statistically significant difference in the expression of monocyte chemoattractant protein-1 (MCP-1) messenger RNA (mRNA) was observed between the Tre/HFD group and the distilled water/standard diet group, whereas a significant increase in the MCP-1 mRNA expression was observed in the Glc/HFD, Mal/HFD, Fru/HFD, and distilled water/HFD groups. Thus, our data indicate that trehalose prevents adipocyte hypertrophy and mitigates insulin resistance in HFD-fed mice by reducing insulin secretion and down-regulating mRNA expression of MCP-1. These findings further suggest that trehalose is a functional saccharide that mitigates insulin resistance. Copyright © 2010 Elsevier Inc. All rights reserved.

Correlation of PD-1/PD-L1 polymorphisms and expressions with clinicopathologic features and prognosis of ovarian cancer.

PubMed

Tan, Dan; Sheng, Li; Yi, Qing-Hua

2018-02-06

To explore the correlation of PD-1/PD-L1 polymorphisms and their expressions with clinicopathologic features and prognosis of ovarian cancer. A total of 164 patients with ovarian cancer were enrolled as case group and 170 healthy women as control group. We conducted quantitative reverse transcription-PCR (qRT-PCR) to determine PD-1/PD-L1 expressions in peripheral blood mononuclear cells (PBMCs). Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and allele-specific amplification were used to detect PD-1 rs2227982 C>T and PD-L1 rs4143815 C>G. PD-1 rs2227982 C>T and PD-L1 rs4143815 C>G polymorphisms increased the risk for ovarian cancer. PD-1 rs2227982 C>T was associated with FIGO stage and differentiation grade, while PD-L1 rs4143815 C>G was correlated with histological type and differentiation grade. Besides, PD-1/PD-L1 expressions were positively correlated in PBMCs of patients with ovarian cancer to be associated with differentiation grade. Compared with wild homozygous patients, PD-1/PD-L1 expressions were significantly decreased in PBMCs of ovarian cancer patients carried with the mutant genotypes of rs2227982 C>T and rs4143815 C>G. The PFS and OS in ovarian cancer patients with wild homozygous genotype of rs2227982 C>T and rs4143815 C>G were significantly higher than those with mutant genotypes, which were significantly lower in patients with low expressions of PD-1/PD-L1 than those with high expressions. Univariate COX regression analysis identified FIGO staging, differentiation grade, rs2227982 C>T, rs4143815 C>G and expressions of PD-1/PD-L1 as the prognostic factors, and multivariate COX regression analysis demonstrated that high FIGO stage and low expressions of PD-1/PD-L1 were independent risk factors for the prognosis of ovarian cancer. PD-1 rs2227982 C>T and PD-L1 rs4143815 C>G polymorphisms increased the risk of ovarian cancer, leading to a poor prognosis, associated with low expressions of PD-1 and PD-L1. While high PD-1 and PD-L1 expressions are indicators of a favorable prognosis in ovarian cancer.

ERβ Expression and Breast Cancer Risk Prediction for Women with Atypias

PubMed Central

Hieken, Tina J; Carter, Jodi M; Hawse, John R; Hoskin, Tanya L; Bois, Melanie; Frost, Marlene; Hartmann, Lynn C; Radisky, Derek C; Visscher, Daniel W; Degnim, Amy C

2015-01-01

Estrogen receptor beta (ERβ) is highly expressed in normal breast epithelium and a putative tumor suppressor. Atypical hyperplasia substantially increases breast cancer risk, but identification of biomarkers to further improve risk stratification is needed. We evaluated ERβ expression in breast tissues from women with atypical hyperplasia and association with subsequent breast cancer risk. ERβ expression was examined by immunohistochemistry in a well-characterized 171 women cohort with atypical hyperplasia diagnosed 1967–1991. Nuclear ERβ percent and intensity was scored in the atypia and adjacent normal lobules. An ERβ sum score (percent + intensity) was calculated and grouped as low, moderate or high. Competing risks regression was used to assess associations of ERβ expression with breast cancer risk. After 15 years median follow-up, 36 women developed breast cancer. ERβ expression was lower in atypia lobules than normal lobules, by percent staining and intensity (both p<0.001). Higher ERβ expression in the atypia or normal lobules, evaluated by percent staining, intensity or sum score, decreased the risk of subsequent breast cancer by 2 (p=0.04) and 2.5-fold (p=0.006). High normal lobule ERβ expression conferred the strongest protective effect in pre-menopausal women: the 20-year cumulative incidence of breast cancer was 0% for women

High-throughput Cloning and Expression of Integral Membrane Proteins in Escherichia coli

PubMed Central

Bruni, Renato

2014-01-01

Recently, several structural genomics centers have been established and a remarkable number of three-dimensional structures of soluble proteins have been solved. For membrane proteins, the number of structures solved has been significantly trailing those for their soluble counterparts, not least because over-expression and purification of membrane proteins is a much more arduous process. By using high throughput technologies, a large number of membrane protein targets can be screened simultaneously and a greater number of expression and purification conditions can be employed, leading to a higher probability of successfully determining the structure of membrane proteins. This unit describes the cloning, expression and screening of membrane proteins using high throughput methodologies developed in our laboratory. Basic Protocol 1 deals with the cloning of inserts into expression vectors by ligation-independent cloning. Basic Protocol 2 describes the expression and purification of the target proteins on a miniscale. Lastly, for the targets that express at the miniscale, basic protocols 3 and 4 outline the methods employed for the expression and purification of targets at the midi-scale, as well as a procedure for detergent screening and identification of detergent(s) in which the target protein is stable. PMID:24510647

Lotus Leaf Aqueous Extract Reduces Visceral Fat Mass and Ameliorates Insulin Resistance in HFD-Induced Obese Rats by Regulating PPARγ2 Expression

PubMed Central

Yan, Kemin; Zhu, Huijuan; Xu, Jian; Pan, Hui; Li, Naishi; Wang, Linjie; Yang, Hongbo; Liu, Meijuan; Gong, FengYing

2017-01-01

Objectives: Lotus leaf is a kind of traditional Chinese medicine. We aimed to explore the effects of lotus leaf aqueous extract (LLAE) on peroxisome proliferative activated receptor γ2 (PPARγ2) expression in preadipocytes and adipocytes and further investigate its effects on high fat diet (HFD)-induced obese rats. Methods: pGL3-Enhancer-PPARγ2 (625 bp)-Luc plasmid, a luciferase reporter gene expression plasmid containing PPARγ2 promoter, was stably transfected into 3T3-L1 preadipocytes. PPARγ2 promoter activities were determined by assaying the luciferase activities. Then PPARγ2 promoter activities in preadipocytes and PPARγ2 mRNA levels in human subcutaneous adipocytes were measured after the administration with LLAE. Additionally, the effects of LLAE on body weight, fat mass, glucose and lipid metabolism and the expression of PPARγ2, insulin receptor substrate 1 and glucose transporter 4 (GLUT4) in visceral adipose tissue (VAT) were measured in HFD-induced obese rats treated with low or high dose [0.5 or 3.0 g crude drug/(kg.d)] LLAE for 6 weeks. Results: Ten μg/ml LLAE significantly increased the luciferase activities in 3T3-L1 cells and the stimulatory action reached 2.51 folds of controls when LLAE was 1000 μg/ml (P < 0.01). After treating 3T3-L1 cells with 100 μg/ml LLAE, the stimulatory role peaked at 32 h where it was 2.58 folds of controls (P < 0.01). Besides, 100 μg/ml LLAE significantly increased PPARγ2 mRNA levels in human adipocytes to 1.91 folds of controls (P < 0.01). In HFD-induced obese rats, administration with both low and high dose LLAE notably reduced visceral fat mass by 45.5 and 58.4%, respectively, and significantly decreased fasting serum insulin levels (P < 0.05). The high dose LLAE also significantly decreased homeostasis model assessment of insulin resistance in obese rats (P < 0.05). Furthermore, the mRNA levels of PPARγ2 and GLUT4 in VAT of obese rats were significantly increased when compared with control rats, and were notably suppressed by LLAE intervention for 6 weeks (P < 0.05). Conclusion: LLAE significantly reduces visceral fat mass and ameliorates insulin resistance in HFD-induced obese rats. These beneficial effects of LLAE may associate with its role in stimulating PPARγ2 expression in preadipocytes and subcutaneous adipocytes and suppressing PPARγ2 and GLUT4 expression in VAT. PMID:28690544

CD151-mediated adhesion is crucial to osteosarcoma pulmonary metastasis

PubMed Central

Sun, Mengxiong; Zhou, Chenghao; Chen, Jian; Yin, Fei; Wang, Hongsheng; Lin, Binhui; Zuo, Dongqing; Li, Suoyuan; Feng, Lijin; Duan, Zhenfeng; Cai, Zhengdong; Hua, Yingqi

2016-01-01

CD151, a tetraspanin family protein involved in cell-cell and cell-extracellular matrix interaction, is differentially expressed in osteosarcoma cell membranes. Thus, this study aimed to investigate the role of CD151 in osteosarcoma metastasis. We analyzed CD151 expression in patient tissue samples using immunohistochemistry. CD151 expression was also silenced with shRNA in osteosarcoma cells of high metastatic potential, and cell adhesion, migration and invasion were evaluated in vitro and pulmonary metastasis was investigated in vivo. Mediators of cell signaling pathways were also examined following suppression of CD151 expression. Overall survival for patients with low versus high CD151 expression level was 94 vs. 41 months (p=0.0451). CD151 expression in osteosarcoma cells with high metastatic potential was significantly higher than in those with low metastatic potential (p<0.001). shRNA-mediated silencing of CD151 did not influence cell viability or proliferation; however, cell adhesion, migration and invasion were all inhibited (all p<0.001). In mice inoculated with shRNA-transduced osteosarcoma cells, the number and size of lung metastatic lesions were reduced compared to the mice inoculated with control-shRNA transduced cells (p<0.001). In addition, CD151 knockdown significantly reduced Akt, p38, and p65 phosphorylation as well as focal adhesion kinase, integrin β1, p70s6, and p-mTOR levels. Taken together, CD151 induced osteosarcoma metastasis likely by regulating cell function through adhesion signaling. Further studies are necessary to fully explore the diagnostic and prognostic value of determining CD151 expression in osteosarcoma patients. PMID:27556355

Characterization of microRNA profile in mammary tissue of dairy and beef breed heifers.

PubMed

Wicik, Z; Gajewska, M; Majewska, A; Walkiewicz, D; Osińska, E; Motyl, T

2016-02-01

MicroRNAs (miRNAs) are small non-coding RNAs that participate in the regulation of gene expression. Their role during mammary gland development is still largely unknown. In this study, we performed a microarray analysis to identify miRNAs associated with high mammogenic potential of the bovine mammary gland. We identified 54 significantly differentially expressed miRNAs between the mammary tissue of dairy (Holstein-Friesian, HF) and beef (Limousin, LM) postpubertal heifers. Fifty-two miRNAs had higher expression in the mammary tissue of LM heifers. The expression of the top candidate miRNAs (bta-miR-10b, bta-miR-29b, bta-miR-101, bta-miR-375, bta-miR-2285t, bta-miR-146b, bta-let7b, bta-miR-107, bta-miR-1434-3p) identified in the microarray experiment was additionally evaluated by qPCR. Enrichment analyses for targeted genes revealed that the major differences between miRNA expression in the mammary gland of HF versus LM were associated with the regulation of signalling pathways that are crucial for mammary gland development, such as TGF-beta, insulin, WNT and inflammatory pathways. Moreover, a number of genes potentially targeted by significantly differentially expressed miRNAs were associated with the activity of mammary stem cells. These data indicate that the high developmental potential of the mammary gland in dairy cattle, leading to high milk productivity, depends also on a specific miRNA expression pattern. © 2015 Blackwell Verlag GmbH.

Investigating the role of the IGF axis as a predictor of biochemical recurrence in prostate cancer patients post-surgery.

PubMed

Breen, Kieran J; O'Neill, Amanda; Murphy, Lisa; Fan, Yue; Boyce, Susie; Fitzgerald, Noel; Dorris, Emma; Brady, Lauren; Finn, Stephen P; Hayes, Brian D; Treacy, Ann; Barrett, Ciara; Aziz, Mardiana Abdul; Kay, Elaine W; Fitzpatrick, John M; Watson, R William G

2017-09-01

Between 20% and 35% of prostate cancer (PCa) patients who undergo treatment with curative intent (ie, surgery or radiation therapy) for localized disease will experience biochemical recurrence (BCR). Alterations in the insulin-like growth factor (IGF) axis and PTEN expression have been implicated in the development and progression of several human tumors including PCa. We examined the expression of the insulin receptor (INSR), IGF-1 receptor (IGF-1R), PTEN, and AKT in radical prostatectomy tissue of patients who developed BCR post-surgery. Tissue microarrays (TMA) of 130 patients post-radical prostatectomy (65 = BCR, 65 = non-BCR) were stained by immunohistochemistry for INSR, IGF-1R, PTEN, and AKT using optimized antibody protocols. INSR, IGF1-R, PTEN, and AKT expression between benign and cancerous tissue, and different Gleason grades was assessed. Kaplan-Meier survival curves were used to examine the relationship between proteins expression and BCR. INSR (P < 0.001), IGF-1R (P < 0.001), and AKT (P < 0.05) expression was significantly increased and PTEN (P < 0.001) was significantly decreased in cancerous versus benign tissue. There was no significant difference in INSR, IGF-1R, or AKT expression in the cancerous tissue of non-BCR versus BCR patients (P = 0.149, P = 0.990, P = 0.399, respectively). There was a significant decrease in PTEN expression in the malignant tissue of BCR versus non-BCR patients (P = 0.011). Combinational analysis of the tissue proteins identified a combination of decreased PTEN and increased AKT or increased INSR was associated with worst outcome. We found that in each case, our hypothesized worst group was most likely to experience BCR and this was significant for combinations of PTEN+INSR and PTEN+AKT but not PTEN+IGF-1R (P = 0.023, P = 0.028, P = 0.078, respectively). Low PTEN is associated with BCR and this association is strongly modified by high INSR and high AKT expression. Measurement of these proteins could help inform appropriate patient selection for postoperative adjuvant therapy and prevent BCR. © 2017 Wiley Periodicals, Inc.

The Pluripotent Stem-Cell Marker Alkaline Phosphatase is Highly Expressed in Refractory Glioblastoma with DNA Hypomethylation.

PubMed

Iwadate, Yasuo; Suganami, Akiko; Tamura, Yutaka; Matsutani, Tomoo; Hirono, Seiichiro; Shinozaki, Natsuki; Hiwasa, Takaki; Takiguchi, Masaki; Saeki, Naokatsu

2017-02-01

Hypomethylation of genomic DNA induces stem-cell properties in cancer cells and contributes to the treatment resistance of various malignancies. To examine the correlation between the methylation status of stem-cell-related genes and the treatment outcomes in patients with glioblastoma (GBM). The genome-wide DNA methylation status was determined using HumanMethylation450 BeadChips, and the methylation status was compared between a group of patients with good prognosis (survival > 4 yr) and a group with poor prognosis (survival < 1 yr). Immunohistochemistry for proteins translated from hypomethylated genes, including alkaline phosphatase (ALPL), CD133, and CD44, was performed in 70 GBMs and 60 oligodendroglial tumors. The genomic DNA in refractory GBM was more hypomethylated than in GBM from patients with relatively long survival (P = .0111). Stem-cell-related genes including ALPL, CD133, and CD44 were also significantly hypomethylated. A validation study using immunohistochemistry showed that DNA hypomethylation was strongly correlated with high protein expression of ALPL, CD133, and CD44. GBM patients with short survival showed high expression of these stem-cell markers. Multivariate analysis confirmed that co-expression of ALPL + CD133 or ALPL + CD44 was a strong predictor of short survival. Anaplastic oligodendroglial tumors without isocitrate dehydrogenase 1 mutation were significantly correlated with high ALPL expression and poor survival. Accumulation of stem-cell properties due to aberrant DNA hypomethylation is associated with the refractory nature of GBM. Copyright © 2017 by the Congress of Neurological Surgeons

Prognostic relevance of epithelial-mesenchymal transition and proliferation in surgically treated primary parotid gland cancer.

PubMed

Busch, Alina; Bauer, Larissa; Wardelmann, Eva; Rudack, Claudia; Grünewald, Inga; Stenner, Markus

2017-05-01

Cancer of the major salivary glands comprises a morphologically diverse group of rare tumours of largely unknown cause. Epithelial-mesenchymal transition (EMT) has been shown to play a significant prognostic role in various human cancers. The aim was to assess the expression of EMT markers in different histological subtypes of parotid gland cancer (PGC) and analyse their prognostic value. We examined 94 PGC samples (13 histological subtypes) for the expression of MIB-1, epithelial cadherin (E-cadherin), β-catenin, vimentin and cytokeratin 8/18 (CK8/18) by means of immunohistochemistry. The experimental findings were correlated with clinicopathological and survival parameters. We detected all analysed EMT and proliferation markers in specifically different constellations within the examined histological subtypes of PGC. We found high epithelial marker expressions (CK8/18, E-cadherin, membranous β-catenin) only in a distinct variety of carcinomas. A high proliferation rate (high MIB-1 expression) as well as a combination of high CK8/18 and low vimentin expression was associated with a significantly worse survival. Our findings indicate that activation of the EMT pathway is a relevant explanation for tumour progression in individual histological subtypes of malignant parotid gland lesions, but by far not in all. Evidence of EMT activation in PGC cannot be seen as an isolated prognostic factor. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Cerebellum Transcriptome of Mice Bred for High Voluntary Activity Offers Insights into Locomotor Control and Reward-Dependent Behaviors.

PubMed

Caetano-Anollés, Kelsey; Rhodes, Justin S; Garland, Theodore; Perez, Sam D; Hernandez, Alvaro G; Southey, Bruce R; Rodriguez-Zas, Sandra L

2016-01-01

The role of the cerebellum in motivation and addictive behaviors is less understood than that in control and coordination of movements. High running can be a self-rewarding behavior exhibiting addictive properties. Changes in the cerebellum transcriptional networks of mice from a line selectively bred for High voluntary running (H) were profiled relative to an unselected Control (C) line. The environmental modulation of these changes was assessed both in activity environments corresponding to 7 days of Free (F) access to running wheel and to Blocked (B) access on day 7. Overall, 457 genes exhibited a significant (FDR-adjusted P-value < 0.05) genotype-by-environment interaction effect, indicating that activity genotype differences in gene expression depend on environmental access to running. Among these genes, network analysis highlighted 6 genes (Nrgn, Drd2, Rxrg, Gda, Adora2a, and Rab40b) connected by their products that displayed opposite expression patterns in the activity genotype contrast within the B and F environments. The comparison of network expression topologies suggests that selection for high voluntary running is linked to a predominant dysregulation of hub genes in the F environment that enables running whereas a dysregulation of ancillary genes is favored in the B environment that blocks running. Genes associated with locomotor regulation, signaling pathways, reward-processing, goal-focused, and reward-dependent behaviors exhibited significant genotype-by-environment interaction (e.g. Pak6, Adora2a, Drd2, and Arhgap8). Neuropeptide genes including Adcyap1, Cck, Sst, Vgf, Npy, Nts, Penk, and Tac2 and related receptor genes also exhibited significant genotype-by-environment interaction. The majority of the 183 differentially expressed genes between activity genotypes (e.g. Drd1) were under-expressed in C relative to H genotypes and were also under-expressed in B relative to F environments. Our findings indicate that the high voluntary running mouse line studied is a helpful model for understanding the molecular mechanisms in the cerebellum that influence locomotor control and reward-dependent behaviors.

Cerebellum Transcriptome of Mice Bred for High Voluntary Activity Offers Insights into Locomotor Control and Reward-Dependent Behaviors

PubMed Central

Caetano-Anollés, Kelsey; Rhodes, Justin S.; Garland, Theodore; Perez, Sam D.; Hernandez, Alvaro G.; Southey, Bruce R.; Rodriguez-Zas, Sandra L.

2016-01-01

The role of the cerebellum in motivation and addictive behaviors is less understood than that in control and coordination of movements. High running can be a self-rewarding behavior exhibiting addictive properties. Changes in the cerebellum transcriptional networks of mice from a line selectively bred for High voluntary running (H) were profiled relative to an unselected Control (C) line. The environmental modulation of these changes was assessed both in activity environments corresponding to 7 days of Free (F) access to running wheel and to Blocked (B) access on day 7. Overall, 457 genes exhibited a significant (FDR-adjusted P-value < 0.05) genotype-by-environment interaction effect, indicating that activity genotype differences in gene expression depend on environmental access to running. Among these genes, network analysis highlighted 6 genes (Nrgn, Drd2, Rxrg, Gda, Adora2a, and Rab40b) connected by their products that displayed opposite expression patterns in the activity genotype contrast within the B and F environments. The comparison of network expression topologies suggests that selection for high voluntary running is linked to a predominant dysregulation of hub genes in the F environment that enables running whereas a dysregulation of ancillary genes is favored in the B environment that blocks running. Genes associated with locomotor regulation, signaling pathways, reward-processing, goal-focused, and reward-dependent behaviors exhibited significant genotype-by-environment interaction (e.g. Pak6, Adora2a, Drd2, and Arhgap8). Neuropeptide genes including Adcyap1, Cck, Sst, Vgf, Npy, Nts, Penk, and Tac2 and related receptor genes also exhibited significant genotype-by-environment interaction. The majority of the 183 differentially expressed genes between activity genotypes (e.g. Drd1) were under-expressed in C relative to H genotypes and were also under-expressed in B relative to F environments. Our findings indicate that the high voluntary running mouse line studied is a helpful model for understanding the molecular mechanisms in the cerebellum that influence locomotor control and reward-dependent behaviors. PMID:27893846

Significantly greater expression of ER, PR, and ECAD in advanced-stage low-grade ovarian serous carcinoma as revealed by immunohistochemical analysis.

PubMed

Wong, Kwong-Kwok; Lu, Karen H; Malpica, Anais; Bodurka, Diane C; Shvartsman, Hyun S; Schmandt, Rosemarie E; Thornton, Angela D; Deavers, Michael T; Silva, Elvio G; Gershenson, David M

2007-10-01

A 2-tier system that classifies ovarian serous carcinoma (OSC) as low grade or high grade is gaining acceptance. Women with low-grade OSC generally have higher 5-year survival rates than do women with high-grade OSC. We examined the expression of various markers to further understand the molecular differences between low-grade and high-grade OSCs: the potential therapeutic targets or prognostic markers Her-2/neu, estrogen receptor, and progesterone receptor (PR); the metastasis-associated markers cyclin D1 (BCL1), E-cadherin, matrix metalloproteinase (MMP) 2, and MMP-9; and the cell proliferation-associated markers BCL1, Ki-67 antigen (Ki-67), and p53. For this immunohistochemical analysis, we used paraffin-embedded specimens from 47 patients with advanced-stage low-grade OSC and from 49 patients with advanced-stage high-grade OSC. Our results showed that low-grade tumors expressed significantly higher levels of estrogen receptor, PR, and E-cadherin than did high-grade tumors, suggesting the involvement of gonadal steroid hormones, especially in the pathogenesis of low-grade OSC; the PR positivity was also observed in the stromal component of these low-grade tumors. On the other hand, high-grade tumors trended toward increased expression of MMP-9, BCL1, p53, and Ki-67, and robust MMP-9 positivity was observed in the stromal component of these high-grade tumors. These differences may lead to the development of different therapeutic strategies for women with either the low-grade or the high-grade form of OSC.

Non-endometrioid and high-grade endometrioid endometrial cancers show DNA fragmentation factor 40 (DFF40) and B-cell lymphoma 2 protein (BCL2) underexpression, which predicts disease-free and overall survival, but not DNA fragmentation factor 45 (DFF45) underexpression.

PubMed

Banas, Tomasz; Pitynski, Kazimierz; Okon, Krzysztof; Winiarska, Aleksandra

2018-04-13

The expression of DNA fragmentation factor 45 (DFF45) and B-cell lymphoma 2 (BCL2) in glands of the normal human endometrium is related to phases of the menstrual cycle and decreases after menopause, whereas the expression of DNA fragmentation factor 40 (DFF40) is stable. Moreover, DF45, BCL2 and DFF40 underexpression has been reported in numerous malignancies, including uterine leiomyosarcomas. In this study, we aimed to investigate DFF45, BCL2 and DFF40 expression in endometrioid and non-endometrioid types of endometrial cancers (ECs). We also evaluated the correlations between DFF45, BCL2 and DFF40 expression levels and clinicopathological parameters and determined the value of these three proteins as prognostic markers of disease-free survival (DFS) and overall survival (OS). Immunohistochemistry was performed to evaluate DFF45, BCL2 and DFF40 expression in 342 cases of ECs. Student's t-test, the Mann-Whitney U-test, and the chi-squared test were used for the statistical analyses as appropriate. The Cox-Mantel test, Cox's proportional hazard model, and relative risk analyses were used to evaluate associations between DFF40, DFF45, and BCL2 expression and clinicopathological characteristics. DFF40 and BCL2, but not DFF45, were significantly underexpressed in non-endometrioid and high-grade endometrioid ECs compared with low- and moderate-grade endometrioid ECs. Women with DFF40- and BCL2-negative tumors had higher risks of disease recurrence, lymph node involvement, lympho-vascular space infiltration, and deep myometrial invasion compared with women with DFF40- and BCL2-positive tumors. Additionally, women with DFF40- and BCL2-negative tumors had significantly lower OS and DFS than women with DFF40- and BCL2-positive tumors. A multivariable analysis of the model, including the clinicopathological characteristics and immunohistochemical results, showed that negative BCL2 expression, lymph node involvement, and high-stage and high-grade disease were independent predictors of OS, whereas negative BCL2 expression, lymph node involvement, and high-stage disease were independent predictors of DFS. Compared with low- and moderate-grade endometrioid ECs, non-endometrioid and high-grade endometrioid ECs showed significant DFF40 and BCL2 underexpression. The absence of DFF40 and BCL2 expression negatively affects DFS and OS. Further prospective studies are warranted to assess the potential utility of DFF40 and BCL2 as targets in the diagnosis or treatment of ECs.

Magnesium supplement promotes sciatic nerve regeneration and down-regulates inflammatory response.

PubMed

Pan, Hung-Chuan; Sheu, Meei-Ling; Su, Hong-Lin; Chen, Ying-Ju; Chen, Chun-Jung; Yang, Dar-Yu; Chiu, Wen-Ta; Cheng, Fu-Chou

2011-06-01

Magnesium (Mg) supplements have been shown to significantly improve functional recovery in various neurological disorders. The essential benefits of Mg supplementation in peripheral nerve disorders have not been elucidated yet. The effect and mechanism of Mg supplementation on a sciatic nerve crush injury model was investigated. Sciatic nerve injury was induced in mice by crushing the left sciatic nerve. Mice were randomly divided into three groups with low-, basal- or high-Mg diets (corresponding to 10, 100 or 200% Mg of the basal diet). Neurobehavioral, electrophysiological and regeneration marker studies were conducted to explore nerve regeneration. First, a high Mg diet significantly increased plasma and nerve tissue Mg concentrations. In addition, Mg supplementation improved neurobehavioral, electrophysiological functions, enhanced regeneration marker, and reduced deposits of inflammatory cells as well as expression of inflammatory cytokines. Furthermore, reduced Schwann cell apoptosis was in line with the significant expression of bcl-2, bcl-X(L) and down-regulated expression of active caspase-3 and cytochrome C. In summary, improved neurological function recovery and enhanced nerve regeneration were found in mice with a sciatic nerve injury that were fed a high- Mg diet, and Schwann cells may have been rescued from apoptosis by the suppression of inflammatory responses.

Clinicopathological Implications of Human Papilloma Virus (HPV) L1 Capsid Protein Immunoreactivity in HPV16-Positive Cervical Cytology

PubMed Central

Lee, Sung-Jong; Lee, Ah-Won; Kang, Chang-Suk; Park, Jong-Sup; Park, Dong-Choon; Ki, Eun-Young; Lee, Keun-Ho; Yoon, Joo-Hee; Hur, Soo-Young; Kim, Tae-Jung

2014-01-01

Background: The objective of this study was to investigate the expression of human papilloma virus (HPV) L1 capsid protein in abnormal cervical cytology with HPV16 infection and analyze its association with cervical histopathology in Korean women. Material and Methods: We performed immunocytochemistry for HPV L1 in 475 abnormal cervical cytology samples from patients with HPV16 infections using the Cytoactiv® HPV L1 screening set. We investigated the expression of HPV L1 in cervical cytology samples and compared it with the results of histopathological examination of surgical specimens. Results: Of a total of 475 cases, 188 (39.6%) were immunocytochemically positive and 287 (60.4%) negative for HPV L1. The immunocytochemical expression rates of HPV L1 in atypical squamous cells of unknown significance (ASCUS), low-grade squamous intraepithelial lesions (LSIL), high-grade squamous intraepithelial lesions (HSIL), and cancer were 21.8%, 59.7%, 19.1%, and 0.0%, respectively. LSIL exhibited the highest rate of HPV L1 positivity. Of a total of 475 cases, the multiple-type HPV infection rate, including HPV16, in HPV L1-negative cytology samples was 27.5%, which was significantly higher than that in HPV L1-positive cytology samples (p = 0.037). The absence of HPV L1 expression in ASCUS and LSIL was significantly associated with high-grade (≥cervical intraepithelial neoplasia [CIN] 2) than low-grade (≤CIN1) histopathology diagnoses (p < 0.05), but was not significantly different between HPV16 single and multiple-type HPV infections (p > 0.05). On the other hand, among 188 HPV L1-positive cases, 30.6% of multiple-type HPV infections showed high-grade histopathology diagnoses (≥CIN3), significantly higher than the percentage of HPV16 single infections (8.6%) (p = 0.0004) Conclusions: Our study demonstrates that the expression of HPV L1 is low in advanced dysplasia. Furthermore, the absence of HPV L1 in HPV16-positive low-grade cytology (i.e., ASCUS and LSIL) is strongly associated with high-grade histopathology diagnoses. The multiplicity of HPV infections may have an important role in high-grade histopathology diagnoses (≥CIN3) in HPV L1-positive cases. PMID:24396289

Flow cytometric analysis of immunoglobulin heavy chain expression in B-cell lymphoma and reactive lymphoid hyperplasia

PubMed Central

Grier, David D; Al-Quran, Samer Z; Cardona, Diana M; Li, Ying; Braylan, Raul C

2012-01-01

The diagnosis of B-cell lymphoma (BCL) is often dependent on the detection of clonal immunoglobulin (Ig) light chain expression. In some BCLs, the determination of clonality based on Ig light chain restriction may be difficult. The aim of our study was to assess the utility of flow cytometric analysis of surface Ig heavy chain (HC) expression in lymphoid tissues in distinguishing lymphoid hyperplasias from BCLs, and also differentiating various BCL subtypes. HC expression on B-cells varied among different types of hyperplasias. In follicular hyperplasia, IgM and IgD expression was high in mantle cells while germinal center cells showed poor HC expression. In other hyperplasias, B cell compartments were blurred but generally showed high IgD and IgM expression. Compared to hyperplasias, BCLs varied in IgM expression. Small lymphocytic lymphomas had lower IgM expression than mantle cell lymphomas. Of importance, IgD expression was significantly lower in BCLs than in hyperplasias, a finding that can be useful in differentiating lymphoma from reactive processes. PMID:22400070

Uncovering robust patterns of microRNA co-expression across cancers using Bayesian Relevance Networks

PubMed Central

2017-01-01

Co-expression networks have long been used as a tool for investigating the molecular circuitry governing biological systems. However, most algorithms for constructing co-expression networks were developed in the microarray era, before high-throughput sequencing—with its unique statistical properties—became the norm for expression measurement. Here we develop Bayesian Relevance Networks, an algorithm that uses Bayesian reasoning about expression levels to account for the differing levels of uncertainty in expression measurements between highly- and lowly-expressed entities, and between samples with different sequencing depths. It combines data from groups of samples (e.g., replicates) to estimate group expression levels and confidence ranges. It then computes uncertainty-moderated estimates of cross-group correlations between entities, and uses permutation testing to assess their statistical significance. Using large scale miRNA data from The Cancer Genome Atlas, we show that our Bayesian update of the classical Relevance Networks algorithm provides improved reproducibility in co-expression estimates and lower false discovery rates in the resulting co-expression networks. Software is available at www.perkinslab.ca. PMID:28817636

Uncovering robust patterns of microRNA co-expression across cancers using Bayesian Relevance Networks.

PubMed

Ramachandran, Parameswaran; Sánchez-Taltavull, Daniel; Perkins, Theodore J

2017-01-01

Co-expression networks have long been used as a tool for investigating the molecular circuitry governing biological systems. However, most algorithms for constructing co-expression networks were developed in the microarray era, before high-throughput sequencing-with its unique statistical properties-became the norm for expression measurement. Here we develop Bayesian Relevance Networks, an algorithm that uses Bayesian reasoning about expression levels to account for the differing levels of uncertainty in expression measurements between highly- and lowly-expressed entities, and between samples with different sequencing depths. It combines data from groups of samples (e.g., replicates) to estimate group expression levels and confidence ranges. It then computes uncertainty-moderated estimates of cross-group correlations between entities, and uses permutation testing to assess their statistical significance. Using large scale miRNA data from The Cancer Genome Atlas, we show that our Bayesian update of the classical Relevance Networks algorithm provides improved reproducibility in co-expression estimates and lower false discovery rates in the resulting co-expression networks. Software is available at www.perkinslab.ca.

Diagnostic value of progesterone receptor, p16, p53 and pHH3 expression in uterine atypical leiomyoma.

PubMed

Liang, Yun; Zhang, Xiaofei; Chen, Xiaoduan; Lü, Weiguo

2015-01-01

The differential diagnosis between atypical leiomyoma and leiomyosarcoma may be hard based on morphological criterion at times. It would be helpful to find out biomarkers that can be used to distinguish them. The aim of the study was to investigate the diagnostic value of progesterone receptor (PR), p16, p53 and pHH3 expression in a series of uterine smooth muscle tumors. Immunohistochemical expression of PR, p16, p53 and pHH3 was investigated on 32 atypical leiomyomas, 15 leiomyosarcomas and 15 usual leomyomas. The difference in expression was compared between atypical leiomyoma and other groups. The expression of PR, p16, and pHH3 was found significantly different between atypical leiomyomas and leiomyosarcomas, but lack of significant difference between atypical leiomyomas and usual leiomyomas. There was no significant difference with regard to p53 distribution among these uterine smooth muscle tumors. High p16, pHH3 expression and low PR expression preferred the diagnosis of leiomyosarcoma. The panel of antibodies used in this study is a useful complementary analysis in the assessment of problematic uterine smooth muscle tumors.

Diagnostic value of progesterone receptor, p16, p53 and pHH3 expression in uterine atypical leiomyoma

PubMed Central

Liang, Yun; Zhang, Xiaofei; Chen, Xiaoduan; Lü, Weiguo

2015-01-01

The differential diagnosis between atypical leiomyoma and leiomyosarcoma may be hard based on morphological criterion at times. It would be helpful to find out biomarkers that can be used to distinguish them. The aim of the study was to investigate the diagnostic value of progesterone receptor (PR), p16, p53 and pHH3 expression in a series of uterine smooth muscle tumors. Immunohistochemical expression of PR, p16, p53 and pHH3 was investigated on 32 atypical leiomyomas, 15 leiomyosarcomas and 15 usual leomyomas. The difference in expression was compared between atypical leiomyoma and other groups. The expression of PR, p16, and pHH3 was found significantly different between atypical leiomyomas and leiomyosarcomas, but lack of significant difference between atypical leiomyomas and usual leiomyomas. There was no significant difference with regard to p53 distribution among these uterine smooth muscle tumors. High p16, pHH3 expression and low PR expression preferred the diagnosis of leiomyosarcoma. The panel of antibodies used in this study is a useful complementary analysis in the assessment of problematic uterine smooth muscle tumors. PMID:26261614

Vascular endothelial growth factor-C (VEGF-C) expression predicts lymph node metastasis of transitional cell carcinoma of the bladder.

PubMed

Suzuki, Kazumi; Morita, Tatsuo; Tokue, Akihiko

2005-02-01

It has been found that expression of vascular endothelial growth factor-C (VEGF-C) in several carcinomas is significantly associated with angiogenesis, lymphangiogenesis and regional lymph node metastasis. However, VEGF-C expression in bladder transitional cell carcinoma (TCC) has not yet been reported. To elucidate the role of VEGF-C in bladder TCC, we examined VEGF-C expression in bladder TCC and pelvic lymph node metastasis specimens obtained from patients who underwent radical cystectomy. Eighty-seven patients who underwent radical cystectomy for clinically organ-confined TCC of the bladder were enrolled in the present study. No neoadjuvant treatments, except transurethral resection of the tumor, were given to these patients. The VEGF-C expressions of 87 bladder tumors and 20 pelvic lymph node metastasis specimens were examined immunohistochemically and the association between VEGF-C expression and clinicopathological factors, including angiogenesis as evaluated by microvessel density (MVD), was also examined. Vascular endothelial growth factor-C expression was found in the cytoplasm of tumor cells, but not in the normal transitional epithelium. Vascular endothelial growth factor-C expression was significantly associated with the pathological T stage (P = 0.0289), pelvic lymph node metastasis (P < 0.0001), lymphatic involvement (P = 0.0008), venous involvement (P = 0.0002) and high MVD (P = 0.0043). The multivariate analysis demonstrated that VEGF-C expression and high MVD in bladder TCC were independent risk factors influencing the pelvic lymph node metastasis. Moreover, the patients with VEGF-C-positive tumors had significantly poorer prognoses than those with the VEGF-C-negative tumors (P = 0.0087) in the univariate analysis. The multivariate analysis based on Cox proportional hazard model showed that the independent prognostic factors were patient age (P = 0.0132) and pelvic lymph node metastasis (P = 0.0333). The present study suggests that VEGF-C expression is an important predictive factor of pelvic lymph node metastasis in bladder cancer patients.

Expression levels of transcription factors c-Fos and c-Jun and transmembrane protein HAb18G/CD147 in urothelial carcinoma of the bladder.

PubMed

Huhe, Muren; Liu, Shuangshuang; Zhang, Yang; Zhang, Zheng; Chen, Zhinan

2017-05-01

The aim of the present study was to investigate the prognostic significance of the expression of transcription factors, c-Fos, c-Jun and transmembrane protein CD147, in urothelial carcinoma of the bladder (UCB). The current study investigated the clinical significance of these factors in the development, progression and survival analysis of UCB. Immunohistochemistry was employed to analyze c‑Fos, c‑Jun and CD147 expression in 41 UCB cases and 34 non‑cancerous human bladder tissues. These results were scored in a semi‑quantitative manner based on the intensity and percentage of tumor cells that presented immunoreactivity. Protein levels of CD147, c‑Fos and c‑Jun expression were upregulated in 22 (53.7%), 10 (24.4%) and 9 (22.0%) UCB cases, respectively. High levels of c‑Jun correlated with the AJCC cancer staging manual (7th edition; P=0.038). Univariate analysis revealed that upregulated CD147 (P=0.038) or c‑Jun (P=0.008) was associated with poor overall survival (OS), respectively. Further analysis revealed that either CD147‑c‑Fos‑c‑Jun co‑expression (P=0.004), or CD147‑c‑Jun co‑expression (P=0.037) and c‑Fos‑c‑Jun co‑expression (P<0.001) were associated with poor OS. Multivariate analysis suggested that either upregulation of CD147, c‑Jun or c‑Fos were independent risk indicators for death in UCB patients. Increased expression of c‑Jun or CD147, as well as co‑expression of CD147‑c‑Jun, c‑Jun‑c‑Fos or CD147‑c‑Jun‑c‑Fos has prognostic significance for UCB patients. Therefore, high CD147 and c‑Jun expression may serve roles in tumor progression and may be diagnostic and therapeutic targets in UCB whether alone or in combination.

Differential expression of cancer associated proteins in breast milk based on age at first full term pregnancy.

PubMed

Qin, Wenyi; Zhang, Ke; Kliethermes, Beth; Ruhlen, Rachel L; Browne, Eva P; Arcaro, Kathleen F; Sauter, Edward R

2012-03-21

First full term pregnancy (FFTP) completed at a young age has been linked to low long term breast cancer risk, whereas late FFTP pregnancy age confers high long term risk, compared to nulliparity. Our hypothesis was that proteins linked to breast cancer would be differentially expressed in human milk collected at three time points during lactation based on age at FFTP. We analyzed breast milk from 72 lactating women. Samples were collected within 10 days of the onset of lactation (baseline-BL), two months after lactation started and during breast weaning (W). We measured 16 proteins (11 kallikreins (KLKs), basic fibroblast growth factor, YKL-40, neutrophil gelatinase-associated lipocalin and transforming growth factor (TGF) β-1 and -2) associated with breast cancer, most known to be secreted into milk. During lactation there was a significant change in the expression of 14 proteins in women < 26 years old and 9 proteins in women > = 26 at FFTP. The most significant (p < .001) changes from BL to W in women divided by FFTP age (< 26 vs. > = 26) were in KLK3,6, 8, and TGFβ2 in women < 26; and KLK6, 8, and TGFβ2 in women > = 26. There was a significant increase (p = .022) in KLK8 expression from BL to W depending on FFTP age. Examination of DNA methylation in the promoter region of KLK6 revealed high levels of methylation that did not explain the observed changes in protein levels. On the other hand, KLK6 and TGFβ1 expression were significantly associated (r2 = .43, p = .0050). The expression profile of milk proteins linked to breast cancer is influenced by age at FFTP. These proteins may play a role in future cancer risk.

Functional Significance of VEGFR-2 on Ovarian Cancer Cells

PubMed Central

Spannuth, Whitney A.; Nick, Alpa M.; Jennings, Nicholas B.; Armaiz-Pena, Guillermo N.; Mangala, Lingegowda S.; Danes, Christopher G.; Lin, Yvonne G.; Merritt, William M.; Thaker, Premal H.; Kamat, Aparna A.; Han, Liz Y.; Tonra, James R.; Coleman, Robert L.; Ellis, Lee M.; Sood, Anil K.

2009-01-01

Vascular endothelial growth factor receptor (VEGFR) has recently been discovered on ovarian cancer cells, but its functional significance is unknown and is the focus of the current study. By protein analysis, A2780-par and HeyA8 ovarian cancer cell lines expressed VEGFR-1 and HeyA8 and SKOV3ip1 expressed VEGFR-2. By in situ hybridization (ISH), 85% of human ovarian cancer specimens showed moderate to high VEGFR-2 expression while only 15% showed moderate to high VEGFR-1 expression. By immunofluorescence, little or no VEGFR-2 was detected in normal ovarian surface epithelial cells, whereas expression was detected in 75% of invasive ovarian cancer specimens. To differentiate between the effects of tumor versus host expression of VEGFR, nude mice were injected with SKOV3ip1 cells and treated with either human VEGFR-2 specific antibody (1121B), murine VEGFR-2 specific antibody (DC101), or the combination. Treatment with 1121B reduced SKOV3ip1 cell migration by 68% (p < 0.01) and invasion by 72% (p < 0.01), but exposure to VEGFR-1 antibody had no effect. Treatment with 1121B effectively blocked VEGF-induced phosphorylation of p130Cas. In vivo, treatment with either DC101 or 1121B significantly reduced tumor growth alone and in combination in the SKOV3ip1 and A2774 models. Decreased tumor burden after treatment with DC101 or 1121B correlated with increased tumor cell apoptosis, decreased proliferative index, and decreased microvessel density. These effects were significantly greater in the combination group (p<0.001). We show functionally active VEGFR-2 is present on most ovarian cancer cells. The observed anti-tumor activity of VEGF-targeted therapies may be mediated by both anti-angiogenic and direct anti-tumor effects. PMID:19058181

Highly Purified Eicosapentaenoic Acid Increases Interleukin-10 Levels of Peripheral Blood Monocytes in Obese Patients With Dyslipidemia

PubMed Central

Satoh-Asahara, Noriko; Shimatsu, Akira; Sasaki, Yousuke; Nakaoka, Hidenori; Himeno, Akihiro; Tochiya, Mayu; Kono, Shigeo; Takaya, Tomohide; Ono, Koh; Wada, Hiromichi; Suganami, Takayoshi; Hasegawa, Koji; Ogawa, Yoshihiro

2012-01-01

OBJECTIVE It has recently been highlighted that proinflammatory (M1) macrophages predominate over anti-inflammatory (M2) macrophages in obesity, thereby contributing to obesity-induced adipose inflammation and insulin resistance. A recent clinical trial revealed that highly purified eicosapentaenoic acid (EPA) reduces the incidence of major coronary events. In this study, we examined the effect of EPA on M1/M2-like phenotypes of peripheral blood monocytes in obese dyslipidemic patients. RESEARCH DESIGN AND METHODS Peripheral blood monocytes were prepared from 26 obese patients without and 90 obese patients with dyslipidemia. Of the latter 90 obese patients with dyslipidemia, 82 patients were treated with or without EPA treatment (1.8 g daily) for 3 months. RESULTS Monocytes in obese patients with dyslipidemia showed a significantly lower expression of interleukin-10 (IL-10), an M2 marker, than those without dyslipidemia. EPA significantly increased serum IL-10 and EPA levels, the EPA/arachidonic acid (AA) ratio, and monocyte IL-10 expression and decreased the pulse wave velocity (PWV), an index of arterial stiffness, compared with the control group. After EPA treatment, the serum EPA/AA ratio was significantly correlated with monocyte IL-10 expression. Only increases in monocyte IL-10 expression and serum adiponectin were independent determinants of a decreased PWV by EPA. Furthermore, EPA significantly increased the expression and secretion of IL-10 in human monocytic THP-1 cells through a peroxisome proliferator–activated receptor (PPAR)γ-dependent pathway. CONCLUSIONS This study is the first to show that EPA increases the monocyte IL-10 expression in parallel with decrease of arterial stiffness, which may contribute to the antiatherogenic effect of EPA in obese dyslipidemic patients. PMID:22912426

Changes in the Expression and Distribution of Claudins, Increased Epithelial Apoptosis, and a Mannan-Binding Lectin-Associated Immune Response Lead to Barrier Dysfunction in Dextran Sodium Sulfate-Induced Rat Colitis

PubMed Central

Yuan, Bosi; Zhou, Shuping; Lu, Youke; Liu, Jiong; Jin, Xinxin; Wan, Haijun; Wang, Fangyu

2015-01-01

Background/Aims This animal study aimed to define the underlying cellular mechanisms of intestinal barrier dysfunction. Methods Rats were fed 4% with dextran sodium sulfate (DSS) to induce experimental colitis. We analyzed the sugars in 24-hour urine output by high pressure liquid chromatography. The expression of claudins, mannan-binding lectin (MBL), and MBL-associated serine proteases 2 (MASP-2) were detected in the colonic mucosa by immunohistochemistry; and apoptotic cells in the colonic epithelium were detected by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling method assay. Results The lactulose and sucralose excretion levels in the urine of rats with DSS-induced colitis were significantly higher than those in the control rats. Mannitol excretion was lower and lactulose/mannitol ratios and sucralose/mannitol ratios were significantly increased compared with those in the control group (p<0.05). Compared with the controls, the expression of sealing claudins (claudin 3, claudin 5, and claudin 8) was significantly decreased, but that of claudin 1 was increased. The expression of pore-forming claudin 2 was upregulated and claudin 7 was downregulated in DSS-induced colitis. The epithelial apoptotic ratio was 2.8%±1.2% in controls and was significantly increased to 7.2%±1.2% in DSS-induced colitis. The expression of MBL and MASP-2 in the intestinal mucosa showed intense staining in controls, whereas there was weak staining in the rats with colitis. Conclusions There was increased intestinal permeability in DSS-induced colitis. Changes in the expression and distribution of claudins, increased epithelial apoptosis, and the MASP-2-induced immune response impaired the intestinal epithelium and contributed to high intestinal permeability. PMID:25717051

Changes in the Expression and Distribution of Claudins, Increased Epithelial Apoptosis, and a Mannan-Binding Lectin-Associated Immune Response Lead to Barrier Dysfunction in Dextran Sodium Sulfate-Induced Rat Colitis.

PubMed

Yuan, Bosi; Zhou, Shuping; Lu, Youke; Liu, Jiong; Jin, Xinxin; Wan, Haijun; Wang, Fangyu

2015-11-23

This animal study aimed to define the underlying cellular mechanisms of intestinal barrier dysfunction. Rats were fed 4% with dextran sodium sulfate (DSS) to induce experimental colitis. We analyzed the sugars in 24-hour urine output by high pressure liquid chromatography. The expression of claudins, mannan-binding lectin (MBL), and MBL-associated serine proteases 2 (MASP-2) were detected in the colonic mucosa by immunohistochemistry; and apoptotic cells in the colonic epithelium were detected by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling method assay. The lactulose and sucralose excretion levels in the urine of rats with DSS-induced colitis were significantly higher than those in the control rats. Mannitol excretion was lower and lactulose/mannitol ratios and sucralose/mannitol ratios were significantly increased compared with those in the control group (p<0.05). Compared with the controls, the expression of sealing claudins (claudin 3, claudin 5, and claudin 8) was significantly decreased, but that of claudin 1 was increased. The expression of pore-forming claudin 2 was upregulated and claudin 7 was downregulated in DSS-induced colitis. The epithelial apoptotic ratio was 2.8%±1.2% in controls and was significantly increased to 7.2%±1.2% in DSS-induced colitis. The expression of MBL and MASP-2 in the intestinal mucosa showed intense staining in controls, whereas there was weak staining in the rats with colitis. There was increased intestinal permeability in DSS-induced colitis. Changes in the expression and distribution of claudins, increased epithelial apoptosis, and the MASP-2-induced immune response impaired the intestinal epithelium and contributed to high intestinal permeability.

Cloning, localization and differential expression of Neuropeptide-Y during early brain development and gonadal recrudescence in the catfish, Clarias gariepinus.

PubMed

Sudhakumari, Cheni-Chery; Anitha, Arumugam; Murugananthkumar, Raju; Tiwari, Dinesh Kumar; Bhasker, Dharavath; Senthilkumaran, Balasubramanian; Dutta-Gupta, Aparna

2017-09-15

Neuropeptide-Y (NPY) has diverse physiological functions which are extensively studied in vertebrates. However, regulatory role of NPY in relation to brain ontogeny and recrudescence with reference to reproduction is less understood in fish. Present report for the first time evaluated the significance of NPY by transient esiRNA silencing and also analyzed its expression during brain development and gonadal recrudescence in the catfish, Clarias gariepinus. As a first step, full-length cDNA of NPY was cloned from adult catfish brain, which shared high homology with its counterparts from other teleosts upon phylogenetic analysis. Tissue distribution revealed dominant expression of NPY in brain and testis. NPY expression increased during brain development wherein the levels were higher in 100 and 150days post hatch females than the respective age-matched males. Seasonal cycle analysis showed high expression of NPY in brain during pre-spawning phase in comparison with other reproductive phases. Localization studies exhibited the presence of NPY, abundantly, in the regions of preoptic area, hypothalamus and pituitary. Transient silencing of NPY-esiRNA directly into the brain significantly decreased NPY expression in both the male and female brain of catfish which further resulted in significant decrease of transcripts of tryptophan hydroxylase 2, catfish gonadotropin-releasing hormone (cfGnRH), tyrosine hydroxylase and 3β-hydroxysteroid dehydrogenase in brain and luteinizing hormone-β/gonadotropin-II (lh-β/GTH-II) in pituitary exhibiting its influence on gonadal axis. In addition, significant decrease of several ovary-related transcripts was observed in NPY-esiRNA silenced female catfish, indicating the plausible role of NPY in ovary through cfGnRH-GTH axis. Copyright © 2017 Elsevier Inc. All rights reserved.

Human NRDRB1, an alternatively spliced isoform of NADP(H)-dependent retinol dehydrogenase/reductase enhanced enzymatic activity of benzil.

PubMed

Yan, Yinxia; Song, Xuhong; Liu, Gefei; Su, Zhongjing; Du, Yongming; Sui, Xuxia; Chang, Xiaolan; Huang, Dongyang

2012-01-01

Human NRDRB1, a 226 amino acid alternatively spliced isoform of the NADP(H)- dependent retinol dehydrogenase/reductase (NRDR), lacks the complete coding region of exon 3, but preserves all the important functional motifs for NRDR catalytic activity. Nevertheless, its tissue distribution and physiological function remain to be elucidated. Expression of NRDRB1 and NRDR in cells and tissues was analyzed by semi-quantitative polymerase chain reaction (PCR) and western blot. NRDRB1 was expressed as a His(6) fusion protein and subjected to kinetics assays. Recombinant NRDRB1 had 1.2 to 8.6 fold higher k(cat)/K(m) values than recombinant NRDR, depending on the substrate. NRDRB1 catalyzed the NADPH-dependent reduction of α-dicarbonyl compounds, such as isatin, 9,10-phenanthrenequinone, and especially benzil. The significantly high catalytic activity and the relatively high expression in human liver of NRDRB1 conferred cellular resistance to benzil-induced cell toxicity and over-expression of NRDRB1 in low expressing Ec109 cells significantly enhanced cell tolerance toward benzil. Based on its substrate specificity, catalytic activity and relatively high expression in human liver tissue, our results suggest that NRDRB1, an alternatively spliced isoform of NRDR in vivo functions better than NRDR as a dicarbonyl reductase for xenobiotics containing reactive carbonyls. Our study is the first reporting this phenomenon of the enzymes involved in biochemical reactions. Copyright © 2012 S. Karger AG, Basel.