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Sample records for poor prognosis non-aml

  1. Podocalyxin is a marker of poor prognosis in colorectal cancer

    PubMed Central

    2014-01-01

    Background Over two decades ago, a proposal was that two different colorectal cancer (CRC) entities existed, based on tumour location either proximal (right) or distal (left) of the splenic flexure. Proximal and distal tumours exhibit different clinical, epidemiological, and biological characteristics. Improvement of the prognostic evaluation of CRC requires new molecular markers. Podocalyxin-like 1 (PODXL), an anti-adhesive transmembrane sialomucin, is associated with an aggressive tumour phenotype and poor prognosis. For colorectal cancer, it has been suggested to be a marker of poor prognosis. The aim of this study was to investigate the role of PODXL in CRC by use of a novel monoclonal antibody. Methods In 1983–2001, 840 consecutive colorectal cancer patients were treated at Helsinki University Central Hospital, of whom 767 were successfully scored for PODXL immunohistochemical expression from tumour tissue microarrays by use of a novel monoclonal in-house antibody. Associations of PODXL expression and tumour location with other clinicopathological variables were explored by Fisher’s exact-test, linear-by- linear association test, and binary logistic regression. Survival analyses were done by the Kaplan-Meier method and Cox proportional hazards model. Results PODXL protein expression was high in 44 (5.7%) specimens. High expression associated strongly with poor differentiation (p < 0.0001), advanced stage (p = 0.011), and location of the tumour in the right hemicolon (RHC) (p < 0.001). Tumours of the RHC were more poorly differentiated (p < 0.0001) and showed higher PODXL expression (p < 0.001). High PODXL expression associated significantly with higher risk for disease-specific death from CRC (hazard ratio (HR) = 2.00; 95% confidence interval (CI) 1.31–3.06, p = 0.001) and also in the subgroups of left hemicolon (LHC) cancers (HR = 2.60; 95% CI 1.45–4.66, p = 0.001) and rectal cancers (HR = 3.03; 95% CI 1.54–5

  2. SPOCK1 Overexpression Confers a Poor Prognosis in Urothelial Carcinoma

    PubMed Central

    Ma, Li-Jung; Wu, Wen-Jen; Wang, Yu-Hui; Wu, Ting-Feng; Liang, Peir-In; Chang, I-Wei; He, Hong-Lin; Li, Chien-Feng

    2016-01-01

    Purpose:The majority deaths of cancer patients are related to metastasis, thus genes associated with cell motility interest us. SPOCK1 was elected by data mining and serial evaluation. In addition, SPOCK1 has been reported to be highly expressed in different human cancers and been related to adverse outcomes. Therefore, we validate its prognostic significance in urothelial carcinoma (UC). Materials and Methods:Real-time RT-PCR assay was used to detect SPOCK1 transcript level in 27 urinary tract urothelial carcinoma (UTUC) and 27 urinary bladder urothelial carcinoma (UBUC) samples. Immunohistochemistry evaluated by H-score determined SPOCK1 expressions in 340 UTUCs and 295 UBUCs. The transcript and protein expression were correlated with clinicopathological features. Further evaluations of the prognostic significance of SPOCK1 for disease-specific survival (DSS) and metastasis-free survival (MeFS) were analyzed. Results:The expressions of SPOCK1 in UC were higher than those in normal urothelium by immunohistochemistry. The statistical analysis of clinicopathologic characteristics and immunohistochemistry showed that the higher expression of SPOCK1 was correlated to pT status (P<0.001), lymph node metastasis (UTUC, P=0.006; UBUC, P=0.033), higher histological grade (UTUC, P<0.001; UBUC, P<0.001), vascular invasion (UTUC, P<0.001; UBUC, P<0.001), perineurial invasion (UTUC, P<0.001; UBUC, P=0.001) and frequent mitosis (UTUC, P<0.001; UBUC, P=0.001). The prognosis of SPOCK1 of UC showed high SPOCK1 expression had significantly worse DSS and MeFS. Conclusions:The investigation demonstrated that the higher expression of SPOCK1 correlates with a poor prognosis in UC. PMID:26918061

  3. CYC1 Predicts Poor Prognosis in Patients with Breast Cancer

    PubMed Central

    Han, Yingyan; Sun, Shujuan; Zhao, Meisong; Zhang, Zeyu; Gong, Song; Gao, Peipei; Liu, Jia; Zhou, Jianfeng; Ma, Ding; Gao, Qinglei; Wu, Peng

    2016-01-01

    Cytochrome c-1 (CYC1) is an important subunit of mitochondrial complex III. However, its role in tumor progression is unclear. We found that CYC1 was upregulated in breast tumor tissues, especially in tissues with lymph node metastasis. And higher expression of CYC1 correlates with poor prognosis in breast cancer patients using online databases and tools. Then we confirmed that CYC1 contributed to metastasis and proliferation in two highly metastatic human breast cancer cell lines. Digging into the biological function of CYC1, we found the activity of mitochondrial complex III decreased due to silencing CYC1. Then the ratio of AMP to ATP increased and AMPK was activated. Analyzing units of other mitochondrial complexes, we did not find knockdown of CYC1 expression reduced expression of any other unit of OXPHOS. We concluded that CYC1 promoted tumor metastasis via suppressing activation of AMPK and contributed to tumor growth via facilitating production of ATP. Our results indicated that CYC1 plays crucial roles in breast cancer progression and might be a predictive factor assisting future patient diagnosis.

  4. Coping with Poor Prognosis in the Pediatric Intensive Care Unit.

    ERIC Educational Resources Information Center

    Waller, David A.; And Others

    1979-01-01

    The intensive care pediatrician who prophesies to parents that their child's illness is irreversible may encounter denial and hostility. Four cases are reported in which parents rejected their child's hopeless prognosis, counterprophesied miraculous cures, resolved to obtain exorcism, criticized the care, or accused nurses of neglect. Journal…

  5. Intestinal obstruction: predictor of poor prognosis in colorectal carcinoma?

    PubMed Central

    Mohd Suan, Mohd Azri; Tan, Wei Leong; Soelar, Shahrul Aiman; Ismail, Ibtisam; Abu Hassan, Muhammad Radzi

    2015-01-01

    OBJECTIVES: The goal of this study was to assess the relationship between intestinal obstruction and the prognosis of colorectal carcinoma. METHODS: Data pertaining to 4,501 colorectal carcinoma patients were extracted from the national colorectal registry and analysed. Survival analysis was performed using the Kaplan-Meier method. The log-rank test was used to compare the survival rate between patients with intestinal obstruction and those without intestinal obstruction. The p-values<0.05 were considered to indicate statistical significance. Simple Cox proportional hazards regression analysis was used to estimate the crude hazard ratio of mortality from colorectal cancer. RESULTS: Intestinal obstruction was reported in more than 13% of patients. The 3-year survival rate after treatment was 48.3% (95% confidence interval [CI], 43.9 to 52.8) for patients with intestinal obstruction (n=593) and 54.9% (95% CI, 53.1 to 56.6) for patients without intestinal obstruction (n=3,908). The 5-year survival rate for patients with intestinal obstruction was 37.3% (95% CI, 31.9 to 42.8), which was lower than that of patients without intestinal obstruction (45.6%; 95% CI, 43.5 to 47.7). After adjusting the hazard ratio for other prognostic variables, intestinal obstruction had a statistically significant negative correlation with the survival rate of colorectal cancer patients, with an adjusted hazard ratio of 1.22 (p=0.008). CONCLUSIONS: The presence of intestinal obstruction is associated with a lower survival rate among colorectal cancer patients. PMID:25868638

  6. Are Early Relapses in Advanced-Stage Ovarian Cancer Doomed to a Poor Prognosis?

    PubMed Central

    Vidal, Fabien; Guerby, Paul; Luyckx, Mathieu; Haddad, Pascale; Stoeckle, Eberhard; Morice, Philippe; Leblanc, Eric; Lecuru, Fabrice; Daraï, Emile; Classe, Jean Marc; Pomel, Christophe; Filleron, Thomas; Ferron, Gwenael; Querleu, Denis; Rafii, Arash

    2016-01-01

    Objective Early recurrence (ER) after completion of therapeutic regimen in advanced-stage ovarian cancer is a challenging clinical situation. Patients are perceived as invariably having a poor prognosis. We investigated the possibility of defining different prognostic subgroups and the parameters implicated in prognosis of ER patients. Study Design We analyzed a multi-centric database of 527 FIGO stage IIIC and IV ovarian cancer patients. We defined patients relapsing within 12 months as ER and investigated using Cox logistic regression the prognostic factors in ER group. We subsequently divided ER patients into good and poor prognosis groups according to a lower or higher overall survival (OS) at 12 months after relapse and determined parameters associated to poor prognosis. Results The median follow up was 49 months. One hundred and thirty eight patients recurred within 12 months. OS and Disease Free Survival (DFS) were 24.6 and 8.6 months, respectively, in this group of patients. Among the ER patients, 73 had a poor prognosis with an OS after relapse below 12 months (mean OS = 5.2 months) and 65 survived after one year (mean OS = 26.9 months). Residual disease (RD) after debulking surgery and mucinous histological subtype negatively impacted prognosis (HR = 1.758, p = 0.017 and HR = 8.641, p = 0.001 respectively). The relative risk of death within 12 months following relapse in ER patients was 1.61 according to RD status. However, RD did not affect DFS (HR = 0.889, p = 0.5). Conclusion ER in advanced-stage ovarian cancer does not inevitably portend a short-term poor prognosis. RD status after initial cytoreduction strongly modulates OS, that gives additional support to the concept of maximum surgical effort even in patients who will experience early recurrence. The heterogeneity in outcomes within the ER group suggests a role for tumor biology in addition to classical clinical parameters. PMID:26820579

  7. APOBEC family mutational signatures are associated with poor prognosis translocations in multiple myeloma

    PubMed Central

    Walker, Brian A; Wardell, Christopher P; Murison, Alex; Boyle, Eileen M; Begum, Dil B; Dahir, Nasrin M; Proszek, Paula Z; Melchor, Lorenzo; Pawlyn, Charlotte; Kaiser, Martin F; Johnson, David C; Qiang, Ya-Wei; Jones, John R; Cairns, David A; Gregory, Walter M; Owen, Roger G; Cook, Gordon; Drayson, Mark T; Jackson, Graham H; Davies, Faith E; Morgan, Gareth J

    2015-01-01

    We have sequenced 463 presenting cases of myeloma entered into the UK Myeloma XI study using whole exome sequencing. Here we identify mutations induced as a consequence of misdirected AID in the partner oncogenes of IGH translocations, which are activating and associated with impaired clinical outcome. An APOBEC mutational signature is seen in 3.8% of cases and is linked to the translocation mediated deregulation of MAF and MAFB, a known poor prognostic factor. Patients with this signature have an increased mutational load and a poor prognosis. Loss of MAF or MAFB expression results in decreased APOBEC3B and APOBEC4 expression, indicating a transcriptional control mechanism. Kataegis, a further mutational pattern associated with APOBEC deregulation, is seen at the sites of the MYC translocation. The APOBEC mutational signature seen in myeloma is, therefore, associated with poor prognosis primary and secondary translocations and the molecular mechanisms involved in generating them. PMID:25904160

  8. Circulating Carnosine Dipeptidase 1 Associates with Weight Loss and Poor Prognosis in Gastrointestinal Cancer

    PubMed Central

    Arner, Peter; Henjes, Frauke; Schwenk, Jochen M.; Darmanis, Spyros; Dahlman, Ingrid; Iresjö, Britt-Marie; Naredi, Peter; Agustsson, Thorhallur; Lundholm, Kent; Nilsson, Peter; Rydén, Mikael

    2015-01-01

    Background Cancer cachexia (CC) is linked to poor prognosis. Although the mechanisms promoting this condition are not known, several circulating proteins have been proposed to contribute. We analyzed the plasma proteome in cancer subjects in order to identify factors associated with cachexia. Design/Subjects Plasma was obtained from a screening cohort of 59 patients, newly diagnosed with suspected gastrointestinal cancer, with (n = 32) or without (n = 27) cachexia. Samples were subjected to proteomic profiling using 760 antibodies (targeting 698 individual proteins) from the Human Protein Atlas project. The main findings were validated in a cohort of 93 patients with verified and advanced pancreas cancer. Results Only six proteins displayed differential plasma levels in the screening cohort. Among these, Carnosine Dipeptidase 1 (CNDP1) was confirmed by sandwich immunoassay to be lower in CC (p = 0.008). In both cohorts, low CNDP1 levels were associated with markers of poor prognosis including weight loss, malnutrition, lipid breakdown, low circulating albumin/IGF1 levels and poor quality of life. Eleven of the subjects in the discovery cohort were finally diagnosed with non-malignant disease but omitting these subjects from the analyses did not have any major influence on the results. Conclusions In gastrointestinal cancer, reduced plasma levels of CNDP1 associate with signs of catabolism and poor outcome. These results, together with recently published data demonstrating lower circulating CNDP1 in subjects with glioblastoma and metastatic prostate cancer, suggest that CNDP1 may constitute a marker of aggressive cancer and CC. PMID:25898255

  9. Malignant Melanoma of the Urethra: A Rare Histologic Subdivision of Vulvar Cancer with a Poor Prognosis

    PubMed Central

    Günther, Veronika; Alkatout, I.; Lez, C.; Altarac, S.; Fures, R.; Cupic, H.; Persec, Z.; Hrgovic, Z.; Mundhenke, C.

    2012-01-01

    Malignant melanoma of the urethra is a rare tumour that is difficult to diagnose and treat, resulting in a poor prognosis. In this paper, we present the case of a 65-year-old woman who was referred to a gynaecologist because of a urethral mass that mimicked a caruncle. The tumour was removed by local excision, and a pathological analysis revealed a malignant melanoma. Distal urethrectomy was performed after three months with no evidence of residual tumour. There was no evidence of disease at a six-year followup. In this paper, we compare the epidemiology, treatment, staging, and prognosis of vulvar cancer in general to malignant melanoma of the vulva in particular. PMID:23320214

  10. MACC1 upregulation promotes gastric cancer tumor cell metastasis and predicts a poor prognosis*

    PubMed Central

    Xie, Qiu-ping; Xiang, Cheng; Wang, Gang; Lei, Ke-feng; Wang, Yong

    2016-01-01

    In various studies, metastasis associated with colon cancer 1 (MACC1) has been frequently reported to be abnormally highly expressed in human lung cancer, colon cancer, and hepatocellular carcinoma. Our study focuses on the association of MACC1 expression with gastric cancer (GC). During our experiment, the MACC1 expression was tested in 105 GC samples using an immunohistochemical (IHC) method. The clinical characteristics and prognosis of these patients were summarized. During analysis, MACC1 distribution in GC samples with distant metastasis was higher than that in normal samples and in tumors with no dissemination. Subsequently, a lower 5-year survival rate had a strong correlation with high MACC1 expression. As a consequence, the present results suggest that MACC1 is more frequently expressed in a poor prognosis phenotype of GC and acts as a promising prognostic prediction parameter for GC. PMID:27143263

  11. Low Expression of Mir-137 Predicts Poor Prognosis in Cutaneous Melanoma Patients

    PubMed Central

    Li, Nan

    2016-01-01

    Background The present study aimed to measure miR-137 expression in patients with cutaneous melanoma (CM) and to estimate the correlation of miR-137 expression and the prognosis of CM patients. Material/Methods The expression level of miR-137 was assayed by quantitative real-time PCR (qRT-PCR) and presented as mean ±SD. Chi-square was used to evaluate the relationship between miR-137 expression and clinical characteristics. We used a Kaplan-Meier survival curve to determine the overall survival rate of CM patients. Moreover, the correlation between miR-137 expression and the prognosis of CM patients was confirmed by Cox regression analysis. Results The relative expression of miR-137 in CM tissue was 1.59±0.43, while that in paired normal tissue was 2.41±0.54, which was significantly higher. Chi-square analysis showed statistical significance between miR-137 expression and clinical characteristics such as TNM stage, ulcer, and occurrence site (P<0.05). However, no association was found between miR-137 expression and age, sex, or family history (P>0.05). According to the survival curve outcome, patients with low miR-137 expression showed relatively higher mortality (P=0.000) and multivariate analysis verified that low expression of miR-137 predicted poor prognosis of CM patients (HR=8.531, 95% CI=2.950–24.668, P=0.000). Conclusions Compared with paired normal tissues, miR-137 expression was lower in CM tissues. Patients with low miR-137 expression had higher mortality than those with high miR-137 expression, suggesting that low miR-137 expression indicated poor prognosis for CM patients. PMID:26763596

  12. Low CDX1 expression predicts a poor prognosis for hepatocellular carcinoma patients after hepatectomy.

    PubMed

    Zheng, Hao; Yang, Yuan; Wang, Meng-Chao; Yuan, Sheng-Xian; Tian, Tao; Han, Jun; Ni, Jun-Sheng; Wang, Jian; Xing, Hao; Zhou, Wei-Ping

    2016-09-01

    The caudal-type homeobox 1 (CDX1) transcription factor is a member of the caudal-related homeobox transcription factor gene family and has been reported to be down-regulated in a variety of cancers. However, the expression status and significance of CDX1 in hepatocellular carcinoma (HCC) is still controversial, and little is known about the role of CDX1 in HCC·In our previous study, we investigated the expression and clinical significance of CDX1 in HCC samples from 313 HCC patients. We found CDX1 was strikingly down-regulated in HCC samples. CDX1 expression was associated with poor differentiation (P = 0.002), and patients with low CDX1 expression had a significantly poorer prognosis. A subgroup analysis revealed a difference in prognosis between groups with low and high CDX1 expression among patients who had tumors <5 cm in size and who were alpha-fetoprotein (AFP) negative. Moreover, low expression was more frequently observed in the early recurrence group (within 2 years, P = 0.002). In addition, multivariate Cox regression analysis indicated that the CDX1 expression level, tumor size, presence of hepatitis B e antigen (HBeAg), vascular invasion, and presence of hepatitis B surface antigen (HBsAg) were independent risk factors for HCC recurrence, and the CDX1 expression level, tumor size, tumor number, and presence of HBsAg were independent predictor of overall survival of HCC patients. In conclusion, the downregulation of CDX1 is associated with poor prognosis; and it may serve as a novel predictor of the prognosis of HCC patients after curative resection. PMID:27566019

  13. Long noncoding RNA SNHG1 predicts a poor prognosis and promotes hepatocellular carcinoma tumorigenesis.

    PubMed

    Zhang, Min; Wang, Wei; Li, Tianyue; Yu, Xiaodong; Zhu, Yufeng; Ding, Feng; Li, Dongsheng; Yang, Tao

    2016-05-01

    Hepatocellular carcinoma (HCC) is the main cause of cancer mortality worldwide. Its poor prognosis is mainly ascribed to high recurrence rate. Identifying novel prognostic biomarkers and therapeutic targets would be vital for HCC management. Long noncoding RNA (lncRNA) is a class of RNA with various roles in tumorigenesis. The aim of this study was to investigate the clinical significance and functions of lncRNA-small nucleolar RNA host gene 1 (SNHG1) in HCC. In this study, we found SNHG1 was upregulated in HCC tissues in comparison with adjacent liver tissues in both publicly available microarray data and our own cohort. High SNHG1 expression was correlated with large tumor size, poor differentiation, and aggressive BCLC stage. Kaplan-Meier survival analysis demonstrated that high SNHG1 expression predicts poor prognosis of HCC patients. Gain-of-function and loss-of function experiments showed that SNHG1 promotes HCC cells proliferation, cell cycle progression, and inhibits HCC cells apoptosis. Further experiments revealed that SNHG1 promotes HCC cells proliferation through inhibiting p53 and p53-target genes expression. Collectively, our results demonstrated the clinical prognostic significance and roles of SNHG1 in HCC, and suggested that SNHG1 may be considered as a prognostic biomarker and therapeutic target for HCC. PMID:27133041

  14. Aldehyde dehydrogenase 1A1 circumscribes high invasive glioma cells and predicts poor prognosis.

    PubMed

    Xu, Sen-Lin; Liu, Sha; Cui, Wei; Shi, Yu; Liu, Qin; Duan, Jiang-Jie; Yu, Shi-Cang; Zhang, Xia; Cui, You-Hong; Kung, Hsiang-Fu; Bian, Xiu-Wu

    2015-01-01

    Glioma is the most aggressive brain tumor with high invasiveness and poor prognosis. More reliable, sensitive and practical biomarkers to reveal glioma high invasiveness remain to be explored for the guidance of therapy. We herein evaluated the diagnostic and prognostic value of aldehyde dehydrogenase 1A1 (ALDH1A1) in the glioma specimens from 237 patients, and found that ADLH1A1 was frequently overexpressed in the high-grade glioma (WHO grade III-IV) as compared to the low-grade glioma (WHO grade I-II) patients. The tumor cells with ALDH1A1 expression were more abundant in the region between tumor and the borderline of adjacent tissue as compared to the central part of the tumor. ALDH1A1 overexpression was associated with poor differentiation and dismal prognosis. Notably, the overall and disease-free survivals of the patients who had ALDH1A1(+) tumor cells sparsely located in the adjacent tissue were much worse. Furthermore, ALDH1A1 expression was correlated with the "classical-like" (CL) subtype as we examined GBM specimens from 72 patients. Multivariate Cox regression analysis revealed that ALDH1A1 was an independent marker for glioma patients' outcome. Mechanistically, both in vitro and in vivo studies revealed that ALDH1A1(+) cells isolated from either a glioblastoma cell line U251 or primary glioblastoma cells displayed significant invasiveness, clonogenicity, and proliferation as compared to ALDH1A1(-) cells, due to increased levels of mRNA and protein for matrix metalloproteinase 2, 7 and 9 (MMP2, MMP7 and MMP9). These results indicate that ALDH1A1(+) cells contribute to the progression of glioma including invasion, proliferation and poor prognosis, and suggest that targeting ALDH1A1 may have important implications for the treatment of highly invasive glioma. PMID:26101711

  15. URI1 amplification in uterine carcinosarcoma associates with chemo-resistance and poor prognosis

    PubMed Central

    Wang, Yu; Garabedian, Michael J; Logan, Susan K

    2015-01-01

    Uterine carcinosarcoma (UCS) is a rare type of cancer and accounts for 5% of uterine malignancies. However, UCS patients suffer a high prevalence of chemo-resistance and a very poor prognosis compared to uterine cancer patients. URI is a chaperone with functions in transcription. We analyzed the somatic URI1 copy number variation in 57 post-menopausal non-metastatic UCS patients in comparison to 363 uterine corpus endometrial carcinomas. URI1 amplification was detected in 40% (23/57) of primary UCS and 5.5% (20/363) of uterine carcinomas. UCS patients with URI1 amplification exhibited 13% (3/23) tumor-free survival compared to 41% (14/34) in the absence of URI amplification (P=0.023). URI1 amplification (OR=6.54, P=0.027), weight (OR=1.068, P=0.024), hypertension (OR=3.35, P=0.044), and tumor stage (OR=2.358, P=0.018) associated with poor survival. Patients treated with hormone replacement therapy (OR=15.87, P=0.011) displayed enhanced overall survival. Combined radiation and chemotherapy improved patient survival (median survival=2043 days) compared to single (median survival=597 days) or no treatment (median survival=317 days, P=0.0016). Importantly, patients with URI1 amplification had poor response to adjuvant treatment compared to control group (P=0.013). Tumors with URI1 amplification displayed decreased transcription of genes encoding tumor suppressor and apoptotic regulators and increased expression of genes regulating oncogenesis, survival and metastasis. Overexpression of URI1 in a cultured cell model induced ATM expression and resistance to cisplatin. Our findings suggest that high prevalence in UCS may associate with poor prognosis and worse response to adjuvant treatment. PMID:26328264

  16. [HEMIHEPATECTOMY FOR RESECTABLE HEPATIC METASTASIS FROM COLORECTAL CANCER WITH POOR PROGNOSIS].

    PubMed

    Patyutko, Yu I; Kotelnikov, A G; Mamontov, K G; Podluzhny, D V; Ponomarenko, A A

    2015-01-01

    The current study aimed at improvement of treatment effects for patients with resectable metastases of colorectal cancer in the liver with a poor prognosis. Overall 437 patients were enrolled with metastatic colorectal cancer in the liver exhibiting at least one adverse factor of long-term prognosis: multiple metastases, bilobar liver metastases, large metastases, the presence of extrahepatic metastases, etc. Combined treatment was performed for 339 (78%) patients: combined treatment with adjuvant systemic chemotherapy (163 patients), combined treatment with perioperative systemic chemotherapy (54 patients), or combined treatment of perioperative regional chemotherapy (122 patients). Surgical treatment was performed in 66 (15%) patients. The remaining group of 32 (7%) patients with resectable metastases who received only systemic chemotherapy was considered separately. All liver resections were extensive due to the widespread metastases. The complication rate stood at 56%. Mortality among operated patients was 4%. Postoperative mortality and complications as well as the intraoperative blood loss were not statistically different in two groups. Adding bevacizumab to preoperative chemotherapy did not increase blood loss. After combined treatment with adjuvant chemotherapy a 5-year survival was 26 ± 4% that significantly outperforming a 5-year survival rate after surgery (17 ± 5%), after just drug treatment a 5-year survival has not been reached, and also after combined treatment with perioperative systemic chemotherapy (13 ± 5%) and not statistically significant exceeded a 5-year survival after combined treatment with perioperative regional chemotherapy (20 ±5%). Thus our study demonstrates the benefits of combined treatment with adjuvant systemic chemotherapy for resectable metastases of colorectal cancer in the liver with a poor prognosis. For initially unresectable metastases with extrahepatic manifestations of the disease treatment should be begun with

  17. Epidermal elafin expression is an indicator of poor prognosis in cutaneous graft-versus-host disease.

    PubMed

    Brüggen, Marie-Charlotte; Petzelbauer, Peter; Greinix, Hildegard; Contassot, Emmanuel; Jankovic, Dragana; French, Lars; Socié, Gérard; Rabitsch, Werner; Kuzmina, Zoya; Kalhs, Peter; Knobler, Robert; Stingl, Georg; Stary, Georg

    2015-04-01

    Graft-versus-host disease (GVHD) remains a common and potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation. In the skin, GVHD can present in an acute (aGVHD), chronic lichenoid (clGVHD), or chronic sclerotic form (csGVHD). Measuring peripheral blood levels of the keratinocyte-derived protease inhibitor elafin has recently emerged as a promising tool for the diagnosis of cutaneous aGVHD. We evaluated whether the analysis of elafin expression in skin would allow distinguishing aGVHD from drug hypersensitivity rashes (DHR) and whether cutaneous elafin expression would correlate with disease severity or altered prognosis of aGVHD and clGVHD/csGVHD. Skin biopsies from aGVHD (n=22), clGVHD (n=15), csGVHD (n=7), and DHR (n=10) patients were collected and epidermal elafin expression and its association with diverse clinical/histological parameters were analyzed. Acute GVHD and DHR displayed varying degrees of elafin expression. No elafin was detectable in csGVHD, whereas the molecule was increased in clGVHD as compared with aGVHD. Elafin-high aGVHD/clGVHD lesions presented with epidermal thickening and were associated with poor prognosis-i.e., decreased overall survival in aGVHD and corticosteroid resistance in clGVHD. Although cutaneous elafin does not seem to discriminate aGVHD from DHR lesions, our study strongly suggests an association between cutaneous elafin expression and poor prognosis for patients with cutaneous GVHD. PMID:25405322

  18. HLA-A11 is associated with poor prognosis in childhood acute lymphoblastic leukemia (ALL).

    PubMed

    Orgad, S; Cohen, I J; Neumann, Y; Vogel, R; Kende, G; Ramot, B; Zaizov, R; Gazit, E

    1988-12-01

    A possible association between HLA antigens, susceptibility or resistance to leukemia, and responsiveness to treatment has been studied in 144 patients with childhood acute lymphoblastic leukemia (ALL) and compared to other prognostic factors, i.e. white blood cell (WBC) counts, age at onset, sex, ethnic origin, and cell surface markers. All sequentially newly diagnosed children (97) comprised the group for the prospective study (PSG) and were followed for 6 years. The group included 37 patients classified as T-ALL, 41 as CALLA+, 27 as NULL, 12 as B and pre-B, and 27 unclassified patients, who were diagnosed before 1980. During the follow-up period, 45 patients of the PSG died. Forty-seven patients designated long-term survivors (LTS) have been followed 6-20 years after diagnosis, having completed a 3-5 year course of anti-leukemia therapy, and having remained disease free thereafter. High WBC counts at diagnosis and T-cell-surface markers were associated with poor prognosis, as were enthnic origin and specific HLA antigens. Thus, there was one (1) a significant increase in HLA-A30 and a decrease in HLA B-14 in the PSG Jewish patients; and (2) a complete absence of HLA-ALL in LTS while, in the PSG, 8 of 9 HLA-All-positive patients died during the follow-up period. This suggests that HLA-All is associated with poor prognosis in childhood ALL. PMID:3199882

  19. Elevated Aurora B expression contributes to chemoresistance and poor prognosis in breast cancer.

    PubMed

    Zhang, Yiqian; Jiang, Chunling; Li, Huilan; Lv, Feng; Li, Xiaoyan; Qian, Xiaolong; Fu, Li; Xu, Bo; Guo, Xiaojing

    2015-01-01

    Aurora-B is a major kinase responsible for appropriate mitotic progression. Elevated expression of Aurora-B has been frequently associated with several types of cancer, including breast cancer. However, it is not clear whether the alteration contributes to tumor responses to therapies and prognosis. In this study, we conducted immunohistochemistry using antibodies against Aurora-B, S1981p-ATM, Ki67, and p53 in paraffin-embedded tumor tissues from 312 invasive breast cancer patients. The correlation between disease-free-survival (DFS) and Aurora-B expression was analyzed using the Kaplan-Meier method and log-rank test. A Cox proportional hazards regression analysis was used to determine whether Aurora-B was an independent prognostic factor for breast cancer. We found that Aurora-B expression was correlated with the proliferation index (P < 0.001) and p53 expression (P = 0.014) in breast cancer tissues. Further we found that Aurora-B expression was associated with lymph node metastasis (P = 0.002) and histological grade (P = 0.001). Multivariate analyses indicated that elevated Aurora-B expression predicted a poor survival. In a subgroup of patients that received neoadjuvant chemotherapy, we found that elevated Aurora-B contributed to chemoresistance (P = 0.011). In conclusion, elevated Aurora-B expression in breast cancer patients contributes to chemoresistance and predicts poor prognosis. PMID:25755770

  20. Podocalyxin Is a Marker of Poor Prognosis in Pancreatic Ductal Adenocarcinoma

    PubMed Central

    Saukkonen, Kapo; Hagström, Jaana; Mustonen, Harri; Juuti, Anne; Nordling, Stig; Fermér, Christian; Nilsson, Olle; Seppänen, Hanna; Haglund, Caj

    2015-01-01

    Aim of the Study Podocalyxin-like 1 is a transmembrane glyco-protein whose overexpression associates in many cancers with poor prognosis and unfavorable clinicopathological characteristics. Until now, its prognostic value has never been studied in pancreatic ductal adenocarcinoma (PDAC). The aim of this study was to investigate podocalyxin expression in PDAC by a novel monoclonal antibody and a commercially available polyclonal antibody. Patients and Materials With tissue microarrays and immuno-histochemistry, podocalyxin expression evaluation involved 168 PDAC patients. The associa-tions of the podocalyxin tumor expression with clinicopathological variables were explored by Fisher’s exact test and the linear-by-linear test. Survival analyses were by Kaplan-Meier anal-ysis and the Cox proportional hazard model. Results The polyclonal antibody revealed membranous podocalyxin expression in 73 (44.0%) specimens and the monoclonal antibody was highly expressed in 36 (21.8%) cases. Membranous expression by the polyclonal antibody was associated with T classification (p=0.045) and perineural invasion (p=0.005), and high expression by the mono-clonal antibody with poor differentiation (p=0.033). High podocalyxin expression associated significantly with higher risk of death from PDAC by both the polyclonal antibody (hazard ratio (HR) = 1.62; 95% confidence interval (CI) 1.12-2.33; p=0.01) and the monoclonal antibody (HR = 2.10, 95% CI 1.38-3.20; p<0.001). The results remained significant in multivariate analysis, adjusted for age, gender, stage, lymph node ratio (≥/< 20%), and perivascular invasion (respectively as HR = 2.03; 95% CI 1.32-3.13, p=0.001; and as HR = 2.36; 95% CI 1.47-3.80, p<0.001). Conclusion We found podocalyxin to be an independent factor for poor prognosis in PDAC. To our knowledge, this is the first such report of its prognostic value. PMID:26053486

  1. Genetic Predictors of Poor Prognosis in Portuguese Patients with Juvenile Idiopathic Arthritis: Data from Reuma.pt

    PubMed Central

    Mourão, Ana Filipa; Santos, Maria José; Mendonça, Sílvia; Oliveira-Ramos, Filipa; Salgado, Manuel; Estanqueiro, Paula; Melo-Gomes, José; Martins, Fernando; Lopes, Ana; Bettencourt, Bruno Filipe; Bruges-Armas, Jácome; Costa, José; Furtado, Carolina; Figueira, Ricardo; Brito, Iva; Branco, Jaime; Fonseca, João Eurico; Canhão, Helena

    2015-01-01

    Introduction. This study aimed to assess the genetic determinants of poor outcome in Portuguese patients with juvenile idiopathic arthritis (JIA). Methods. Our study was conducted in Reuma.pt, the Rheumatic Diseases Portuguese Register, which includes patients with JIA. We collected prospectively patient and disease characteristics and a blood sample for DNA analysis. Poor prognosis was defined as CHAQ/HAQ >0.75 at the last visit and/or the treatment with biological therapy. A selected panel of single nucleotide polymorphisms (SNPs) associated with susceptibility was studied to verify if there was association with poor prognosis. Results. Of the 812 patients with JIA registered in Reuma.pt, 267 had a blood sample and registered information used to define “poor prognosis.” In univariate analysis, we found significant associations with poor prognosis for allele A of TNFA1P3/20 rs6920220, allele G of TRAF1/C5 rs3761847, and allele G of PTPN2 rs7234029. In multivariate models, the associations with TRAF1/C5 (1.96 [1.17–3.3]) remained significant at the 5% level, while TNFA1P3/20 and PTPN2 were no longer significant. Nevertheless, none of associations found was significant after the Bonferroni correction was applied. Conclusion. Our study does not confirm the association between a panel of selected SNP and poor prognosis in Portuguese patients with JIA. PMID:26504858

  2. Decreased FOXD3 Expression Is Associated with Poor Prognosis in Patients with High-Grade Gliomas

    PubMed Central

    Wang, Dongliang; Zhang, Qingjun; Xue, Yake; Jiao, Hongliang; Zhan, Lei; Ma, Qian; Wei, Xinting

    2015-01-01

    Background The transcription factor forkhead box D3 (FOXD3) plays important roles in the development of neural crest and has been shown to suppress the development of various cancers. However, the expression and its potential biological roles of FOXD3 in high-grade gliomas (HGGs) remain unknown. Methods The mRNA and protein expression levels of FOXD3 were examined using real-time quantitative PCR and western blotting in 23 HGG and 13 normal brain samples, respectively. Immunohistochemistry was used to validate the expression FOXD3 protein in 184 HGG cases. The association between FOXD3 expression and the prognosis of HGG patients were analyzed using Kaplan-Meier survival curves and Cox proportional hazards regression models. In addition, we further examined the effects of FOXD3 on the proliferation and serum starvation-induced apoptosis of glioma cells. Results In comparison to normal brain tissues, FOXD3 expression was significantly decreased in HGG tissues at both mRNA and protein levels. Immunohistochemistry further validated the expression of FOXD3 in HGG tissues. Moreover, low FOXD3 expression was significantly associated with poor prognosis in HGG patients. Depletion of FOXD3 expression promoted glioma cell proliferation and inhibited serum starvation-induced apoptosis, whereas overexpression of FOXD3 inhibited glioma cell proliferation and promoted serum starvation-induced apoptosis. Conclusions Our results indicated that FOXD3 might serve as an independent prognostic biomarker and a potential therapeutic target for HGGs, which warrant further investigation. PMID:26011451

  3. Chronic Activation of Innate Immunity Correlates With Poor Prognosis in Cancer Patients Treated With Oncolytic Adenovirus.

    PubMed

    Taipale, Kristian; Liikanen, Ilkka; Juhila, Juuso; Turkki, Riku; Tähtinen, Siri; Kankainen, Matti; Vassilev, Lotta; Ristimäki, Ari; Koski, Anniina; Kanerva, Anna; Diaconu, Iulia; Cerullo, Vincenzo; Vähä-Koskela, Markus; Oksanen, Minna; Linder, Nina; Joensuu, Timo; Lundin, Johan; Hemminki, Akseli

    2016-02-01

    Despite many clinical trials conducted with oncolytic viruses, the exact tumor-level mechanisms affecting therapeutic efficacy have not been established. Currently there are no biomarkers available that would predict the clinical outcome to any oncolytic virus. To assess the baseline immunological phenotype and find potential prognostic biomarkers, we monitored mRNA expression levels in 31 tumor biopsy or fluid samples from 27 patients treated with oncolytic adenovirus. Additionally, protein expression was studied from 19 biopsies using immunohistochemical staining. We found highly significant changes in several signaling pathways and genes associated with immune responses, such as B-cell receptor signaling (P < 0.001), granulocyte macrophage colony-stimulating factor (GM-CSF) signaling (P < 0.001), and leukocyte extravasation signaling (P < 0.001), in patients surviving a shorter time than their controls. In immunohistochemical analysis, markers CD4 and CD163 were significantly elevated (P = 0.020 and P = 0.016 respectively), in patients with shorter than expected survival. Interestingly, T-cell exhaustion marker TIM-3 was also found to be significantly upregulated (P = 0.006) in patients with poor prognosis. Collectively, these data suggest that activation of several functions of the innate immunity before treatment is associated with inferior survival in patients treated with oncolytic adenovirus. Conversely, lack of chronic innate inflammation at baseline may predict improved treatment outcome, as suggested by good overall prognosis. PMID:26310629

  4. CHKA mediates the poor prognosis of lung adenocarcinoma and acts as a prognostic indicator

    PubMed Central

    Zhang, Li; Chen, Ping; Yang, Shen; Li, Guodong; Bao, Wentao; Wu, Peng; Jiang, Shujuan

    2016-01-01

    Choline kinase α (CHKA), the enzyme that converts choline to phosphocholine, has been studied in human carcinogenesis widely. However, the expression and underlying clinicopathological characteristics of CHKA in lung adenocarcinoma remains elusive. In the present study, a tissue microarray of 119 pairs of lung adenocarcinoma samples and corresponding adjacent normal mucosae was used to analysis CHKA expression by immunohistochemistry, and CHKA was observed to exhibit enhanced expression in lung adenocarcinoma tissues. Elevated CHKA expression in lung adenocarcinoma tissues at the gene and protein level was observed. The levels of CHKA expression were closely associated with the poor prognosis status of lung adenocarcinoma patients. Furthermore, certain clinicopathological characteristics such as tumor diameter and differentiation were observed to be significant in those lung adenocarcinoma patients who displayed enhanced CHKA expression. The analysis of CHKA expression could provide a more precise way to predict the prognosis of lung adenocarcinoma patients. Collectively, the present study revealed a novel biomarker in lung adenocarcinoma, and indicated that CHKA may be a promising prognostic marker and therapeutic target for lung adenocarcinoma. PMID:27588131

  5. Identification and targeting of a TACE-dependent autocrine loopwhich predicts poor prognosis in breast cancer

    SciTech Connect

    Kenny, Paraic A.; Bissell, Mina J.

    2005-06-15

    The ability to proliferate independently of signals from other cell types is a fundamental characteristic of tumor cells. Using a 3D culture model of human breast cancer progression, we have delineated a protease-dependent autocrine loop which provides an oncogenic stimulus in the absence of proto-oncogene mutation. Inhibition of this protease, TACE/ADAM17, reverts the malignant phenotype by preventing mobilization of two crucial growth factors, Amphiregulin and TGF{alpha}. We show further that the efficacy of EGFR inhibitors is overcome by physiological levels of growth factors and that successful EGFR inhibition is dependent on reducing ligand bioavailability. Using existing patient outcome data, we demonstrate a strong correlation between TACE and TGF{alpha} expression in human breast cancers that is predictive of poor prognosis.

  6. Acute Escherichia coli Mastitis in Dairy Cattle: Diagnostic Parameters Associated with Poor Prognosis

    PubMed Central

    HAGIWARA, Seiichi; MORI, Kouichiro; OKADA, Hiroyuki; OIKAWA, Shin; NAGAHATA, Hajime

    2014-01-01

    ABSTRACT This study aimed to identify the diagnostic characteristics associated with poor prognosis and mortality in dairy cows with acute clinical Escherichia coli mastitis. On 17 dairy farms, 24 dairy cows with acute E. coli mastitis that had received therapeutic treatment were categorized into 2 groups by outcome: 17 cows that recovered (survivors) and 7 cows that died or were euthanized (non-survivors). Two days after onset of acute E. coli mastitis, dysstasia was observed in non-survivors, but not in survivors. Compared with survivors, significantly increased hematocrit (HCT) values and non-esterified fatty acid (NEFA) concentrations, and significantly decreased antithrombin activity and platelet counts were found in non-survivors on days 2 and 3 after therapy. Dysstasia, associated with decreased antithrombin activity and platelet counts, and with increased HCT and NEFA concentrations, was considered to be the major prognostic indicator associated with high mortality after therapeutic treatment in acute E. coli mastitis. PMID:25056677

  7. GLI1 expression is an important prognostic factor that contributes to the poor prognosis of rhabdomyosarcoma.

    PubMed

    Wang, Yuanyuan; Sun, Chao; Jiang, Jinfang; Xie, Yuwen; Li, Bingcheng; Cui, Xiaobin; Chen, Yunzhao; Liu, Chunxia; Li, Feng

    2016-03-01

    The GLI1 and MDM2 genes are amplified or exhibit copy number gains in rhabdomyosarcoma (RMS). Here, we used immunohistochemistry to determine the relationships between GLI1 and MDM2 protein expression and several clinicopathological variables of RMS. GLI1 and MDM2-positivity rates were 61.36% and 13.64%, respectively. GLI1 expression correlated with presence of the PAX3-FOXO1 fusion gene (P=0.040) and lymph node metastasis (P=0.034), and a significant association was found between GLI1 expression and overall survival (OS) (P=0.008). However, there was no association between MDM2 expression and any of the clinicopathological parameters or OS. Thus, GLI1 may be a biomarker of poor prognosis in RMS patients, and could itself be a therapeutic target. This contrasts with the apparent lack of clinical importance of MDM2 in RMS pathology, at least in the cohorts we examined. PMID:26544916

  8. Total corporal synechiae due to tuberculosis carry a very poor prognosis following hysteroscopic synechialysis.

    PubMed

    Bukulmez, O; Yarali, H; Gurgan, T

    1999-08-01

    Twelve consecutive patients with total corporal synechiae due to tuberculosis were reviewed in terms of intrauterine adhesion re-formation rate following hysteroscopic surgery. All patients presented with secondary amenorrhoea and infertility. The diagnosis was based on a 'glove finger appearance' at hysterosalpingography and classical laparoscopic and tubal biopsy findings. Intrauterine synechiae re-formation was assessed by postoperative hysterosalpingograms performed 3-4 months after the procedure. The 12 patients underwent 15 attempts for hysteroscopic lysis of total corporal synechiae. Three perforations occurred and all were managed with laparoscopic extracorporal suturing. Ultimately, adequate uterine cavity was obtained in all cases. Total intracorporal synechiae recurred in all patients at control postoperative hysterosalpingograms. We conclude that total corporal synechiae caused by tuberculosis, unlike other causes, carry a poor prognosis following hysteroscopic lysis. Surrogacy may be the only option for fertility in such couples. PMID:10438408

  9. Subclonal mutations in SETBP1 confer a poor prognosis in juvenile myelomonocytic leukemia

    PubMed Central

    Troup, Camille B.; Gelston, Laura C.; Haliburton, John; Chow, Eric D.; Yu, Kristie B.; Akutagawa, Jon; Taylor-Weiner, Amaro N.; Liu, Y. Lucy; Wang, Yong-Dong; Beckman, Kyle; Emanuel, Peter D.; Braun, Benjamin S.; Abate, Adam; Gerbing, Robert B.; Alonzo, Todd A.; Loh, Mignon L.

    2015-01-01

    Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasm of childhood associated with a poor prognosis. Recently, massively parallel sequencing has identified recurrent mutations in the SKI domain of SETBP1 in a variety of myeloid disorders. These lesions were detected in nearly 10% of patients with JMML and have been characterized as secondary events. We hypothesized that rare subclones with SETBP1 mutations are present at diagnosis in a large portion of patients who relapse, but are below the limits of detection for conventional deep sequencing platforms. Using droplet digital polymerase chain reaction, we identified SETBP1 mutations in 17/56 (30%) of patients who were treated in the Children’s Oncology Group sponsored clinical trial, AAML0122. Five-year event-free survival in patients with SETBP1 mutations was 18% ± 9% compared with 51% ± 8% for those without mutations (P = .006). PMID:25395418

  10. NEK2 regulates stem-like properties and predicts poor prognosis in hepatocellular carcinoma.

    PubMed

    Lin, Shuang; Zhou, Senjun; Jiang, Shaojie; Liu, Xiaolong; Wang, Yifan; Zheng, Xueyong; Zhou, Haimeng; Li, Xuhui; Cai, Xiujun

    2016-08-01

    NEK2 has been estimated to play an important role in cancer progression. However, its relevance in hepatocellular carcinoma (HCC) has not yet been explored. Immunohistochemistry revealed NEK2 expression was upregulated in HCC. NEK2-positive hepatocellular carcinoma patients were associated with poor prognosis after surgery compared with NEK2-negative patients based on Kaplan-Meier curves. Deletion of NEK2 reduced self-renewal properties and chemotherapeutic resistance, and decreased the stemness associated genes in cell lines. NEK2 was associated with unfavorable outcomes in HCC patients, and was revealed to regulate self-renewal property by means of Wnt/β-catenin signaling, and chemotherapeutic resistance by preferential regulation of the expression of ABCG2 and ALDH1A1 in HCC cells. PMID:27349376

  11. Multigenerational Positive Family History of Psychiatric Disorders Is Associated With a Poor Prognosis in Bipolar Disorder.

    PubMed

    Post, Robert M; Altshuler, Lori; Kupka, Ralph; McElroy, Susan L; Frye, Mark A; Rowe, Michael; Grunze, Heinz; Suppes, Trisha; Keck, Paul E; Leverich, Gabriele S; Nolen, Willem A

    2015-01-01

    The authors assessed how family history loading affected the course of illness in patients from the United States. A total of 676 outpatients with bipolar disorder from the United States rated their illness and provided a parental and grandparental history of mood disorder, substance abuse, and other clinical conditions. A positive family history for each illness was associated with almost all of the seven poor prognosis factors established in the study (abuse in childhood, early onset, anxiety and substance abuse comorbidity, rapid cycling, multiple episodes, and worsening of severity or frequency of episodes). Family history for psychiatric difficulties in parents and grandparents was associated with a more complex and difficult course of bipolar illness. PMID:26258489

  12. SOX2 Expression Is Regulated by BRAF and Contributes to Poor Patient Prognosis in Colorectal Cancer

    PubMed Central

    Lundberg, Ida V.; Löfgren Burström, Anna; Edin, Sofia; Eklöf, Vincy; Öberg, Åke; Stenling, Roger; Palmqvist, Richard; Wikberg, Maria L.

    2014-01-01

    Sporadic colorectal cancer (CRC) is a common malignancy and also one of the main causes of cancer deaths worldwide. Aberrant expression of the transcription factor SOX2 has recently been observed in several cancer types, but its role in CRC has not been fully elucidated. Here we studied the expression of SOX2 in 441 CRC patients by immunohistochemistry and related the expression to clinicopathological and molecular variables and patient prognosis. SOX2 was expressed in 11% of the tumors and was significantly associated to BRAFV600E mutation, but not to KRAS mutations (codon 12 and 13). SOX2 positivity was correlated to poor patient survival, especially in BRAFV600E mutated cases. In vitro studies showed that cells expressing the constitutively active BRAFV600E had increased SOX2 expression, a finding not found in cells expressing KRASG12V. Furthermore, blocking downstream BRAF signalling using a MEK-inhibitor resulted in a decreased expression of SOX2. Since SOX2 overexpression has been correlated to increased migration and invasion, we investigated the SOX2 expression in human CRC liver metastasis and found that a SOX2 positive primary CRC also had SOX2 expression in corresponding liver metastases. Finally we found that cells overexpressing SOX2 in vitro showed enhanced expression of FGFR1, which has been reported to correlate with liver metastasis in CRC. Our novel findings suggest that SOX2 expression is partly regulated by BRAF signalling, and an increased SOX2 expression may promote CRC metastasis and mediate a poor patient prognosis. PMID:25010701

  13. Fibroblast growth factor receptor 4 promotes progression and correlates to poor prognosis in cholangiocarcinoma

    SciTech Connect

    Xu, Yun-Fei; Yang, Xiao-Qing; Lu, Xiao-Fei; Guo, Sen; Liu, Yi; Iqbal, Mohammad; Ning, Shang-Lei; Yang, Hui; Suo, Ning; Chen, Yu-Xin

    2014-03-28

    Highlights: • FGFR4 is significantly related with N stage in IHCC, with T stage and TNM stage in PHCC. • FGFR4 is an independent prognostic factor in IHCC and PHCC. • FGFR4 promotes proliferation, invasion and EMT in cholangiocarinoma cell lines. • Inhibitor AP24354 can decrease proliferation, invasion and induce apoptosis of CCA. - Abstract: Fibroblast growth factor receptor 4 (FGFR4) is related to poor prognosis of several cancers, but the correlation between FGFR4 expression and cholangiocarcinoma (CCA) has not been well elucidated. We investigated the expression of FGFR4 in 83 intrahepatic cholangiocarcinomas (IHCCs), 75 perihilar cholangiocarcinomas (PHCCs) and 41 distal cholangiocarcinomas (DCCs) by immunohistochemistry (IHC), and subsequently evaluated association of FGFR4 with clinicopathologic parameters and survival rate. The rate of FGFR4 higher expression was 61.4% (51/83) in IHCCs, 53.3% (40/75) in PHCCs and 56.1% (23/41) in DCCs. FGFR4 expression was significantly related to poor prognosis of IHCC (P = 0.002) and PHCC (P = 0.019) with univariate analysis, and also identified as an independent prognostic factor in IHCC (P = 0.045) and PHCC (P = 0.049) with multivariate analysis. Additionally, with functional assays in vitro, we found FGFR4 can induce proliferation, invasion and epithelial–mesenchymal transition (EMT) of CCA cell lines with FGF19 stimulation. Moreover, FGFR4 inhibitor AP24354 can suppress proliferation, invasion and induce apoptosis of CCA cells. In conclusion, FGFR4 expression can be identified as a significant independent prognostic biomarker of IHCC and PHCC. FGFR4 played a pivotal role in proliferation, invasion and EMT of CCA. FGFR4 inhibitor can suppress proliferation, invasion and induce apoptosis of CCA, indicating that FGFR4 may act as a potential therapeutic target.

  14. Overexpression of the PSAT1 Gene in Nasopharyngeal Carcinoma Is an Indicator of Poor Prognosis

    PubMed Central

    Liao, Kuang-Ming; Chao, Tung-Bo; Tian, Yu-Feng; Lin, Ching-Yih; Lee, Sung-Wei; Chuang, Hua-Ying; Chan, Ti-Chun; Chen, Tzu-Ju; Hsing, Chung-Hsi; Sheu, Ming-Jen; Li, Chien-Feng

    2016-01-01

    Purpose: Nasopharyngeal carcinoma (NPC) is a common cancer in southern China and Southeast Asia, but risk stratification and treatment outcome in NPC patients remain suboptimal. Our study identified and validated metabolic drivers that are relevant to the pathogenesis of NPC using a published transcriptome. Phosphoserine aminotransferase 1 (PSAT1) is an enzyme that is involved in serine biosynthesis, and its overexpression is associated with colon cancer, non-small cell lung cancer and breast cancer. However, its expression has not been systemically evaluated in patients with NPC. Materials and Methods: We evaluated two public transcriptomes of NPC tissues and benign nasopharyngeal mucosal epithelial tissues that deposited in the NIH Gene Expression Omnibus database under accession number GSE34574 and GSE12452. We also performed immunohistochemical staining and assessment of PSAT1 in a total of 124 NPC patients received radiotherapy and were regularly followed-up until death or loss. The endpoints analyzed were local recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), disease-specific survival (DSS), and overall survival (OS). Results: We retrospectively evaluated 124 patients with NPC and found that high PSAT1 expression was associated with poor prognosis of NPC and indicator of advanced tumor stage. High PSAT1 expression also correlated with an aggressive clinical course, with significantly shorter DSS (HR= 2.856, 95% CI 1.599 to 5.101), DMFS (HR= 3.305, 95% CI 1.720 to 6.347), LRFS (HR= 2.834, 95% CI 1.376 to 5.835), and OS HR= 2.935, 95% CI 1.646-5.234) in multivariate analyses. Conclusions: Our study showed that PSAT1 is a potential prognostic biomarker and higher expression of PSAT1 is associated with a poor prognosis in NPC. PMID:27326252

  15. High preoperative blood levels of HE4 predicts poor prognosis in patients with ovarian cancer

    PubMed Central

    2012-01-01

    Abstract The aim of this study was to assess the clinical value of preoperative blood levels of HE4 as a predictor of overall survival in patients with ovarian cancer and to validate previous data of HE4 and the ROMA algorithm including HE4 and CA125 in discriminating benign and malignant ovarian tumors. Experimental design The preoperative plasma levels of HE4 and CA125 were analyzed with ELISA in 312 patients with adnexal lesions. Tumors were classified as benign (n= 206), borderline (i.e. low malignant potential tumors) (n= 25), and well (n= 14), moderately (n= 15), and poorly (n= 51) differentiated malignant. Results In univariate Cox regression analyses high levels (dichotomized at the median) of HE4, CA125, increased age (continuous variable), advanced-stage of disease 2–4, histological grade 3 and non-optimal tumor debulking at primary surgery were all significantly associated with shorter overall survival. A multivariate Cox regression model including pre-operative available covariates HE4 and CA125 both dichotomized at median in addition to age as continuous variable showed that high levels of HE4 was an independent prognostic marker for worse prognosis HR 2.02 (95% CI 1.1-3.8). In postmenopausal women the ROMA algorithm gave the highest AUC of 0.94 (95% CI, 0.90-0.97) which was higher than the separate markers HE4 AUC 0.91 (95% CI 0.86-0.95) and CA125 AUC 0.91(95% CI 0.87-0.96). Conclusions High concentration of plasma HE4 is an independent preoperative marker of poor prognosis in patients with ovarian cancer. The algorithm ROMA discriminates in postmenopausal women between malignant and benign tumors with an AUC of 0.94. PMID:22909379

  16. Epitope Spreading of Autoantibody Response to PLA2R Associates with Poor Prognosis in Membranous Nephropathy.

    PubMed

    Seitz-Polski, Barbara; Dolla, Guillaume; Payré, Christine; Girard, Christophe A; Polidori, Joel; Zorzi, Kevin; Birgy-Barelli, Eléonore; Jullien, Perrine; Courivaud, Cécile; Krummel, Thierry; Benzaken, Sylvia; Bernard, Ghislaine; Burtey, Stéphane; Mariat, Christophe; Esnault, Vincent L M; Lambeau, Gérard

    2016-05-01

    The phospholipase A2 receptor (PLA2R1) is the major autoantigen in idiopathic membranous nephropathy. However, the value of anti-PLA2R1 antibody titers in predicting patient outcomes is unknown. Here, we screened serum samples from 50 patients positive for PLA2R1 for immunoreactivity against a series of PLA2R1 deletion mutants covering the extracellular domains. We identified reactive epitopes in the cysteine-rich (CysR), C-type lectin domain 1 (CTLD1), and C-type lectin domain 7 (CTLD7) domains and confirmed the reactivity with soluble forms of each domain. We then used ELISAs to stratify 69 patients positive for PLA2R1 by serum reactivity to one or more of these domains: CysR (n=23), CysRC1 (n=14), and CysRC1C7 (n=32). Median ELISA titers measured using the full-length PLA2R1 antigens were not statistically different between subgroups. Patients with anti-CysR-restricted activity were younger (P=0.008), had less nephrotic range proteinuria (P=0.02), and exhibited a higher rate of spontaneous remission (P=0.03) and lower rates of renal failure progression (P=0.002) and ESRD (P=0.01) during follow-up. Overall, 31 of 69 patients had poor renal prognosis (urinary protein/creatinine ratio >4 g/g or eGFR<45 ml/min per 1.73 m(2) at end of follow-up). High anti-PLA2R1 activity and epitope spreading beyond the CysR epitope were independent risk factors of poor renal prognosis in multivariable Cox regression analysis. Epitope spreading during follow-up associated with disease worsening (n=3), whereas reverse spreading from a CysRC1C7 profile back to a CysR profile associated with favorable outcome (n=1). We conclude that analysis of the PLA2R1 epitope profile and spreading is a powerful tool for monitoring disease severity and stratifying patients by renal prognosis. PMID:26567246

  17. Downregulated Ku70 and ATM associated to poor prognosis in colorectal cancer among Chinese patients

    PubMed Central

    Lu, Yuanfang; Gao, Jingyan; Lu, Yuanming

    2014-01-01

    Background Double-strand DNA breaks (DSBs) are a key factor in carcinogenesis. The necessary repair of DSBs is pivotal in maintaining normal cell division. To address the relationship between altered expression of DSB repair of proteins Ku70 and ataxia-telangiectasia mutated (ATM) in colorectal cancer (CRC), we examined the expression levels and patterns of Ku70 and ATM in CRC samples. Methods Expression and coexpression of Ku70 and ATM were investigated by using real-time quantitative polymerase chain reaction assays and confirmed further with fluorescent immunohistochemistry in CRC and pericancerous samples from 112 Chinese patients. Results Downexpression patterns for both Ku70 and ATM were found in the CRC samples and were significantly associated with advanced tumor node metastasis stage and decreased 5-year overall survival rate. Conclusion Downregulated Ku70 and ATM were associated with poor disease-free survival. Loss of Ku70 and ATM expression might act as a biomarker to predict poor prognosis in patients with CRC. PMID:25368522

  18. Periostin in tumor microenvironment is associated with poor prognosis and platinum resistance in epithelial ovarian carcinoma

    PubMed Central

    Sung, Pi-Lin; Jan, Yi-Hua; Lin, Shih-Chieh; Huang, Chao-Cheng; Lin, Hao; Wen, Kuo-Chang; Chao, Kuan-Chong; Lai, Chiung-Ru; Wang, Peng-Hui; Chuang, Chi-Mu; Wu, Hua-Hsi; Twu, Nae-Fang; Yen, Ming-Shyen; Hsiao, Michael; Huang, Chi-Ying F.

    2016-01-01

    The interplay between tumor microenvironment and cancer that causes chemoresistance remains unclear. By analyzing public available microarray datasets, we identified that periostin (POSTN) was overexpressed in cancer stroma in epithelial ovarian cancer (EOC) patients. Immunohistochemistry analysis showed overexpression of stromal POSTN is a powerful independent poor prognostic predictor for EOC patients. Furthermore, patients with high levels of stromal POSTN tend to have higher percentage of cisplatin resistance compared to those with low levels of stromal POSTN. Moreover, we found POSTN treatment can induce cisplatin resistant and activate AKT pathway in A2780 cells in vitro. Inhibition of AKT activity by AKT inhibitor MK-2206 abolished POSTN-induced AKT activation and cisplatin resistance in vitro. Taken together, we found high POSTN expression in cancer microenvironment is correlated with poor prognosis in EOC patients and associated with platinum resistance. The effect of POSTN in cancer stroma cells may activate AKT pathway in tumor and AKT inhibitor can be beneficial to augment the efficacy of existing cancer therapeutics. PMID:26716408

  19. Matrix-Gla protein promotes osteosarcoma lung metastasis and associates with poor prognosis.

    PubMed

    Zandueta, Carolina; Ormazábal, Cristina; Perurena, Naiara; Martínez-Canarias, Susana; Zalacaín, Marta; Julián, Mikel San; Grigoriadis, Agamemnon E; Valencia, Karmele; Campos-Laborie, Francisco J; Rivas, Javier De Las; Vicent, Silvestre; Patiño-García, Ana; Lecanda, Fernando

    2016-08-01

    Osteosarcoma (OS) is the most prevalent osseous tumour in children and adolescents and, within this, lung metastases remain one of the factors associated with a dismal prognosis. At present, the genetic determinants driving pulmonary metastasis are poorly understood. We adopted a novel strategy using robust filtering analysis of transcriptomic profiling in tumour osteoblastic cell populations derived from human chemo-naive primary tumours displaying extreme phenotypes (indolent versus metastatic) to uncover predictors associated with metastasis and poor survival. We identified MGP, encoding matrix-Gla protein (MGP), a non-collagenous matrix protein previously associated with the inhibition of arterial calcification. Using different orthotopic models, we found that ectopic expression of Mgp in murine and human OS cells led to a marked increase in lung metastasis. This effect was independent of the carboxylation of glutamic acid residues required for its physiological role. Abrogation of Mgp prevented lung metastatic activity, an effect that was rescued by forced expression. Mgp levels dramatically altered endothelial adhesion, trans-endothelial migration in vitro and tumour cell extravasation ability in vivo. Furthermore, Mgp modulated metalloproteinase activities and TGFβ-induced Smad2/3 phosphorylation. In the clinical setting, OS patients who developed lung metastases had high serum levels of MGP at diagnosis. Thus, MGP represents a novel adverse prognostic factor and a potential therapeutic target in OS. Microarray datasets may be found at: http://bioinfow.dep.usal.es/osteosarcoma/ Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID:27172275

  20. Periostin in tumor microenvironment is associated with poor prognosis and platinum resistance in epithelial ovarian carcinoma.

    PubMed

    Sung, Pi-Lin; Jan, Yi-Hua; Lin, Shih-Chieh; Huang, Chao-Cheng; Lin, Hao; Wen, Kuo-Chang; Chao, Kuan-Chong; Lai, Chiung-Ru; Wang, Peng-Hui; Chuang, Chi-Mu; Wu, Hua-Hsi; Twu, Nae-Fang; Yen, Ming-Shyen; Hsiao, Michael; Huang, Chi-Ying F

    2016-01-26

    The interplay between tumor microenvironment and cancer that causes chemoresistance remains unclear. By analyzing public available microarray datasets, we identified that periostin (POSTN) was overexpressed in cancer stroma in epithelial ovarian cancer (EOC) patients. Immunohistochemistry analysis showed overexpression of stromal POSTN is a powerful independent poor prognostic predictor for EOC patients. Furthermore, patients with high levels of stromal POSTN tend to have higher percentage of cisplatin resistance compared to those with low levels of stromal POSTN. Moreover, we found POSTN treatment can induce cisplatin resistant and activate AKT pathway in A2780 cells in vitro. Inhibition of AKT activity by AKT inhibitor MK-2206 abolished POSTN-induced AKT activation and cisplatin resistance in vitro. Taken together, we found high POSTN expression in cancer microenvironment is correlated with poor prognosis in EOC patients and associated with platinum resistance. The effect of POSTN in cancer stroma cells may activate AKT pathway in tumor and AKT inhibitor can be beneficial to augment the efficacy of existing cancer therapeutics. PMID:26716408

  1. Expression of ADP-ribosyltransferase 1 Is Associated with Poor Prognosis of Glioma Patients.

    PubMed

    Li, Zhen; Yan, Xinling; Sun, Yuyan; Yang, Xiaoqing

    2016-01-01

    Glioma has a poor prognosis due to its rapid overgrowth, diffuse invasion, and chemotherapy resistance. The improvements in clinical outcome are still limited and the identification of novel biomarkers involved in the progression of gliomas is still under critical demands. Amino acid ADP-ribosyltransferase 1 (ART1) is an enzyme that catalyzes the mono-ADP-ribosylation, a reversible post-translational modification. For example, the mono-ADP-ribosylation of transcription factors can affect their binding to target gene promoters. However, the functional significance of ART1 in glioma has not been reported. We collected 107 glioma cases from Qianfoshan Hospital and Yidu Central Hospital of Weifang between April 2008 and September 2015 to analyze the prognosis value of ART1 in gliomas. RT-qPCR analysis showed that the expression level of ART1 mRNA in glioma tissues was 4-fold higher than that in normal brain tissues. According to the immunohistochemical staining results, 44 patients (41.1%) were categorized as ART1 positive (≥ 20% of stained glioma cells), while the other 63 patients (58.9%) categorized as ART1 negative (< 20% of stained glioma cells). Moreover, the mean percentage of ART1-positive cells was 43.7%, 53.6% and 64.2% in WHO grade II, III and IV specimens, respectively. Through univariate and multivariate analyses, we identified ART1 as an independent prognostic factor. We also found that ART1 overexpression in U251 glioblastoma cells could significantly decrease the susceptibility to vincristine, one of tubulin-targeted drugs, which is widely used in clinical treatment for glioma. Taken together, we propose that up-regulation of ART1 expression is associated with the aggressiveness of glioma. PMID:27466078

  2. HBV is a risk factor for poor patient prognosis after curative resection of hepatocellular carcinoma

    PubMed Central

    Li, Zhonghu; Zhao, Xin; Jiang, Peng; Xiao, Senlin; Wu, Guo; Chen, Kai; Zhang, Xi; Liu, Hui; Han, Xiuguo; Wang, Shuguang; Li, Xiaowu

    2016-01-01

    Abstract Controversy exists regarding pathological factors affecting the prognosis of hepatocellular carcinoma (HCC) patients with hepatitis B virus (HBV-HCC). Their postoperative clinical behaviors and the exact HBV Deoxyribonucleic Acid (DNA) thresholds that distinguish good and poor prognoses are unknown. This study aimed to compare clinicopathological, pre- and postoperative clinical factors and overall and recurrence-free survival (RFS) between HBV-HCC patients and nonhepatitis B and nonhepatitis C HCC (NBC-HCC) patients to determine the optimal prognostic HBV DNA threshold. Data from 1440 patients with HBV-HCC and NBC-HCC who underwent curative hepatectomy were retrospectively analyzed. Liver function in the HBV-HCC group was significantly worse than in the NBC-HCC group. Compared with NBC-HCC patients, HBV-HCC patients had significantly more vascular invasion and advanced HCC. The HBV-HCC patients also had significantly worse liver function and more complications. Further survival analysis showed significantly lower overall and RFS rates and a higher early recurrence rate in the HBV-HCC group. Univariate analysis indicated that HBV was a risk factor for overall and RFS. Finally, X-tile analysis revealed that the optimal HBV DNA cutoff points for predicting RFS and overall survival in HCC patients were 10,100 and 12,800 IU/mL, respectively. After hepatectomy for HCC, HBV-HCC patients had more complications and a worse prognosis than NBC-HCC patients. Antiviral therapy should be considered before hepatectomy in patients with high (more than approximately 104 IU/mL) HBV DNA levels. PMID:27495026

  3. Up-regulation of Tim-3 is associated with poor prognosis of patients with colon cancer

    PubMed Central

    Zhou, Encheng; Huang, Qing; Wang, Ji; Fang, Chengfeng; Yang, Leilei; Zhu, Min; Chen, Jianhui; Chen, Lihua; Dong, Milian

    2015-01-01

    Tim-3 (T cell immunoglobulin and mucin domain 3), belonging to the member of the novel Tim family, has been confirmed that it plays a critical negative role in regulating the immune responses against viral infection and carcinoma. Recently, it has also been reported that the over-expression of Tim-3 is associated with poor prognosis in solid tumors. However, the role of Tim-3 in colorectal cancer remains largely unknown. In the current study, we aim to investigate the expression of Tim-3 in colorectal carcinoma and discuss the relationship between Tim-3 expression and colon cancer prognosis, thus speculating the possible role of Tim-3 in colon cancer progression. Colon cancer tissues and paired normal tissue were obtained from 201 patients with colon cancer for preparation of tissue microarray. Tim-3 expression was evaluated by immunohistochemical staining. The Tim-3 expression level was evaluated by q-RT-PCR, western blot and immunocytochemistry in four colon cancer cell lines (HT-29, HCT116, LoVo, SW620). Tim-3 was expressed in 92.5% tumor tissue samples and 86.5% corresponding normal tissue samples. Expression of Tim-3 was significantly higher in tumor tissues than in normal tissues (P < 0.0001). Tim-3 expression in colon cancer tissues is in correlation with colon cancer lymphatic metastasis and TNM (P < 0.0001). Multivariate analysis demonstrated that Tim-3 expression could be a potential independent prognostic factor for colon cancer patients (P < 0.0001). Kaplan-Meier survival analysis result showed that patients with higher Tim-3 expression had a significantly shorter survival time than those with lower Tim-3 expression patients. Our results indicated that Tim-3 might participate in the tumorgenesis of colon cancer and Tim-3 expression might be a potential independent prognostic factor for patients with colorectal cancer. PMID:26339368

  4. Reduced miRNA-218 expression in pancreatic cancer patients as a predictor of poor prognosis.

    PubMed

    Li, B-S; Liu, H; Yang, W-L

    2015-01-01

    microRNA-218 (miR-218) is a vertebrate-specific miRNA that plays a crucial role in tumorigenesis and tumor progression. This study analyzed the miR-218 expression level and clinical significance in pancreatic cancer. One hundred and seven pairs of pancreatic cancer and adjacent normal tissues were analyzed by quantitative reverse-transcriptase polymerase chain reaction. The correlation between miR-218 expression and clinicopathological characters was determined by the two-sample Student t-test. The survival correlations were analyzed by the Kaplan-Meier method and Cox proportional hazards model. The relative expression of miR-218 in pancreatic cancer tissues (2.63 ± 1.59) was significantly lower than that in matched noncancerous pancreatic tissues (6.52 ± 2.50, P < 0.001). The low expression of miR-218 in the pancreatic cancer tissues were strongly correlated with the TNM classification (P = 0.02), distant metastasis (P = 0.001), and tumor differentiation (P = 0.003). The low level of miR-218 expression was significantly correlated with the shorter overall survival time of pancreatic cancer patients (5-year overall survival rate: 7.5 vs 34.9%; log-rank test: P < 0.001). Multivariate analyses confirmed that a low level of miR-218 expression was an independent predictor of poor prognosis in pancreatic cancer patients (Hazard ratio: 7.24; 95% confidence interval: 2.01-18.28; P = 0.007). Our findings suggested a significant downregulation in the expression of miR-218; this might have considerable potential value in the prognosis for pancreatic cancer. PMID:26662432

  5. Elevated expression of chloride intracellular channel 1 is correlated with poor prognosis in human gliomas

    PubMed Central

    2012-01-01

    Background Chloride intracellular channel 1 (CLIC1) is expressed ubiquitously in human tissues and is involved in the regulation of cell cycle, cell proliferation and differentiation. Recent studies have shown that CLIC1 is highly expressed in several human malignant tumors. However, its roles in human gliomas are still unclear. The aim of this study was to investigate the clinicopathological significance and prognostic value of CLIC1 expression in human gliomas. Methods CLIC1 expression in human gliomas and nonneoplastic brain tissues was measured by real-time quantitative RT-PCR assay and immunohistochemistry. Its association with clinicopathological factors or prognosis in patients with gliomas was statistically analyzed. Results The expression of CLIC1 at both mRNA and protein levels was significantly increased in high-grade (Grade III~IV) glioma tissues compared with that in low-grade (Grade I~II) and nonneoplastic brain tissues, and was up-regulated with ascending tumor World Health Organization (WHO) grades. The elevated expression of CLIC1 protein was also significantly correlated with low Karnofsky performance score (KPS) (P=0.008). Moreover, both univariate and multivariate analysis shown that high CLIC1 expression was significantly associated with poor prognosis in patients with gliomas (P<0.001 and P=0.01, respectively). In particular, the elevated CLIC1 expression also correlated with shorter overall survival in different glioma subgroups stratified according to the WHO grading. Conclusions Our data provide the first evidence that CLIC1 expression might play an important role in the regulation of aggressiveness in human gliomas. The elevated expression of CLIC1 might represent a valuable prognostic marker for this disease. PMID:22578365

  6. Downregulation of microRNA-504 is associated with poor prognosis in high-grade glioma

    PubMed Central

    Guan, Yanlei; Chen, Ling; Bao, Yijun; Pang, Chao; Cui, Run; Li, Guangyu; Liu, Jiyuan; Wang, Yunjie

    2015-01-01

    Several previous reports indicated that microRNA-504 (miR-504) has an oncogenic function through negatively regulating p53. On the other hand, a recent study revealed that miR-504 inhibits cancer cell proliferation through targeting CDK6 in hypopharyngeal squamous cell carcinoma (HSCC), suggesting the tumor suppressive role of this miRNA. However, the role of miR-504 in human malignant glioma remains unclear. Therefore, the aim of this study was to investigate the clinical significance of miR-504 expression in high pathological grade glioma. Quantitative real-time reverse transcriptive-PCR (qRT-PCR) was performed to examine miR-504 expression levels in 63 glioma tissues including 13 anaplastic astrocytomas (AA, WHO grade III) and 50 glioblastomas (GBM, WHO grade IV), as well as 10 non-neoplastic brain tissues. Associations between miR-504 expression and clinicopathological factors and prognosis of glioma patients were statistically analyzed. MiR-504 showed significant decreased expression levels both in AAs and GBMs relative to non-neoplastic brains (P ≤ 0.001, respectively). Additionally, low expression level of miR-504 was significantly associated with advanced WHO grade (P = 0.01). Moreover, Kaplan-Meier survival analysis showed that patients with low expression of miR-504 had significantly poor survival rate (P = 0.002). Cox regression analysis showed that miR-504 expression was independent prognosis-predicting factor for malignant glioma patients (P = 0.038; risk ration = 2.5). Our results suggest that miR-504 may be a prognostic predictor and be involved in tumorigencity as a tumor suppressor of malignant glioma. PMID:25755767

  7. Overexpression of chaperonin containing TCP1, subunit 3 predicts poor prognosis in hepatocellular carcinoma

    PubMed Central

    Cui, Xiao; Hu, Zhi-Ping; Li, Zhao; Gao, Peng-Ji; Zhu, Ji-Ye

    2015-01-01

    AIM: To investigate the value of chaperonin containing TCP1, subunit 3 (CCT3) to predict the prognosis of patients with hepatocellular carcinoma (HCC) and determine its function in HCC progression. METHODS: CCT3 expression levels were examined in human non-cancerous liver tissues and a variety of HCC cell lines by quantitative real-time PCR and immunoblotting. CCT3 expression was suppressed by small interfering RNA. The effects of reducing CCT3 expression in HCC cells were tested. The 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide (MTT) assay, cell counting experiment, cell cycle assay, apoptosis assay and invasion assay were employed to evaluate cell functions in vitro. Immunohistochemistry was performed on HCC specimens. In addition, CCT3 expression in HCC specimens was also assessed at the protein and mRNA level. Associations between clinicopathological characteristics and prognosis were analyzed, along with the possible mechanisms involved in CCT3’s function in HCC progression. RESULTS: The expression levels of CCT3 mRNA and protein were upregulated in HCC cell lines in contrast to adjacent non-cancerous tissues. Reducing CCT3 expression not only suppressed cell proliferation in cell counts, MTT assay, cell cycle assay and induced cell apoptosis (P < 0.05 vs negative control), but also inhibited the tumor cell invasion capacity in vitro (P < 0.01 vs negative control). Overexpression of CCT3 in the nuclei of cancer cells in HCC specimens (58 of 104 patients, 55.8%) was associated with poor prognosis in HCC patients (3-year survival rate, 55.5% vs 84.2%, P = 0.020) after hepatectomy. Mechanistic analyses showed that signal transducer and activator of transcription 3 (STAT3) activation was decreased even when stimulated by interleukin-6 after knocking down CCT3 in the HepG2 cell line. CONCLUSION: Overexpression of CCT3 in the nuclei of cancerous cells is associated with HCC progression. CCT3 may be a target that affects the activation of STAT3 in

  8. Down-regulation of sirtuin 3 is associated with poor prognosis in hepatocellular carcinoma after resection

    PubMed Central

    2014-01-01

    Background Sirtuin 3 (Sirt3), one of the seven Sirtuins family members, plays critical roles in the progression of multiple cancer types. However, its role in the prognosis of hepatocellular carcinoma (HCC) has not yet been investigated systematically. Methods The correlation of Sirtuins expression with prognosis of HCC was determined by immunohistochemistry (IHC) in a large HCC patient cohort (n = 342). Expression of Sirt3 in tumoral and peritumoral tissues of HCC patients were further determined by western blotting (WB). Results IHC and WB studies both showed a decreased expression of Sirt3 in tumoral tissues compared with peritumoral tissues (P = 0.003 for IHC, P = 0.0042 for WB). Decreased expression of Sirt3 in both tumoral and peritumoral tissues was associated with increased recurrence probability and decreased overall survival rate by univariate analyses (intratumoral Sirt3: P = 0.011 for TTR, P = 0.001 for OS; peritumoral Sirt3: P = 0.017 for TTR, P = 0.023 for OS), the prognostic value was strengthened by multivariate analyses (intratumoral Sirt3: P = 0.031 for TTR, P = 0.001 for OS; peritumoral Sirt3: P = 0.047 for TTR, P = 0.031 for OS). Intratumoral Sirt3 also showed a favorable prognostic value in patients with BCLC stage A (TTR, P = 0.011; OS, P < 0.001). In addition, we found that IHC studies of other sirtuin members showed a decreased expression of Sirt2, Sirt4 and Sirt5 and an increased expression of Sirt1, Sirt6 and Sirt7 in intratumoral tissues compared with peritumoral tissues. In contrast to Sirt3, other members did not showed a remarkable correlation with HCC prognosis. Conclusions Down-regulation of intratumoral and peritumoral Sirt3 were both associated with poor outcome in HCC, moreover, intratumoral Sirt3 was a favorable prognostic predictor in early stage patients. PMID:24774224

  9. Surgical Rehabilitation Techniques in Children with Poor Prognosis Short Bowel Syndrome.

    PubMed

    Dore, Mariela; Junco, Paloma Triana; Andres, Ane M; Sánchez-Galán, Alba; Amesty, Maria Virginia; Ramos, Esther; Prieto, Gerardo; Hernandez, Francisco; Lopez Santamaria, Manuel

    2016-02-01

    Intestinal failure (IF) requires a multidisciplinary management based on nutritional support, surgical and medical rehabilitation, and transplantation. The aim of this study is to review our experience with surgical rehabilitation techniques (SRTs: enteroplasty, Bianchi, Serial Transverse Enteroplasty Procedure [STEP]) in patients with short bowel syndrome (SBS) and poor prognosis due to complex abdominal pathology. We performed a single-center retrospective study of patients with IF evaluated for intestinal transplantation in the Intestinal Rehabilitation Unit who underwent an SRT. Nonparametric tests were used for statistical analysis.A total of 205 patients (107 males/98 females) with mean age of 25 ± 7 months were assessed for IF. A total of 433 laparotomies were performed on 130 patients including intestinal resection, enteroplasties, adhesiolysis, and transit reconstruction. SRT were performed in 22 patients: 12 enteroplasties, 8 STEPs, and 4 Bianchi procedures. All patients were parenteral nutrition (PN) dependent with different stages of liver disease: mild (13), moderate (5), and severe (4). The adaptation rate for patients who underwent enteroplasty, STEP, and Bianchi were 70, 63, and 25%, respectively, although the techniques are not comparable. Overall, intestinal adaptation was achieved in nine (41%) patients, and four (18%) patients showed significant reduction of PN needs. One child did not respond to SRT and did not meet transplantation criteria. The remaining eight (36%) patients were included on the waiting list for transplant: four were transplanted, two are still on the waiting list, and two died. Better outcomes were observed in milder cases of liver disease (mild 77%, moderate 40%, severe 25%) (p < 0.05). Conversely, a trend toward a poorer outcome was observed in cases with ultrashort bowel (p > 0.05). One patient required reoperation after a Bianchi procedure due to intestinal ischemia and six needed further re-STEP or adhesiolysis

  10. B7-H4 overexpression correlates with a poor prognosis for cervical cancer patients.

    PubMed

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

    2014-03-01

    Cervical cancer is a major global public health care concern and the second most commonly diagnosed malignancy among females worldwide. B7-H4 is an immunoregulatory protein that has been shown to be overexpressed in several types of cancer and is often associated with more advanced disease and poor prognosis. We investigated whether B7-H4 is a prognostic maker for cervical cancer by detecting its expression in cervical cancer specimens. Formalin-fixed, paraffin-embedded tissue blocks from cervical cancer were evaluated for B7-H4 expression by immunohistochemistry with free R software analysis. The intensity of B7-H4 immunoexpression was evaluated according to age, histological type, International Federation of Gynecology and Obstetrics (FIGO) stage, lymphovascular space invasion (LVSI) and lymph node status. We investigated the distribution and expression of B7-H4 in 102 cervical cancer specimens and determined the association between its expression and clinicopathological characteristics, including patient outcomes. Of the 102 specimens, 31 were found to be negative for B7-H4 immunoexpression, whereas 71 were B7-H4-positive. When classified by negative vs. positive expression, B7-H4 was not found to be associated with any of the clinicopathological parameters investigated. A positive B7-H4 expression significantly predicted poor overall survival (OS) when compared to negative expression (P<0.05). In the multivariate analysis, positive B7-H4 expression was identified as an independent prognostic factor for OS (P<0.05). Our data suggested that positive B7-H4 expression may be a useful biomarker in patients with cervical cancer likely to have an unfavorable clinical outcome. PMID:24649336

  11. p27 Loss Is Associated with Poor Prognosis in Gastroenteropancreatic Neuroendocrine Tumors

    PubMed Central

    Kim, Hee Sung; Lee, Hye Seung; Nam, Kyung Han; Choi, Jiwoon; Kim, Woo Ho

    2014-01-01

    Purpose Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) represent a heterogeneous disease group originating from the neuroendocrine cells. Identification of prognostic markers, related to neuroendocrine tissue-selective tumorigenesis, is necessary to find therapeutic targets. Materials and Methods A total of 327 patients with GEP-NETs were included in this study; there were 49 gastric, 29 duodenal, 49 pancreatic, 12 hepatobiliary, 33 appendiceal, 5 proximal colon, and 150 distal colon cases. We performed immunostaining with the tissue microarray method for menin, p27, and p18. Results We observed negative staining for menin, p27, and p18 in 34%, 21%, and 56% of GEP-NETs, respectively. The loss of p27, but not menin, was positively correlated with the grade of Ki-67. Menin–/p27–, menin–/p27+, menin+/p27–, and menin+/p27+ phenotype groups included 13%, 22%, 8%, and 57% of patients, respectively. A dichotomized comparison showed that menin– or p27– tumors were significantly associated with foregut and midgut localizations, high World Health Organization (WHO) grade, lymph node metastasis, and more advanced stage as compared to menin+/p27+ patients. Kaplan-Meier analysis for the overall survival showed that p27 loss was significantly associated with decreased survival. Multivariate analysis showed that p27 loss is an independent factor for poor overall survival. Conclusion Our results revealed that the loss of p27 is associated with poor prognosis and the menin-p27 pathway is important in the tumorigenesis of GEP-NETs. PMID:25036575

  12. Overexpression of MutSα Complex Proteins Predicts Poor Prognosis in Oral Squamous Cell Carcinoma

    PubMed Central

    Wagner, Vivian Petersen; Webber, Liana Preto; Salvadori, Gabriela; Meurer, Luise; Fonseca, Felipe Paiva; Castilho, Rogério Moraes; Squarize, Cristiane Helena; Vargas, Pablo Agustin; Martins, Manoela Domingues

    2016-01-01

    Abstract The DNA mismatch repair (MMR) system is responsible for the detection and correction of errors created during DNA replication, thereby avoiding the incorporation of mutations in dividing cells. The prognostic value of alterations in MMR system has not previously been analyzed in oral squamous cell carcinoma (OSCC). The study comprised 115 cases of OSCC diagnosed between 1996 and 2010. The specimens collected were constructed into tissue microarray blocks. Immunohistochemical staining for MutSα complex proteins hMSH2 and hMSH6 was performed. The slides were subsequently scanned into high-resolution images, and nuclear staining of hMSH2 and hMSH6 was analyzed using the Nuclear V9 algorithm. Univariable and multivariable Cox proportional hazard regression models were performed to evaluate the prognostic value of hMSH2 and hMSH6 in OSCC. All cases in the present cohort were positive for hMSH2 and hMSH6 and a direct correlation was found between the expression of the proteins (P < 0.05). The mean number of positive cells for hMSH2 and hMSH6 was 64.44 ± 15.21 and 31.46 ± 22.38, respectively. These values were used as cutoff points to determine high protein expression. Cases with high expression of both proteins simultaneously were classified as having high MutSα complex expression. In the multivariable analysis, high expression of the MutSα complex was an independent prognostic factor for poor overall survival (hazard ratio: 2.75, P = 0.02). This study provides a first insight of the prognostic value of alterations in MMR system in OSCC. We found that MutSα complex may constitute a molecular marker for the poor prognosis of OSCC. PMID:27258499

  13. Upregulation of CDK7 in gastric cancer cell promotes tumor cell proliferation and predicts poor prognosis.

    PubMed

    Wang, Qiuhong; Li, Manhua; Zhang, Xunlei; Huang, Hua; Huang, Jianfei; Ke, Jing; Ding, Haifang; Xiao, Jinzhang; Shan, Xiaohang; Liu, Qingqing; Bao, Bojun; Yang, Lei

    2016-06-01

    CDK7 has been known as a component of CDK activating kinase (CAK) complex, the complex was composed of CDK7, Cyclin H and RING finger protein Mat1 that contribute to cell cycle progression by phosphorylating other CDKs. In addition, the complex is also an essential component of general transcription factor TFIIH which controls transcription via activating RNA polymerase II by serines 5 and 7 phosphorylation of the carboxyl-terminal domain (CTD) of its largest subunit. However, the role of CDK7 in the pathogenesis of gastric cancer has not been identified. Our study showed that CDK7 was significantly upregulated and positively correlated with tumor grade, infiltration depth, lymph node, Ki-67, and predicted poor prognosis in 173 gastric cancer specimens by immunohistochemistrical analyses. Furthermore, in vitro results indicated that CDK7 promoted proliferation of gastric cancer cells by CCK8, clone formation analyses and flow cytometric analyses, while CDK7 knockdown led to decreased cell proliferation. Our study will provide a theoretical basis for the study of CDK7 in gastric cancer. PMID:27155449

  14. Underweight status predicts a poor prognosis in elderly patients with colorectal cancer

    PubMed Central

    Kaneko, Manabu; Sasaki, Shin; Ozaki, Kosuke; Ishimaru, Kazuhiro; Terai, Emi; Nakayama, Hiroshi; Watanabe, Toshiyuki

    2016-01-01

    The aim of the present study was to evaluate the effect of underweight status on the survival of elderly patients undergoing surgery for colorectal cancer (CRC). A total of 113 patients aged ≥75 years who underwent curative surgery for CRC were included. In addition to standard perioperative variables, body mass index (BMI) was assessed. The patients were categorized as underweight (BMI<18.5 kg/m2) or non-underweight (BMI≥18.5 kg/m2). The 3-year overall survival (OS) and cancer-specific survival (CSS) were analyzed. Of the 113 patients, 24 (21%) were underweight. The two groups were well-balanced regarding all factors evaluated. In the multivariate analysis, underweight status was an independent indicator of lower 3-year OS [hazard ratio (HR)=2.65; 95% confidence interval (CI): 1.08–6.50; P=0.033] and CSS (HR=3.51, 95% CI: 1.16–10.60; P=0.025) rates. Compared with the non-underweight group, the underweight group had significantly worse 3-year OS (66.7 vs. 86.5%, respectively; P=0.017) and CSS (74.1 vs. 90.9%, respectively; P=0.025) rates. Therefore, underweight status was a significant risk factor for poor survival in elderly CRC patients. The development of effective nutritional interventions may improve the prognosis of such patients. PMID:27602223

  15. Trop2 is overexpressed in gastric cancer and predicts poor prognosis

    PubMed Central

    Zhang, Shu; Yong, Hongmei; Wang, Wei; Zhou, Yan; Wang, Bing; Wen, Jinbo; Qiu, Zhenning; Ding, Guipeng; Feng, Zhenqing; Zhu, Jin

    2016-01-01

    The cell surface protein Trop2 is overexpressed in a variety of human cancers. Trop2 expression increases tumor development and metastasis and reduces patient survival. However, little is known about the role of Trop2 expression and its prognostic value in gastric cancer (GC), particularly in Chinese populations. We analyzed Trop2 expression in GC tissues collected from Chinese GC patients. Quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry on tissue microarrays were performed to assess levels of Trop2 mRNA and protein in GC, and correlations between Trop2 expression and clinical characteristics and prognosis were analyzed. Trop2 expression was higher in GC tissues than in neighboring non-tumor tissues. Increased Trop2 protein levels in GC were associated with increased differentiation, tumor node metastasis stage, tumor size, lymph node metastasis, distant metastasis, and H. pylori infection. GC patients with high Trop2 expression also had poor overall survival rates. These data suggest Trop2 is a useful prognostic biomarker for GC. PMID:26716416

  16. Abnormal expression of calcyphosine is associated with poor prognosis and cell biology function in colorectal cancer

    PubMed Central

    Shao, Weiwei; Wang, Quhui; Wang, Feiran; Jiang, Yasu; Xu, Meirong; Xu, Junfei

    2016-01-01

    The aim of this study was to investigate the calcyphosine (CAPS) expression in human colorectal cancer (CRC) and to explore its clinical and prognostic significances. CAPS expression was measured by Western blot, real-time polymerase chain reaction analysis, and immunohistochemistry. The relationships between the CAPS expression levels and the clinicopathological factors were investigated. The Kaplan–Meier method and log-rank test were used to investigate the overall survival of the patients. Moreover, the effects of CAPS on biological roles of CRC cells were also evaluated by MTT assay, colony formation assay, and transwell assay. CAPS was significantly overexpressed in cancerous tissue and CRC cell lines compared with adjacent nontumor tissue and a normal human intestinal epithelial cell line. Overexpression of CAPS was significantly associated with histological grade (P=0.004), invasive depth (P<0.001), lymph node metastasis (P=0.003), tumor node metastasis stage (P=0.017), and distant metastasis (P=0.042). Furthermore, silencing of CAPS expression in CRC cells inhibited their proliferation, colony formation, migration, and invasion. Kaplan–Meier survival analysis showed that high CAPS expression might demonstrate poor prognosis in CRC patients. Cox regression analysis revealed that CAPS expression was an independent prognostic factor of CRC. Our data suggested that the upregulation of CAPS might play a role in the carcinogenesis and progression of CRC. CAPS could be used as a potential diagnostic factor and be an independent good prognostic indicator for CRC patients. PMID:26889086

  17. Overexpression of HOXC8 is Associated With Poor Prognosis in Epithelial Ovarian Cancer.

    PubMed

    Lu, Shumin; Liu, Rong; Su, Min; Wei, Yingze; Yang, Shuyun; He, Song; Wang, Xia; Qiang, Fulin; Chen, Chen; Zhao, Shuyang; Qian, Li; Shao, Mengting; Mao, Guoxin

    2016-07-01

    Homeobox C8 (HOXC8) is a transcription factor that has been reported as a potential driver oncogene in several tumors and involved in the regulation of many cancer-related proteins. In this study, we investigated the expression and role of HOXC8 in ovarian cancer. Western blot and immunohistochemistry analyses were performed to detect the expression of HOXC8. Kaplan-Meier curve showed that high expression of HOXC8 was related to poor prognosis of patients with epithelial ovarian cancer (EOC). Starvation and refeeding assay were used to assess cell cycle, suggesting that HOXC8 played a critical role in EOC cell proliferation. HOXC8 depletion by small interfering RNA inhibited cell proliferation, migration, and induced apoptosis in EOC cells. Moreover, HOXC8 knockdown increased the expression of ZAC1. Owing to the overexpression of HOXC8, our findings implied that HOXC8 is involved in the progression of EOC and could be a potential therapeutical approach of EOC. PMID:26763553

  18. Upregulation of KPNβ1 in gastric cancer cell promotes tumor cell proliferation and predicts poor prognosis.

    PubMed

    Zhu, Jia; Wang, Yingying; Huang, Hua; Yang, Qichang; Cai, Jing; Wang, Qiuhong; Gu, Xiaoling; Xu, Pan; Zhang, Shusen; Li, Manhua; Ding, Haifang; Yang, Lei

    2016-01-01

    KPNβ1, also known as importin β, P97, is reported as one of soluble transport factors that mediates transportion of proteins and RNAs between the nucleus and cytoplasm in cellular process. Recent studies show that KPNβ1 is a tumor gene which is highly expressed in several malignant tumors such as ovarian cancer, cervical tumor, neck cancer, and lung cancer via promoting cell proliferation or inhibiting cell apoptotic pathways. However, the the role of KPNβ1 in gastric cancer remains unclear. In this study, Western blot and immunohistochemistrical analyses showed that KPNβ1 was significantly upregulated in clinical gastric cancer specimens compared with adjacent noncancerous tissues. KPNβ1 was positively correlated with tumor grade, Ki-67, and predicted poor prognosis of gastric cancer. More importantly, through starvation-refeeding model, CCK8 assay, flow cytometry, colony formation assays, the vitro studies demonstrated that KPNβ1 promoted proliferation of gastric cancer cells, while KPNβ1 knockdown led to decreased cell proliferation and arrested cell cycle at G1 phase. Furthermore, our results also indicated that KPNβ1 expression could result in docetaxel resistance. And, KPNβ1 could interact with Stat1, contributed to its nucleus import in gastric cancer cells. These findings provided a novel promising therapeutic targets for clinical treatment against human gastric cancer. PMID:26242264

  19. High Ki-67 Immunohistochemical Reactivity Correlates With Poor Prognosis in Bladder Carcinoma

    PubMed Central

    Luo, Yihuan; Zhang, Xin; Mo, Meile; Tan, Zhong; Huang, Lanshan; Zhou, Hong; Wang, Chunqin; Wei, Fanglin; Qiu, Xiaohui; He, Rongquan; Chen, Gang

    2016-01-01

    Abstract Ki-67 is considered as one of prime biomarkers to reflect cell proliferation and immunohistochemical Ki-67 staining has been widely applied in clinical pathology. To solve the widespread controversy whether Ki-67 reactivity significantly predicts clinical prognosis of bladder carcinoma (BC), we performed a comprehensive meta-analysis by combining results from different literature. A comprehensive search was conducted in the Chinese databases of WanFang, China National Knowledge Infrastructure and Chinese VIP as well as English databases of PubMed, ISI web of science, EMBASE, Science Direct, and Wiley online library. Independent studies linking Ki-67 to cancer-specific survival (CSS), disease-free survival (DFS), overall survival (OS), progression-free survival (PFS), and recurrence-free survival (RFS) were included in our meta-analysis. With the cut-off values literature provided, hazard ratio (HR) values between the survival distributions were extracted and later combined with STATA 12.0. In total, 76 studies (n = 13,053 patients) were eligible for the meta-analysis. It was indicated in either univariate or multivariate analysis for survival that high Ki-67 reactivity significantly predicted poor prognosis. In the univariate analysis, the combined HR for CSS, DFS, OS, PFS, and RFS were 2.588 (95% confidence interval [CI]: 1.623–4.127, P < 0.001), 2.697 (95%CI: 1.874–3.883, P < 0.001), 2.649 (95%CI: 1.632–4.300, P < 0.001), 3.506 (95%CI: 2.231–5.508, P < 0.001), and 1.792 (95%CI: 1.409–2.279, P < 0.001), respectively. The pooled HR of multivariate analysis for CSS, DFS, OS, PFS, and RFS were 1.868 (95%CI: 1.343–2.597, P < 0.001), 2.626 (95%CI: 2.089–3.301, P < 0.001), 1.104 (95%CI: 1.008–1.209, P = 0.032), 1.518 (95%CI: 1.299–1.773, P < 0.001), and 1.294 (95%CI: 1.203–1.392, P < 0.001), respectively. Subgroup analysis of univariate analysis by origin showed that Ki-67 reactivity significantly

  20. Decreased Expression of AZGP1 Is Associated with Poor Prognosis in Primary Gastric Cancer

    PubMed Central

    Chen, Yi-bing; Li, Yuan-fang; Jiang, Shan-shan; Wang, Wei; Pan, Ke; Zheng, Yan; Zhao, Bai-wei; Wang, Dan-dan; Chen, Yong-ming; Yang, Lei; Zhou, Zhi-wei; Xia, Jian-chuan

    2013-01-01

    Background 2-Zinc-glycoprotein 1 (AZGP1) is a multidisciplinary protein that participates in many important functions in the human body, including fertilization, immunoregulation and lipid mobilization. Recently, it has been shown that AZGP1 is also involved in carcinogenesis and tumor differentiation. In this study, we investigated the expression levels and prognostic value of AZGP1 in primary gastric cancers. Methods and Results We examined the expression of AZGP1 in 35 paired cancerous and matched adjacent noncancerous gastric mucosa tissues by real-time quantitative RT-PCR (qRT-PCR) and western blotting. Furthermore, we analyzed AZGP1 expression in 248 patients who underwent resection procedures between 2005 and 2007 using immunohistochemistry. The relationships between the AZGP1 expression levels, the clinicopathological factors, and patient survival were investigated. AZGP1 expression was significantly reduced at both the mRNA (P = 0.023) and protein levels (P = 0.019) in tumor tissue samples, compared with expression in matched adjacent non-tumor tissue samples. The immunohistochemical staining data showed that AZGP1 expression was significantly decreased in 52.8% (131/248) of gastric adenocarcinoma cases. Clinicopathological analysis showed that the reduced expression of AZGP1 was significantly correlated with tumor location (P = 0.011), histological grade (P = 0.005) and T stage (P = 0.008). Kaplan–Meier survival curves revealed that the reduced expression of AZGP1 was associated with a poor prognosis in gastric adenocarcinoma patients (P = 0.009). Multivariate Cox analysis identified AZGP1 expression was an independent prognostic factor for overall survival of gastric adenocarcinoma patients (HR = 1.681, 95% CI = 1.134–2.494, P = 0.011). Conclusions Our study suggests that AZGP1 might serve as a candidate tumor suppressor and a potential prognostic biomarker in gastric carcinogenesis. PMID:23935945

  1. High c-Cbl expression in gliomas is associated with tumor progression and poor prognosis

    PubMed Central

    JING, ZHITAO; LI, LONG; WANG, XIN; WANG, MINGHAO; CAI, YING; JIN, ZI; ZHANG, YE

    2016-01-01

    Casitas B-lineage lymphoma (c-Cbl) expression has been linked to the development of several types of cancer. However, no studies on the association of c-Cbl and glioma have been published thus far. The present study examined glioma samples obtained from 136 patients treated at The First Hospital of China Medical University (Shenyang, China) from January 2007 to December 2009, and the expression levels of c-Cbl in the samples were evaluated by reverse transcription-quantitative polymerase chain reaction, immunohistochemistry and western blotting. Kaplan-Meier survival curves were generated and subjected to Cox regression analysis. The messenger RNA and protein levels of c-Cbl were observed to be upregulated in high-grade glioma, compared with low-grade glioma. A multivariate analysis revealed that the protein levels of c-Cbl were independently associated with overall survival [hazard ratio (HR)=4.923, 95% confidence interval (CI)=3.163–7.662; P<0.001]. Furthermore, the grade of the glioma (according to the World Health Organization criteria) was observed to be independent prognostic factors for progression-free survival and overall survival time (HR=8.842, 95% CI=7.827–9.989; P<0.001, and HR=10.247, 95% CI=9.009–11.655; P<0.001, respectively). Kaplan-Meier analysis and log-rank test indicated that high protein expression levels of c-Cbl were significantly associated with overall and progression-free survival (P<0.001). To the best of our knowledge, these results provide the first evidence that the overexpression of c-Cbl is correlated with advanced clinicopathological features and poor prognosis in patients with glioma. PMID:27073553

  2. Aquaporin 1 Is an Independent Marker of Poor Prognosis in Lung Adenocarcinoma

    PubMed Central

    Yun, Sumi; Sun, Ping-Li; Jin, Yan; Kim, Hyojin; Park, Eunhyang; Park, Soo Young; Lee, Kyuho; Lee, Kyoungyul; Chung, Jin-Haeng

    2016-01-01

    Background: Aquaporin 1 (AQP1) overexpression has been shown to be associated with uncontrolled cell replication, invasion, migration, and tumor metastasis. We aimed to evaluate AQP1 expression in lung adenocarcinomas and to examine its association with clinicopathological features and prognostic significance. We also investigated the association between AQP1 overexpression and epithelial-mesenchymal transition (EMT) markers. Methods: We examined AQP1 expression in 505 cases of surgically resected lung adenocarcinomas acquired at the Seoul National University Bundang Hospital from 2003 to 2012. Expression of AQP1 and EMT-related markers, including Ecadherin and vimentin, were analyzed by immunohistochemistry and tissue microarray. Results: AQP1 overexpression was associated with several aggressive pathological parameters, including venous invasion, lymphatic invasion, and tumor recurrence. AQP1 overexpression tended to be associated with higher histological grade, advanced pathological stage, and anaplastic lymphoma kinase (ALK) translocation; however, these differences were not statistically significant. In addition, AQP1 overexpression positively correlated with loss of E-cadherin expression and acquired expression of vimentin. Lung adenocarcinoma patients with AQP1 overexpression showed shorter progression-free survival (PFS, 46.1 months vs. 56.2 months) compared to patients without AQP1 overexpression. Multivariate analysis confirmed that AQP1 overexpression was significantly associated with shorter PFS (hazard ratio, 1.429; 95% confidence interval, 1.033 to 1.977; p=.031). Conclusions: AQP1 overexpression was thereby concluded to be an independent factor of poor prognosis associated with shorter PFS in lung adenocarcinoma. These results suggested that AQP1 overexpression might be considered as a prognostic biomarker of lung adenocarcinoma. PMID:27271108

  3. Increased frequency of minimal homozygous deletions is associated with poor prognosis in primary malignant melanoma patients.

    PubMed

    Boi, Sebastiana; Tebaldi, Toma; Re, Angela; Cantaloni, Chiara; Adami, Valentina; Barbareschi, Mattia; Cristofolini, Mario; Pasini, Luigi; Quattrone, Alessandro

    2014-06-01

    Identification of prognostic melanoma-associated copy number alterations (CNAs) is still an area of active research. Here, we investigated by high-resolution array comparative genomic hybridization (aCGH) a cohort of 31 paraffin-preserved primary malignant melanomas (MMs), whose prognosis was not predictable on the basis of conventional histopathological parameters. Although we identified a variety of highly recurrent sites of genomic lesions, the total number of CNAs per patient was not a discriminator of MM outcome. Furthermore, validation of aCGH by quantitative PCR on an extended population of 65 MM samples confirmed the absence of predictive value for the most recurrent CNA loci. Instead, our analysis revealed specific prognostic potential of the frequency of homozygous deletions (representing less than 3% of the total CNAs on average per sample), which was strongly associated with sentinel lymph node (SLN) invasion (P = 0.003), and distant metastasis (P = 0.003). Increased number of homozygous deletions was also indicative of poor patient survival (P = 0.01), both in our samples and in an independent validation of public dataset of primary and metastatic MMs. Moreover, we identified 77 hotspots of minimal common homozygous deletions, enriched in genes involved in cell adhesion processes and cell-communication functions, which preferentially accumulated in primary MMs showing the most severe outcome. Therefore, specific loss of gene loci in regions of minimal homozygous deletion may represent a pivotal type of genomic alteration accumulating during MM progression with potential prognostic implication. PMID:24615732

  4. Overexpression of Rab27B is correlated with distant metastasis and poor prognosis in ovarian cancer

    PubMed Central

    Ren, Ping; Yang, Xiao-Qing; Zhai, Xiao-Lu; Zhang, Yu-Quan; Huang, Jian-Fei

    2016-01-01

    The secretory small guanosine-5′-triphosphate-binding enzyme, Rab27B, has been identified to be an oncogene that is involved in the progression of certain tumors. The current study was designed to evaluate the expression pattern of Rab27B in ovarian cancer (OC), borderline tumors and benign ovarian adenoid tumors, as well as its association with survival prognosis and clinical parameters. The expression of Rab27B protein was examined by immunohistochemistry in 204 patients who had undergone ovarian resection without preoperative systemic chemotherapy at the Surgical Department of the Affiliated Hospital of Nantong University (Nantong, China), including 57 benign ovarian adenoid tumors, 44 borderline tumors and 103 malignant tumors. Rab27B expression and clinicopathological features were analyzed with the χ2 test. Patient survival rate was analyzed with the Kaplan-Meier method. Univariate and multivariate analysis of the prognostic factors was performed using the Cox regression model. Increased expression of Rab27B was positively correlated with histological type (P=0.012), level of differentiation (P=0.015), lymph node metastasis (P=0.024), distant metastasis (P<0.001) and International Federation of Gynecology and Obstetrics stage (P=0.001). Survival analysis revealed an association between Rab27B-positivity and poor overall survival rate. Multivariate analysis indicated that Rab27B (P<0.031) and distant metastases (P=0.031) were independent prognostic factors for OC patients' survival. The results of the present study supported the hypothesis that Rab27B may be a valuable prognostic indicator in patients with OC. PMID:27446467

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

    PubMed

    Liu, Chenchen; Yue, Ben; Yuan, Chenwei; Zhao, Senlin; Fang, Changyi; Yu, Yang; Yan, Dongwang

    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) 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. PMID:26545775

  6. Increased Plasma Levels of Pentraxin 3 Are Associated with Poor Prognosis of Colorectal Carcinoma Patients.

    PubMed

    Zhang, Jie; Wang, Tai-Yong; Niu, Xue-Cai

    2016-01-01

    Colorectal carcinoma (CRC) is one of the most common cancers globally. It is essential to identify a prognostic predictor for CRC. Pentraxin 3 (PTX3) is a glycoprotein that is secreted by a variety of human cells. It plays an important role in inflammation and immune regulation. Increasing evidence reveals that elevated PTX3 expression is related to poor prognosis in various cancers. The aim of the study was to determine the usefulness of plasma PTX3 level as a prognostic predictor in CRC. Total 184 CRC patients and 216 controls were included. Plasma levels of PTX3 were determined using Enzyme-linked immunosorbent assays. On admission, plasma PTX3 levels in CRC patients were higher than those in controls (11.8 ± 2.5 ng/ml vs. 3.1 ± 0.9 ng/ml, P < 0.001). After resection, plasma PTX3 levels in patients were decreased (6.0 ± 1.4 ng/ml, P = 0.007), and were elevated at the time of relapse (10.8 ± 2.8 ng/ml, P < 0.001). During the 60-month follow-up period, 108 patients suffered from relapse. Plasma PTX3 levels of ≥ 12 ng/ml on admission were associated with relapse (OR: 3.11, 95% CI: 1.74 ~ 6.29), and tumor-free survival rate in those patients with plasma PTX3 levels of ≥ 12 ng/ml was lower than that in other patients (P = 0.001). Furthermore, plasma PTX3 levels on admission showed positive linear correlations with plasma complement 3, 4 and 5b9 levels (P < 0.001, P < 0.001, P < 0.001). Therefore, we propose that PTX3 is an independent prognostic indicator in CRC. PMID:27568661

  7. High expression of cellular retinol binding protein-1 in lung adenocarcinoma is associated with poor prognosis

    PubMed Central

    Doldo, Elena; Costanza, Gaetana; Ferlosio, Amedeo; Pompeo, Eugenio; Agostinelli, Sara; Bellezza, Guido; Mazzaglia, Donatella; Giunta, Alessandro; Sidoni, Angelo; Orlandi, Augusto

    2015-01-01

    Purpose Adenocarcinoma, the most common non-small cell lung cancer is a leading cause of death worldwide, with a low overall survival (OS) despite increasing attempts to achieve an early diagnosis and accomplish surgical and multimodality treatment strategies. Cellular retinol binding protein-1 (CRBP-1) regulates retinol bioavailability and cell differentiation, but its role in lung cancerogenesis remains uncertain. Experimental design CRBP-1 expression, clinical outcome and other prognostic factors were investigated in 167 lung adenocarcinoma patients. CRBP-1 expression was evaluated by immunohistochemistry of tissue microarray sections, gene copy number analysis and tumor methylation specific PCR. Effects of CRBP-1 expression on proliferation/apoptosis gene array, protein and transcripts were investigated in transfected A549 lung adenocarcinoma cells. Results CRBP-1High expression was observed in 62.3% of adenocarcinomas and correlated with increased tumor grade and reduced OS as an independent prognostic factor. CRBP-1 gene copy gain also associated with tumor CRBP-1High status and dedifferentiation. CRBP-1-transfected (CRBP-1+) A549 grew more than CRBP-1− A549 cells. At >1μM concentrations, all trans-retinoic acid and retinol reduced viability more in CRBP-1+ than in CRBP-1− A549 cells. CRBP-1+ A549 cells showed up-regulated RARα/ RXRα and proliferative and transcriptional genes including pAkt, pEGFR, pErk1/2, creb1 and c-jun, whereas RARβ and p53 were strongly down-regulated; pAkt/pErk/ pEGFR inhibitors counteracted proliferative advantage and increased RARα/RXRα, c-jun and CD44 expression in CRBP-1+ A549 cells. Conclusion CRBP-1High expression in lung adenocarcinoma correlated with increased tumor grade and reduced OS, likely through increased Akt/Erk/EGFR-mediated cell proliferation and differentiation. CRBP-1High expression can be considered an additional marker of poor prognosis in lung adenocarcinoma patients. PMID:26807202

  8. DEPTOR suppresses the progression of esophageal squamous cell carcinoma and predicts poor prognosis

    PubMed Central

    Zheng, Xiang; Li, Sheng-Bao; Wei, Zhi-Qiang; Liu, Tao; Cheng, Dong-Liang; Liu, Ping; Song, Kuncheng; Tan, Tao; Zhu, Hua; Guo, Jia-Long

    2016-01-01

    As a naturally occurring inhibitor of mTOR, accumulated evidence has suggested that DEPTOR plays a pivotal role in suppressing the progression of human malignances. However, the function of DEPTOR in the development of esophageal squamous cell carcinoma (ESCC) is still unclear. Here we report that the expression of DEPTOR is significantly reduced in tumor tissues derived from human patients with ESCC, and the downregulation of DEPTOR predicts a poor prognosis of ESCC patients. In addition, we found that the expression of DEPTOR negatively regulates the tumorigenic activities of ESCC cell lines (KYSE150, KYSE510 and KYSE190). Furthermore, ectopic DEPTOR expression caused a significant suppression of the cellular proliferation, migration and invasion of KYSE150 cells, which has the lowest expression level of DEPTOR in the three cell lines. Meanwhile, CRISPR/Cas9 mediated knockout of DEPTOR in KYSE-510 cells significantly promoted cellular proliferation, migration and invasion. In addition, in vivo assays further revealed that tumor growth was significantly inhibited in xenografts with ectopic DEPTOR expression as compared to untreated KYSE150 cells, and was markedly enhanced in DEPTOR knockout KYSE-510 cells. Biochemical studies revealed that overexpression of DEPTOR led to the suppression of AKT/mTOR pathway as evidenced by reduced phosphorylation of AKT, mTOR and downstream SGK1, indicating DEPTOR might control the progression of ESCC through AKT/mTOR signaling pathway. Thus, these findings, for the first time, demonstrated that DEPTOR inhibits the tumorigenesis of ESCC cells and might serve as a potential therapeutic target or prognostic marker for human patients with ESCC. PMID:26893358

  9. Cortactin is a sensitive biomarker relative to the poor prognosis of human hepatocellular carcinoma

    PubMed Central

    2013-01-01

    Background Cortactin is an important regulator involved in invasion and migration of hepatocellular carcinoma (HCC). The aim of this study was to elucidate the forecasting role of cortactin in resectable HCCs. Methods We compared the invasiveness and motility among liver epithelial cell line and HCC cell lines by using Transwell assay and wound healing assay. We further investigated the CTTN mRNA expression by real-time PCR. Next, 91 HCC and 20 normal liver tissue samples were detected by IHC and real-time PCR. Finally, we analyzed the clinicopathologic features and survival time of the HCC cases. Results We identified that HepG2, LM3, and SK-Hep-1 had more invasiveness and motility (P <0.05). Compared with liver epithelial cell line, CTTN expression was higher in LM3, HepG2, and MHCC97-L (P <0.01) and lower in SK-Hep-1 (P <0.05). IHC examination showed cortactin expression was closely relative to TNM stage (AJCC/UICC), cancer embolus, and metastasis (P <0.01). Cortactin overexpression indicated a longer survival time of 52 ± 8.62 months and low expression of a shorter survival time of 20 ± 4.95 months (P <0.01). Cortactin examination has more predictive power in patients with Child-Pugh grade A and BCLC stage 0-B. Conclusions Overexpression of cortactin is closely associated with poor human HCCs prognosis that caused by cancer embolus and metastasis. Cortactin and CTTN should be used for differentiating varieties of survival for patients after HCC resection. PMID:23518204

  10. PTEN gene mutations correlate to poor prognosis in glioma patients: a meta-analysis

    PubMed Central

    Han, Feng; Hu, Rong; Yang, Hua; Liu, Jian; Sui, Jianmei; Xiang, Xin; Wang, Fan; Chu, Liangzhao; Song, Shibin

    2016-01-01

    Background We conducted this meta-analysis based on eligible trials to investigate the relationship between phosphatase and tensin homolog (PTEN) genetic mutation and glioma patients’ survival. Methods PubMed, Web of Science, and EMBASE were searched for eligible studies regarding the relationship between PTEN genetic mutation and glioma patients’ survival. The primary outcome was the overall survival of glioma patient with or without PTEN genetic mutation, and second outcome was prognostic factors for the survival of glioma patient. A fixed-effects or random-effects model was used to pool the estimates according to the heterogeneity among the included studies. Results Nine cohort studies, involving 1,173 patients, were included in this meta-analysis. Pooled results suggested that glioma patients with PTEN genetic mutation had a significant shorter overall survival than those without PTEN genetic mutation (hazard ratio [HR] =2.23, 95% confidence interval [CI]: 1.35, 3.67; P=0.002). Furthermore, subgroup analysis indicated that this association was only observed in American patients (HR =2.19, 95% CI: 1.23, 3.89; P=0.008), but not in Chinese patients (HR =1.44, 95% CI: 0.29, 7.26; P=0.657). Histopathological grade (HR =1.42, 95% CI: 0.07, 28.41; P=0.818), age (HR =0.94, 95% CI: 0.43, 2.04; P=0.877), and sex (HR =1.28, 95% CI: 0.55, 2.98; P=0.564) were not significant prognostic factors for the survival of patients with glioma. Conclusion Current evidence indicates that PTEN genetic mutation is associated with poor prognosis in glioma patients. However, this finding is derived from data in observational studies, potentially subject to selection bias, and hence well conducted, high-quality randomized controlled trials are warranted. PMID:27366085

  11. Expression of E2F-4 in invasive breast carcinomas is associated with poor prognosis.

    PubMed

    Rakha, Emad A; Pinder, Sarah E; Paish, E Claire; Robertson, John F; Ellis, Ian O

    2004-07-01

    The E2F family of transcription factors plays a key role in the control of cellular proliferation and apoptosis. Some family members act as oncogenes and others act as tumour suppressor genes (TSGs), behaviour which appears to be tissue-specific. E2F-4 is a member of the E2F family, located at chromosome band 16q22.1, that shows frequent deletion in breast cancer, suggesting that it may function as a TSG in breast carcinogenesis. In the present study, the expression of E2F-4 was assessed immunohistochemically on paraffin wax sections from 265 breast carcinomas and expression was compared with both clinicopathological variables and disease outcome in an attempt to identify its possible role as a TSG and to assess its prognostic value, if any, in breast cancer. E2F-4 protein expression was detected in the nuclei and in the cytoplasm of normal and malignant breast epithelial cells. In the malignant tissues, no significant loss or decrease of expression was seen in association with any specific tumour type. There was a correlation between increased nuclear expression of E2F-4 and indicators of poor prognosis including larger tumour size (p = 0.000), grade 3 lesions (p = 0.033), lymph node stage (p = 0.037), and poorer Nottingham prognostic index group (p = 0.003). Increased immunoreactivity was also seen in association with the development of recurrent disease (p = 0.004), distant metastasis (p = 0.001), and poorer outcome including poorer overall survival time (p = 0.002) and shorter disease-free interval (p = 0.001). In multivariate analysis, E2F-4 was of independent prognostic significance along with grade and lymph node stage. These results suggest that E2F-4 may play a role in breast cancer progression and that increased nuclear expression is associated with more advanced tumours with poor outcomes. E2F-4 appears to have an oncogenic role rather than a tumour suppressor role in breast carcinogenesis and, hence, it is not the gene targeted by 16q22.1 loss in breast

  12. Alternatively activated macrophages are associated with metastasis and poor prognosis in prostate adenocarcinoma

    PubMed Central

    HU, WENXUE; QIAN, YUNJUAN; YU, FENG; LIU, WEI; WU, YANHUA; FANG, XIAOWU; HAO, WENKE

    2015-01-01

    Recent studies have revealed that alternatively activated macrophages (AAMs) are involved in tumor progression. However, the effect of AAMs on the metastasis of prostate cancer is poorly understood. In the present study, the prostate tissues of 42 patients with prostate adenocarcinoma (PCa) were used in the analysis of tumor associated macrophages (TAMs) and AAMs by immunofluorescence. The patients were followed up for 5 years. The associations of TAMs and AAMs with the clinicopathological features and outcome in these cases were evaluated. Immunofluorescent analysis indicated that the mean number of TAMs (CD68-positive cells) in the prostate tissues of PCa patients with metastasis [45.29±7.25 cells/high-power field (HPF)] was significantly higher compared with that of PCa patients without metastasis (33.57±5.25 cells/HPF; P<0.01). The mean numbers of AAMs (CD68- and CD206-positive cells) in the tissues of PCa patients with and without metastasis were 29.43±5.68 and 9.14±5.29 cells/HPF, respectively. In addition, the percentage of AAMs (number of AAMs/number of TAMs) was 65.11±9.68 and 27.32±7.85% in patients with and without metastasis, respectively. The differences in the number and percentage of AAMs between the two groups were statistically significant (P<0.01). The number and percentage of AAMs was positively correlated with tumor grade and serum prostate-specific antigen (PSA) level. Univariate analysis indicated that the level of PSA, Gleason score, metastatic status, T grade, number of TAMs, number of AAMs and percentage of AAMs were predictors of the overall survival. Furthermore, multivariate analyses revealed that Gleason score, level of PSA and number of TAMs were predictors for overall survival rate. These results indicate that TAMs and AAMs may be important in the metastasis of PCa, and that TAMs and AAMs may be used as potential biomarkers of poor prognosis in late-stage PCa patients. PMID:26622679

  13. Cytoplasmic Kaiso is associated with poor prognosis in non-small cell lung cancer

    PubMed Central

    2009-01-01

    -regulation of the nuclear expresses Kaiso in vitro, both proliferative and invasive abilities of three cancer cell lines were significantly enhanced, along with the up-regulation of Kaiso target gene, matrilysin. Conclusion Our data suggest cytoplasmic Kaiso expression is associated with poor prognosis of NSCLC and various subcellular localizations of Kaiso may play differential biological roles in NSCLC. PMID:19508730

  14. Low expression of ARID1A correlates with poor prognosis in intrahepatic cholangiocarcinoma

    PubMed Central

    Yang, Song-Zhu; Wang, An-Qiang; Du, Juan; Wang, Jian-Tao; Yu, Wei-Wei; Liu, Qing; Wu, Yan-Fang; Chen, Shu-Guang

    2016-01-01

    AIM: To investigate the relationship between ARID1A expression and clinicopathologic parameters, as well as its prognostic value, for patients with intrahepatic cholangiocarcinoma (IHCC). METHODS: We assessed ARID1A protein and mRNA expression in IHCC tissues and paracarcinomatous (PC) tissues from 57 patients with IHCC using western blot and quantitative real-time reverse transcription polymerase chain reaction, respectively. We used Fisher’s exact and χ2 tests to analyze relationships between clinicopathological parameters and ARID1A expression. The Kaplan-Meier method and Cox regression were used to analyze survival. RESULTS: The mean ARID1A protein level in IHCC tissues was 1.16 ± 0.36 relative units (RU), which was significantly lower than that in PC tissues (1.26 ± 0.21 RU, P < 0.01) and NL tissues (1.11 ± 0.31, P < 0.001). The mean ARID1A mRNA level in IHCC tissues (1.20 ± 0.18) was also lower than that in PC tissues (1.27 ± 0.15, P < 0.001) and normal liver tissues (1.15 ± 0.34, P < 0.001). Low ARID1A expression was significantly associated with tumor nodules, vein invasion, and recurrence. Median overall survival (OS) and disease-free survival (DFS) for the low ARID1A expression group was 15.0 and 7.0 mo, respectively, which were significantly shorter than those for the high ARID1A expression group at 25.0 and 22.0 mo (OS: P < 0.01; DFS: P < 0.001), respectively. Low ARID1A expression was significantly associated with worse OS (HR = 3.967, 95%CI: 1.299-12.118, P = 0.016) in multivariate analyses. CONCLUSION: Low expression of ARID1A is associated with poor prognosis in patients with IHCC, and thus may be a potential prognostic biomarker candidate in IHCC. PMID:27433094

  15. Expression of the Stem Cell Factor Nestin in Malignant Pleural Mesothelioma Is Associated with Poor Prognosis

    PubMed Central

    Thies, Svenja; Friess, Martina; Frischknecht, Lukas; Korol, Dimitri; Felley-Bosco, Emanuela; Stahel, Rolf; Vrugt, Bart; Weder, Walter; Opitz, Isabelle; Soltermann, Alex

    2015-01-01

    Background The epithelioid and sarcomatoid histologic variants of malignant pleural mesothelioma (MPM) can be considered as E- and M-parts of the epithelial-mesenchymal transition (EMT) axis; the biphasic being an intermediate. EMT is associated with an increase of stem cell (SC) traits. We correlated the neural crest SC marker nestin and the EMT marker periostin with histology, type of neo-adjuvant chemotherapy (CT) and overall survival (OS) of MPM patients. Patients and Methods Tumor tissues of a historic cohort 1 (320 patients) and an intended induction chemotherapy followed by extrapleural pneumonectomy (EPP) cohort 2 (145 patients) were immunohistochemically H-scored (intensity of immunoreactivity multiplied by frequency of stained cells). Paired chemo-naïve biopsies and -treated surgical specimens were available for 105/145 patients. CT included platinum/gemcitabine (Pla/Gem) or platinum/pemetrexed (Pla/Pem). Results Expression of any cytosolic nestin progressively increased from epithelioid to biphasic to sarcomatoid MPM in cohort 1, whereas the diagnostic markers calretinin and podoplanin decreased. In cohort 2, Pla/Pem CT increased the expression level of nestin in comparison to Pla/Gem, whereas the opposite was found for periostin. In Pla/Pem treated patients, nestin was higher in biphasic MPM compared to epithelioid. In addition to non-epithelioid histology, any expression of nestin in chemo-naïve biopsies (median overall survival: 22 vs. 17 months) and chemo-treated surgical specimens (18 vs. 12 months) as well as high periostin in biopsies (23 vs. 15 months) were associated with poor prognosis. In the multivariate survival analysis, any nestin expression in chemo-naïve biopsies proved to be an independent prognosticator against histology. In both pre- and post-CT situations, the combination of nestin or periostin expression with non-epithelioid histology was particularly/ dismal (all p-values <0.05). Conclusions The SC marker nestin and the EMT

  16. Overexpression of periostin predicts poor prognosis in non-small cell lung cancer

    PubMed Central

    HONG, LING-ZHI; WEI, XIAO-WEI; CHEN, JIN-FEI; SHI, YI

    2013-01-01

    -level periostin expression (periostin-L; n=27) and 45.4% for patients with high-level periostin expression (periostin-H; n=22). Similarly, pathological node (pN) status was a significant prognostic marker in the univariate Cox survival analysis. Notably, periostin-H expression was also identified as an independent prognostic factor by the multivariate analysis (P=0.011). These results showed that the overexpression of periostin predicts a poor prognosis, therefore it may be regarded as a novel molecule in the progression and development of NSCLC. The results provide an additional target for the adjuvant treatment of NSCLC. PMID:24273600

  17. Generation of 2,000 breast cancer metabolic landscapes reveals a poor prognosis group with active serotonin production

    PubMed Central

    Leoncikas, Vytautas; Wu, Huihai; Ward, Lara T.; Kierzek, Andrzej M.; Plant, Nick J.

    2016-01-01

    A major roadblock in the effective treatment of cancers is their heterogeneity, whereby multiple molecular landscapes are classified as a single disease. To explore the contribution of cellular metabolism to cancer heterogeneity, we analyse the Metabric dataset, a landmark genomic and transcriptomic study of 2,000 individual breast tumours, in the context of the human genome-scale metabolic network. We create personalized metabolic landscapes for each tumour by exploring sets of active reactions that satisfy constraints derived from human biochemistry and maximize congruency with the Metabric transcriptome data. Classification of the personalized landscapes derived from 997 tumour samples within the Metabric discovery dataset reveals a novel poor prognosis cluster, reproducible in the 995-sample validation dataset. We experimentally follow mechanistic hypotheses resulting from the computational study and establish that active serotonin production is a major metabolic feature of the poor prognosis group. These data support the reconsideration of concomitant serotonin-specific uptake inhibitors treatment during breast cancer chemotherapy. PMID:26813959

  18. Increased interleukin-6 expression is associated with poor prognosis and acquired cisplatin resistance in head and neck squamous cell carcinoma.

    PubMed

    Gao, Jian; Zhao, Sen; Halstensen, Trond S

    2016-06-01

    Increased expression of interleukin 6 (IL-6) is associated with poor prognosis and chemoresistance in many different carcinomas, but its role in head and neck squamous cell carcinoma (HNSCC) is still unsettled. Analyzing tumorous mRNA expression data from 399 HNSCC patients revealed that high IL-6 expression predicted poor prognosis. Similar tendency was observed in platinum treated patients, suggesting an IL-6 associated cisplatin resistance. IL-6 increase was also found in two in-house acquired cisplatin‑resistant HNSCC cell lines (both basaloid and conventional squamous cell carcinoma) by using microarray analysis. However, although the in-house acquired cisplatin-resistant cell lines had higher basal and markedly increased cisplatin-induced IL-6 expression, IL-6 did not mediate the cisplatin resistance as neither exogenous IL-6 nor IL-6R/gp130 inhibitors affected cisplatin sensitivity. Moreover, the IL-6/STAT3 pathway was impaired in the resistant cell lines, partly due to decreased IL-6R expression. Thus, high IL-6 expression correlated to poor prognosis and acquired cisplatin resistance, but it did not mediate cisplatin resistance in the HNSCC cell lines. PMID:27108527

  19. Increased interleukin-6 expression is associated with poor prognosis and acquired cisplatin resistance in head and neck squamous cell carcinoma

    PubMed Central

    GAO, JIAN; ZHAO, SEN; HALSTENSEN, TROND S.

    2016-01-01

    Increased expression of interleukin 6 (IL-6) is associated with poor prognosis and chemoresistance in many different carcinomas, but its role in head and neck squamous cell carcinoma (HNSCC) is still unsettled. Analyzing tumorous mRNA expression data from 399 HNSCC patients revealed that high IL-6 expression predicted poor prognosis. Similar tendency was observed in platinum treated patients, suggesting an IL-6 associated cisplatin resistance. IL-6 increase was also found in two in-house acquired cisplatin-resistant HNSCC cell lines (both basaloid and conventional squamous cell carcinoma) by using microarray analysis. However, although the in-house acquired cisplatin-resistant cell lines had higher basal and markedly increased cisplatin-induced IL-6 expression, IL-6 did not mediate the cisplatin resistance as neither exogenous IL-6 nor IL-6R/gp130 inhibitors affected cisplatin sensitivity. Moreover, the IL-6/STAT3 pathway was impaired in the resistant cell lines, partly due to decreased IL-6R expression. Thus, high IL-6 expression correlated to poor prognosis and acquired cisplatin resistance, but it did not mediate cisplatin resistance in the HNSCC cell lines. PMID:27108527

  20. High neutrophil-lymphocyte ratio indicates poor prognosis for acute-on-chronic liver failure after liver transplantation

    PubMed Central

    Lin, Bing-Yi; Zhou, Lin; Geng, Lei; Zheng, Zhi-Yun; Jia, Jun-Jun; Zhang, Jing; Yao, Jia; Zheng, Shu-Sen

    2015-01-01

    AIM: To investigate the significance of pre-transplant neutrophil-lymphocyte ratio (NLR) in determining the prognosis of liver transplant (LT) recipients with acute-on-chronic liver failure (ACLF). METHODS: Data were collected from the liver transplantation data bank. The NLR values and other conventional inflammatory markers were evaluated for their ability to predict the prognosis of 153 patients with ACLF after LT. The NLR cut-off value was based on a receiver operating characteristic curve analysis. A Kaplan-Meier curve analysis and univariate and multivariate Cox regression models were used to define the independent risk factors for poor outcomes. RESULTS: The optimal NLR cut-off value was 4.6. Out of 153 patients, 83 (54.2%) had an NLR ≥ 4.6. The 1-, 3-, and 5-year overall survival rates were 94.3%, 92.5% and 92.5%, respectively, in the normal NLR group and 74.7%, 71.8% and 69.8%, respectively, in patients with high NLRs (P < 0.001). Furthermore, there was a significant difference in infectious complications after LT between the high and normal NLR groups. There were no significant differences for other complications. In the multivariate Cox regression model, a high NLR was defined as a significant predictor of poor outcomes for LT. CONCLUSION: A high NLR is a convenient and available predictor for prognosis of LT patients and can potentially optimize the current criteria for LT in ACLF. PMID:25805939

  1. Stathmin1 regulates p27 expression, proliferation and drug resistance, resulting in poor clinical prognosis in cholangiocarcinoma

    PubMed Central

    Watanabe, Akira; Suzuki, Hideki; Yokobori, Takehiko; Tsukagoshi, Mariko; Altan, Bolag; Kubo, Norio; Suzuki, Shigemasa; Araki, Kenichiro; Wada, Satoshi; Kashiwabara, Kenji; Hosouchi, Yasuo; Kuwano, Hiroyuki

    2014-01-01

    Patients with extrahepatic cholangiocarcinoma (EHCC) have a poor prognosis; postoperative survival depends on cancer progression and therapeutic resistance. The mechanism of EHCC progression needs to be clarified to identify ways to improve disease prognosis. Stathmin1 (STMN1) is a major cytosolic phosphoprotein that regulates microtubule dynamics and is associated with malignant phenotypes and chemoresistance in various cancers. Recently, STMN1 was reported to interact with p27, an inhibitor of cyclin-dependent kinase complexes. Eighty EHCC cases were studied using immunohistochemistry and clinical pathology to determine the correlation between STMN1 and p27 expression; RNA interference to analyze the function of STMN1 in an EHCC cell line was also used. Cytoplasmic STMN1 expression correlated with venous invasion (P = 0.0021) and nuclear p27 underexpression (P = 0.0011). Patients in the high-STMN1-expression group were associated with shorter recurrence-free survival and overall survival than those in the low-expression group. An in vitro protein-binding assay revealed that cytoplasmic STMN1 bound to p27 in the cytoplasm, but not in the nucleus of EHCC cells. Moreover, p27 accumulated in EHCC cells after STMN1 suppression. STMN1 knockdown inhibited proliferation and increased the sensitivity of EHCC cells to paclitaxel. STMN1 contributes to a poor prognosis and cancer progression in EHCC patients. Understanding the regulation of p27 by STMN1 could provide new insights for overcoming therapeutic resistance in EHCC. PMID:24708177

  2. ZFX is a Strong Predictor of Poor Prognosis in Renal Cell Carcinoma

    PubMed Central

    Li, Changying; Li, Hongjie; Zhang, Ting; Li, Jianmin; Ma, Fuling; Li, Mei; Sui, Zhifang; Chang, Jiwu

    2015-01-01

    Background This study was designed to assay the expression of zinc finger protein X-linked (ZFX) in renal cell carcinoma (RCC) tissues and evaluate the correlation between ZFX expression and prognosis of RCC patients. Material/Methods The expressions of ZFX mRNA in 53 RCC tissues and 51 normal tissues were determined by quantitative real-time polymerase chain reaction (qRT-PCR). Immunohistochemistry (IHC) technology was used to measure the expression of ZFX protein. Then chi-square test was conducted to verify the association between ZFX expression and clinical parameters. Next, we explored the overall survival rate of RCC patients with Kaplan-Meier analysis. Finally, the correlation between ZFX expression and the prognosis of RCC patients was evaluated by Cox regression analysis. Results The qRT-PCR result showed that the ZFX was significantly up-regulated in RCC tissues. As for the IHC consequence, the positive rate of ZFX expression in RCC specimens was 79.2%, while that in the normal control tissues was only 17.6%. Chi-square test showed that ZFX expression shared no close relationship with age, sex, or smoking (P>0.05), but was tightly associated with TNM stage, tumor size, and lymph node metastasis (P<0.05). Kaplan-Meier analysis showed that patients with ZFX positive expression had higher mortality than those with negative expression (P<0.05). Cox regression analysis revealed that ZFX expression had tight correlation with prognosis of RCC patients (HR=4.997, P=0.045, 95%CI=1.033–24.180). Conclusions Our findings show that ZFX could be considered as a predictor for prognosis of RCC patients. PMID:26540164

  3. Promoter CpG island methylation of RET predicts poor prognosis in stage II colorectal cancer patients.

    PubMed

    Draht, Muriel X G; Smits, Kim M; Tournier, Benjamin; Jooste, Valerie; Chapusot, Caroline; Carvalho, Beatriz; Cleven, Arjen H G; Derks, Sarah; Wouters, Kim A D; Belt, Eric J T; Stockmann, Hein B A C; Bril, Herman; Weijenberg, Matty P; van den Brandt, Piet A; de Bruïne, Adriaan P; Herman, James G; Meijer, Gerrit A; Piard, Françoise; Melotte, Veerle; van Engeland, Manon

    2014-05-01

    Improved prognostic stratification of patients with TNM stage II colorectal cancer (CRC) is desired, since 20-30% of high-risk stage II patients may die within five years of diagnosis. This study was conducted to investigate REarranged during Transfection (RET) gene promoter CpG island methylation as a possible prognostic marker for TNM stage II CRC patients. The utility of RET promoter CpG island methylation in tumors of stage II CRC patients as a prognostic biomarker for CRC related death was studied in three independent series (including 233, 231, and 294 TNM stage II patients, respectively) by using MSP and pyrosequencing. The prognostic value of RET promoter CpG island methylation was analyzed by using Cox regression analysis. In the first series, analyzed by MSP, CRC stage II patients (n = 233) with RET methylated tumors had a significantly worse overall survival as compared to those with unmethylated tumors (HRmultivariable = 2.51, 95%-CI: 1.42-4.43). Despite a significant prognostic effect of RET methylation in stage III patients of a second series, analyzed by MSP, the prognostic effect in stage II patients (n = 231) was not statistically significant (HRmultivariable = 1.16, 95%-CI 0.71-1.92). The third series (n = 294), analyzed by pyrosequencing, confirmed a statistically significant association between RET methylation and poor overall survival in stage II patients (HRmultivariable = 1.91, 95%-CI: 1.04-3.53). Our results show that RET promoter CpG island methylation, analyzed by two different techniques, is associated with a poor prognosis in stage II CRC in two independent series and a poor prognosis in stage III CRC in one series. RET methylation may serve as a useful and robust tool for clinical practice to identify high-risk stage II CRC patients with a poor prognosis. This merits further investigation. PMID:24560444

  4. BC200 LncRNA a potential predictive marker of poor prognosis in esophageal squamous cell carcinoma patients

    PubMed Central

    Zhao, Rui-Hua; Zhu, Cai-hua; Li, Xiang-Ke; Cao, Wei; Zong, Hong; Cao, Xin-Guang; Hu, Hai-Yan

    2016-01-01

    Objective To explore the expression and prognosis significance of BC200 in esophageal squamous cell carcinoma (ESCC) patients who received radical resection. Methods We used quantitative real-time polymerase chain reaction to detect the expression level of BC200 in cancer tissue and paired adjacent normal tissue samples from 70 ESCC patients who received radical surgical resection and analyzed the correlation of the relative expression level of BC200 with clinical-pathological features and prognosis. Results We found that the relative expression of BC200 was significantly higher in ESCC tissues compared with adjacent normal tissue samples (P=0.023). But the expression of BC200 were not related to clinical-pathological features, such as age, TNM stages, and histological grade (P>0.05). Kaplan–Meier analysis showed that high expression levels of BC200 were correlated with poor prognosis in ESCC patients. Patients with a high level of BC200 had a shorter disease-free survival and overall survival than those with low BC200 expression (P=0.034 and P=0.031, respectively). On multivariate analysis, the hazard ratio (HR) of BC200 expression was 2.17 (95% confidence interval [CI]=1.12–4.19, P=0.022) for disease-free survival and 2.24 (95% CI=1.12–4.49, P=0.023) for overall survival. Conclusion Our results indicate that high expression of BC200 reflects poor prognosis and could serve as a novel predictive marker for ESCC patients who received radical resection. PMID:27143917

  5. Mast Cells Comprise the Major of Interleukin 17-Producing Cells and Predict a Poor Prognosis in Hepatocellular Carcinoma

    PubMed Central

    Tu, Jian-Fei; Pan, Hong-Ying; Ying, Xi-Hui; Lou, Jian; Ji, Jian-Song; Zou, Hai

    2016-01-01

    Abstract IL-17 and IL-17-producing cells have been found in many types of human cancers and murine models. However, the source of tumor-infiltrating IL-17 and IL-17-producing cells in HCC and the prognostic values remain poorly understood. A total of 57 HCC patients were enrolled in this study, and immunofluorescence double stain was used to evaluate the colocalization of CD3+ T cells, CD4+ T cells, CD56+ NK cells, CD20+ B cells, CD68+ Macrophages, and MCT+ mast cells with IL-17. The prognostic value of IL-17-producing cells was evaluated by Kaplan–Meier analysis and Cox regression model. MCT+ mast cells, but not other cells, were the predominant IL-17-producing cell type. Overall survival analysis revealed that the increasing intratumoral-infiltrated MCT+ mast cells were significantly associated with poor prognosis. Immunofluorescence double stain showed a positive correlation between the number of MCT+ mast cells and MCVs. These findings indicated the major IL-17-producing cells in HCC were MCT+ mast cells and these cells infiltration may promote tumor progression by angiogenesis. Increased MCT+ mast cells was associated with a poor prognosis, indicating therapy targeting MCT+ mast cells might be an effective strategy in controlling intratumor IL-17 infiltration and MCVs. PMID:27043690

  6. Nuclear Ep-ICD Expression Is a Predictor of Poor Prognosis in “Low Risk” Prostate Adenocarcinomas

    PubMed Central

    Assi, Jasmeet; Srivastava, Gunjan; Matta, Ajay; MacMillan, Christina

    2015-01-01

    Introduction Molecular markers for predicting prostate cancer (PCa) that would have poor prognosis are urgently needed for a more personalized treatment for patients. Regulated intramembrane proteolysis of Epithelial cell adhesion molecule results in shedding of the extracellular domain (EpEx) and release of its intracellular domain (Ep-ICD) which triggers oncogenic signaling and might correlate to tumor aggressiveness. This study aimed to explore the potential of Ep-ICD and EpEx to identify PCa that have poor prognosis. Methods Immunohistochemical analysis of Ep-ICD and EpEx was carried out in normal prostate tissues (n = 100), benign prostate hyperplasia (BPH, n = 83), and prostate cancer (n = 249) using domain specific antibodies. The expression of Ep-ICD and EpEx was correlated with clinico- pathological parameters and disease free survival (DFS). Results Reduced expression of nuclear Ep-ICD and membrane EpEx was observed in PCa in comparison with BPH and normal prostate tissues (p = 0.006, p < 0.001 respectively). For patients who had PCa with Gleason Score less than 7, preserved nuclear Ep-ICD emerged as the most significant marker in multivariate analysis for prolonged DFS, where these patients did not have recurrence during follow up of up to 12 years (p = 0.001). Conclusion Reduced expression of nuclear Ep-ICD was associated with shorter disease free survival in patients with a Gleason Score less than 7 and may be useful in identifying patients likely to have aggressive tumors with poor prognosis. Furthermore, nuclear Ep-ICD can differentiate between normal and prostate cancer tissues for ambiguous cases. PMID:25695234

  7. TSLP Expression and High Serum TSLP Level Indicate a Poor Prognosis in Gastric Cancer Patients

    PubMed Central

    Watanabe, Joji; Saito, Hiroaki; Miyatani, Kozo; Ikeguchi, Masahide; Umekita, Yoshihisa

    2015-01-01

    Background Thymic stromal lymphopoietin (TSLP) plays an important role in promoting tumor survival, by manipulating the immune response and angiogenesis. However, the clinical significance of TSLP in gastric cancer is unclear. Methods Immunohistochemistry was used to investigate TSLP expression in non-cancerous gastric mucosa and gastric cancer tissue from patients with gastric cancer. Serum TSLP levels were measured using an enzyme-linked immunosorbent assay. Results Tumors with TSLP expression were significantly larger than those without TSLP expression. TSLP expression was observed more frequently in advanced (T2/T3/T4) than in early (T1) gastric cancer and in stage 3/4 than in stage 1/2. Lymph node metastasis, liver metastasis, positive peritoneal lavage cytology, lymphatic invasion, and vascular invasion occurred significantly more often in TSLP-expressing than in non-expressing tumors. The prognosis of patients with TSLP-positive tumors was significantly worse than that of patients with TSLP-negative tumors. Patients with high serum TSLP concentrations also had a significantly worse prognosis than those with low concentrations. Multivariate analysis identified serum TSLP level as an independent prognostic indicator. Conclusion TSLP is closely related to the progression of gastric cancer and may predict survival in these patients. PMID:26538800

  8. Upregulation of PD-L1 and APE1 is associated with tumorigenesis and poor prognosis of gastric cancer

    PubMed Central

    Qing, Yi; Li, Qing; Ren, Tao; Xia, Wei; Peng, Yu; Liu, Gao-Lei; Luo, Hao; Yang, Yu-Xin; Dai, Xiao-Yan; Zhou, Shu-Feng; Wang, Dong

    2015-01-01

    Introduction Gastric cancer is a fatal malignancy with a rising incidence rate. Effective methods for early diagnosis, monitoring metastasis, and prognosis are currently unavailable for gastric cancer. In this study, we examined the association of programmed death ligand-1 (PD-L1) and apurinic/apyrimidinic endonuclease 1 (APE1) expression with the prognosis of gastric cancer. Methods The expressions of PD-L1 and APE1 were detected by immunohistochemistry in 107 cases of human gastric carcinoma. The correlation of PD-L1 and APE1 expression with the clinicopathologic features of gastric carcinoma was analyzed by SPSS version 19.0. Results The positive expression rates of PD-L1 and APE1 in gastric cancer tissues were 50.5% (54/107) and 86.9% (93/107), respectively. PD-L1 and APE1 positive expressions were significantly associated with depth of invasion, lymph node metastasis, pathological type, overall survival, and higher T stage. Furthermore, the expression of PD-L1 in highly differentiated gastric cancers was higher than that in poorly differentiated cancers (P=0.008). Moreover, the expression of APE1 and PD-L1 in gastric cancers was positively correlated (r=0.336, P<0.01). Multivariate analysis showed that the depth of invasion was a significant prognostic factor (risk ratio 19.91; P=0.000), but there was no significant relationship with PD-L1, APE1, prognosis, and other characteristics. Conclusion The deregulation of PD-L1 and APE1 might contribute to the development and the poor prognosis of gastric cancer. Our findings suggest that high expression of PD-L1 and APE1 is a risk factor of gastric cancer and a new biomarker to predict the prognosis of gastric cancer. Furthermore, our findings suggest that targeting the PD-L1 and APE1 signaling pathways may be a new strategy for cancer immune therapy and targeted therapy for gastric cancer, especially in patients with deep invasion and lymph node metastasis. PMID:25733810

  9. Ack1 overexpression promotes metastasis and indicates poor prognosis of hepatocellular carcinoma

    PubMed Central

    Chen, Guo-dong; Ou, Di-peng; Qiu, Xiao-xin; Zuo, Chao-hui; Yang, Lian-Yue

    2015-01-01

    Despite the substantial data supporting the oncogenic role of Ack1, the predictive value and biologic role of Ack1 in hepatocellular carcinoma (HCC) metastasis remains unknown. In this study, both correlations of Ack1 expression with prognosis of HCC, and the role of Ack1 in metastasis of HCC were investigated in vitro and in vivo. Our results showed that Ack1 was overexpressed in human HCC tissues and cell lines. High Ack1 expression was associated with HCC metastasis and determined as a significant and independent prognostic factor for HCC after liver resection. Ack1 promoted HCC invasion and metastasis in vitro and in vivo. Mechanistically, we confirmed that Ack1 enhanced invasion and metastasis of HCC via EMT by mediating AKT phosphorylation. In conclusion, our study shows Ack1 is a novel prognostic biomarker for HCC and promotes metastasis of HCC via EMT by activating AKT signaling. PMID:26536663

  10. High DEPTOR expression correlates with poor prognosis in patients with esophageal squamous cell carcinoma

    PubMed Central

    Liu, Nan-bo; Zhang, Jun-hua; Liu, Yu-fan; Li, Jun; Zhang, Zhen-zhong; Li, Ji-wei; Liu, Wen-yue; Huang, Chen; Shen, Tao; Gu, Cheng-wei; Gao, Dong-yun; Wu, Xia; Wu, Xu

    2015-01-01

    Objective The disheveled, Egl-10, and pleckstrin (DEP) domain containing mammalian target of rapamycin (mTOR)-interacting protein (DEPTOR) is a binding protein containing mTOR complex 1 (mTORC1), mTOR complex 2 (mTORC2), and an endogenous mTOR inhibitor. DEPTOR shows abnormal expressions in numerous types of solid tumors. However, how DEP-TOR is expressed in esophageal squamous cell carcinoma (ESCC) remains elusive. Methods The expression of DEPTOR in 220 cases of ESCC and non-cancerous adjacent tissues was detected by immunohistochemistry. DEPTOR levels in ESCC and paired normal tissue were quantified using reverse transcription-polymerase chain reaction and Western blot analysis to verify the immunohistochemical results. The relationship between DEPTOR expression and the clinicopathological features of ESCC was analyzed based on the results of immunohistochemistry. Finally, we analyzed the relationship between DEPTOR expression and the prognosis of patients with ESCC. Results Immunohistochemical staining showed that the expression rate of DEPTOR in ESCC tissues was significantly increased. DEPTOR mRNA and protein expression was significantly higher in ESCC tissues than in normal adjacent esophageal squamous tissues. High DEPTOR expression was significantly correlated with regional lymph node status in the TNM stage of patients with ESCC. Kaplan–Meier survival curves showed that the rate of overall survival was significantly lower in patients with high DEPTOR expression than in those with low DEPTOR expression. Additionally, high DEPTOR expression was an independent prognostic predictor for ESCC patients. Conclusion High DEPTOR expression is an independent prognostic biomarker indicating a worse prognosis for patients with ESCC. PMID:26640385

  11. Upregulation of KLHDC4 Predicts a Poor Prognosis in Human Nasopharyngeal Carcinoma.

    PubMed

    Lian, Yi-Fan; Yuan, Jing; Cui, Qian; Feng, Qi-Sheng; Xu, Miao; Bei, Jin-Xin; Zeng, Yi-Xin; Feng, Lin

    2016-01-01

    Kelch proteins are implicated in the pathogenesis of many human diseases, including cancer. Nasopharyngeal carcinoma (NPC) is a rare malignancy in most countries, but prevalent in southern China and certain areas of Southeast Asia. In this study, we identified Kelch Domain Containing 4 (KLHDC4), an orphan member of the kelch repeat superfamily, as a prognosis marker for NPC. We examined the expression of KLHDC4 in 168 NPC cases by immunohistochemical staining and found a substantially higher level of KLHDC4 in NPC biopsies compared to adjacent normal nasopharyngeal mucosa. KLHDC4 expression was significantly related to the T classification (P <0.05), N classification (P <0.05) and total staging (P <0.01) in NPC, and patients with higher KLHDC4 expression had poorer overall (P <0.01) and metastasis-free survival (P <0.05) rates. Knockout (KO) of KLHDC4 via CRISPR/Cas9-mediated gene editing in NPC cell line dramatically inhibited cell proliferation, colony formation in soft agar and tumor formation in nude mice. In addition, cell migration and invasion were also impaired by KLHDC4 depletion as revealed by wound healing and Transwell assay. Mechanically, loss of KLHDC4 markedly induced spontaneous apoptosis in NPC cells, as evidenced by increased levels of cleaved caspase-3 and cleaved PARP. Consistently, KLHDC4 knockout cell-derived xenografts also showed elevated cleaved caspase-3 and PARP but reduced Ki-67 staining. In conclusion, our results suggest that KLHDC4 promotes NPC oncogenesis by suppressing cellular apoptosis. Thus, KLHDC4 may serve as a prognosis biomarker and a potential therapeutic target for NPC. PMID:27030985

  12. Upregulation of KLHDC4 Predicts a Poor Prognosis in Human Nasopharyngeal Carcinoma

    PubMed Central

    Feng, Qi-Sheng; Xu, Miao; Bei, Jin-Xin; Zeng, Yi-Xin; Feng, Lin

    2016-01-01

    Kelch proteins are implicated in the pathogenesis of many human diseases, including cancer. Nasopharyngeal carcinoma (NPC) is a rare malignancy in most countries, but prevalent in southern China and certain areas of Southeast Asia. In this study, we identified Kelch Domain Containing 4 (KLHDC4), an orphan member of the kelch repeat superfamily, as a prognosis marker for NPC. We examined the expression of KLHDC4 in 168 NPC cases by immunohistochemical staining and found a substantially higher level of KLHDC4 in NPC biopsies compared to adjacent normal nasopharyngeal mucosa. KLHDC4 expression was significantly related to the T classification (P <0.05), N classification (P <0.05) and total staging (P <0.01) in NPC, and patients with higher KLHDC4 expression had poorer overall (P <0.01) and metastasis-free survival (P <0.05) rates. Knockout (KO) of KLHDC4 via CRISPR/Cas9-mediated gene editing in NPC cell line dramatically inhibited cell proliferation, colony formation in soft agar and tumor formation in nude mice. In addition, cell migration and invasion were also impaired by KLHDC4 depletion as revealed by wound healing and Transwell assay. Mechanically, loss of KLHDC4 markedly induced spontaneous apoptosis in NPC cells, as evidenced by increased levels of cleaved caspase-3 and cleaved PARP. Consistently, KLHDC4 knockout cell-derived xenografts also showed elevated cleaved caspase-3 and PARP but reduced Ki-67 staining. In conclusion, our results suggest that KLHDC4 promotes NPC oncogenesis by suppressing cellular apoptosis. Thus, KLHDC4 may serve as a prognosis biomarker and a potential therapeutic target for NPC. PMID:27030985

  13. Over-Expression of CD200 Predicts Poor Prognosis in Cutaneous Squamous Cell Carcinoma

    PubMed Central

    Li, Li; Tian, YanLi; Shi, ChengFang; Zhang, Hua; Zhou, Zhi

    2016-01-01

    Background CD200 is reported to be involved in tumor progression and can serve as a prognostic marker in several cancers. The purpose of this study was to evaluate the prognostic significance of CD200 in cutaneous squamous cell carcinoma (CSCC). Material/Methods The relative mRNA and protein expression of CD200 in the tumor tissues and corresponding normal tissues of 102 CSCC patients were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis, respectively. The chi-square test was used to analyze the association between CD200 expression and clinical features of CSCC patients. In addition, the overall survival of the patients according to the expression level of CD200 was estimated by Kaplan-Meier analysis and the prognostic significance of the gene was analyzed by Cox regression analysis. Results Increased expression of CD200 was detected in the tumor tissues compared with the corresponding normal tissues both at mRNA and protein level. And CD200 expression level was associated with tumor differentiation grade (P=0.041) and clinical stage (P=0.004). Patients with high expression level of CD200 had a shorter overall survival than those with low expression (31.3 months vs. 41.9 months) and there was a significant difference between them (log-rank test, P<0.001). Cox regression analysis indicated that CD200 could be an independent marker for the prognosis of CSCC. Conclusions CD200 is up-regulated and may be a novel biomarker for the prognosis in CSCC, and it may be a potential therapeutic target for CSCC. PMID:27035797

  14. Overexpression of vascular adhesion protein-1 is associated with poor prognosis of astrocytomas.

    PubMed

    Kostoro, Joanna; Chang, Shu-Jyuan; Clark Lai, Yen-Chang; Wu, Chun-Chieh; Chai, Chee-Yin; Kwan, Aij-Lie

    2016-06-01

    Vascular adhesion protein-1 (VAP-1) is one of the endothelial adhesion molecules that is believed to play a role in tumor progression and metastasis, supporting cancer cell extravasation. Very few studies have been performed on analyzing the contribution of VAP-1 in brain tumor. Astrocytomas are the most common type of brain tumors, which are classified by World Health Organization (WHO) into four grades according to the degree of malignancy. This study was designed to investigate VAP-1 expression level in different astrocytoma grades and its correlation with clinicopathological features as well as prognosis of astrocytoma patients. Eighty-seven patients with different grades of astrocytoma (WHO Grade I-Grade IV) were enrolled in this study. The expression of VAP-1 was assayed by immunohistochemistry. The correlation between VAP-1 expression and clinicopathological features was evaluated by Chi-square test, and overall survival was analyzed by Kaplan-Meier method. Cox regression analysis was applied to analyze the independent influence of each parameter on overall survival. The expression level of VAP-1 was significantly higher in diffuse astrocytoma than those of pilocytic astrocytoma (p < 0.0001). In the subgroup analysis, upregulated VAP-1 expression was frequently found in older age patients (≥50 years). The VAP-1 expression was found to be significantly correlated with the overall survival (p = 0.0002). There was a statistical correlation between VAP-1(high) tumors in diffuse astrocytoma and VAP-1(low) tumors in pilocytic astrocytoma (p < 0.0001). Multivariate Cox analysis indicated VAP-1 was an independent predictive marker for poorer prognosis (p = 0.0036). Therefore, VAP-1 could be a promising prognostic biomarker in astrocytoma. PMID:26935340

  15. “Frequent exacerbator” is a phenotype of poor prognosis in Japanese patients with chronic obstructive pulmonary disease

    PubMed Central

    Tomioka, Ryusuke; Kawayama, Tomotaka; Suetomo, Masashi; Kinoshita, Takashi; Tokunaga, Yoshihisa; Imaoka, Haruki; Matsunaga, Kazuko; Okamoto, Masaki; Hoshino, Tomoaki

    2016-01-01

    Background The prognosis of Japanese patients with COPD who suffer repeated exacerbations is unclear, although Westerners with such episodes have a poor prognosis. Materials and methods We conducted a 1-year prospective observational trial involving 90 Japanese patients with COPD: 58 nonexacerbators, 12 infrequent exacerbators, and 20 frequent exacerbators classified on the basis of exacerbation frequency (zero, one, and two or more exacerbations/year), respectively, during the previous year were observed prospectively for 1 year. The characteristics of frequent exacerbators, the frequency of exacerbation, and the period until the first event were then compared among the groups. Results A total of 78 patients completed the study. Frequent exacerbators had a significantly higher risk of frequent exacerbation in the following year than the case for nonexacerbators (odds ratio [95% confidence interval] 2.94 [1.21–7.17], P=0.0340), but not in comparison with infrequent exacerbators (1.51 [0.49–4.63], P>0.05). The mean annual frequency of exacerbations in the following year was significantly (P=0.0020) higher in the frequent exacerbators (1.4 exacerbations/year) than in the nonexacerbators (0.4), but not in the infrequent exacerbators (0.9, P>0.05). The mean period until the first exacerbation was significantly shorter in the frequent exacerbators than in the infrequent or nonexacerbators (P=0.0012). Independent risk factors for future frequent exacerbation included the presence of gastroesophageal reflux disease, more severe airflow obstruction, and use of inhaled corticosteroids. Conclusion Our present results indicate that Japanese COPD patients suffering frequent exacerbation have a poor prognosis. The characteristics of Japanese and Western COPD patients suffering frequent exacerbation are similar. PMID:26893552

  16. Peritumoral vascular invasion and NHERF1 expression define an immunophenotype of grade 2 invasive breast cancer associated with poor prognosis

    PubMed Central

    2012-01-01

    Background Traditional determinants proven to be of prognostic importance in breast cancer include the TNM staging, histological grade, proliferative activity, hormone receptor status and HER2 overexpression. One of the limitations of the histological grading scheme is that a high percentage of breast cancers are still classified as grade 2, a category with ambiguous clinical significance. The aim of this study was to best characterize tumors scored as grade 2. Methods We investigated traditional prognostic factors and a panel of tumor markers not used in routine diagnosis, such as NHERF1, VEGFR1, HIF-1α and TWIST1, in 187 primary invasive breast cancers by immunohistochemistry, stratifying patients into good and poor prognostic groups by the Nottingham Prognostic Index. Results Grade 2 subgroup analysis showed that the PVI (p = 0.023) and the loss of membranous NHERF1 (p = 0.028) were adverse prognostic factors. Relevantly, 72% of grade 2 tumors were associated to PVI+/membranous NHERF1- expression phenotype, characterizing an adverse prognosis (p = 0.000). Multivariate logistic regression analysis in the whole series revealed poor prognosis correlated with PVI and MIB1 (p = 0.000 and p = 0.001, respectively). Furthermore, in the whole series of breast cancers we found cytoplasmic NHERF1 expression positively correlated to VEGFR1 (r = 0.382, p = 0.000), and in VEGFR1-overexpressing tumors the oncogenic receptor co-localized with NHERF1 at cytoplasmic level. Conclusions The PVI+/membranous NHERF1- expression phenotype identifies a category of grade 2 tumors with the worst prognosis, including patient subgroup with a family history of breast cancer. These observations support the idea of the PVI+/membranous NHERF1- expression immunophenotype as a useful marker, which could improve the accuracy of predicting clinical outcome in grade 2 tumors. PMID:22439624

  17. Upregulation of the long noncoding RNA PCAT-1 correlates with advanced clinical stage and poor prognosis in esophageal squamous carcinoma.

    PubMed

    Shi, Wei-hong; Wu, Qing-quan; Li, Su-qing; Yang, Tong-xin; Liu, Zi-hao; Tong, Yu-suo; Tuo, Lei; Wang, Shan; Cao, Xiu-Feng

    2015-04-01

    Recent studies reveal that long noncoding RNAs (lncRNAs) play critical regulatory roles in cancer biology. Prostate cancer-associated ncRNA transcript 1 (PCAT-1) is one of the lncRNAs involved in cell apoptosis and proliferation of prostate cancer. This study aimed to assess the potential role of PCAT-1 specifically in the pathogenesis of esophageal squamous cell carcinoma (ESCC). Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression level of PCAT-1 in matched cancerous tissues and adjacent noncancerous tissues from 130 patients with ESCC, 34 patients with non-small cell lung cancer (NSCLC), and 30 patients with gastric carcinoma (GC). The correlation of PCAT-1 with clinicopathological features and prognosis were also analyzed. The expression of PCAT-1 was significantly higher in human ESCC compared with the adjacent noncancerous tissues (70.8%, p < 0.01), and the high level of PCAT-1 expression was significantly correlated with invasion of the tumor (p = 0.024), advanced clinical stage (p = 0.003), lymph node metastasis (p = 0.032), and poor prognosis. However, PCAT-1 mRNA expression had no significant difference between paired primary cancerous tissues and the adjacent noncancerous tissues in 34 cases of NSCLC (p = 0.293) and 30 cases of GC (p = 0.125). High expression of PCAT-1 was specifically correlated with invasion of cancer tissues, metastasis of lymph node, and advanced tumor stage of ESCC. High expression of PCAT-1 might reflect poor prognosis of ESCC and indicate a potential diagnostic target in ESCC patients. Adjuvant therapy targeting PCAT-1 molecule might be effective in treatment of ESCC. PMID:25731728

  18. CXCL17 Expression Predicts Poor Prognosis and Correlates with Adverse Immune Infiltration in Hepatocellular Carcinoma

    PubMed Central

    Xu, Jing; Liu, Chao-Qun; Zhen, Zuo-Jun; Chen, Huan-Wei; Ji, Yong; Wu, Zhi-Peng; Hu, Jian-Yuan; Zheng, Limin; Lau, Wan Yee

    2014-01-01

    CXC ligand 17 (CXCL17) is a novel CXC chemokine whose clinical significance remains largely unknown. In the present study, we characterized the prognostic value of CXCL17 in patients with hepatocellular carcinoma (HCC) and evaluated the association of CXCL17 with immune infiltration. We examined CXCL17 expression in 227 HCC tissue specimens by immunohistochemical staining, and correlated CXCL17 expression patterns with clinicopathological features, prognosis, and immune infiltrate density (CD4 T cells, CD8 T cells, B cells, natural killer cells, neutrophils, macrophages). Kaplan-Meier survival analysis showed that both increased intratumoral CXCL17 (P = 0.015 for overall survival [OS], P = 0.003 for recurrence-free survival [RFS]) and peritumoral CXCL17 (P = 0.002 for OS, P<0.001 for RFS) were associated with shorter OS and RFS. Patients in the CXCL17low group had significantly lower 5-year recurrence rate compared with patients in the CXCL17high group (peritumoral: 53.1% vs. 77.7%, P<0.001, intratumoral: 58.6% vs. 73.0%, P = 0.001, respectively). Multivariate Cox proportional hazards analysis identified peritumoral CXCL17 as an independent prognostic factor for both OS (hazard ratio [HR] = 2.066, 95% confidence interval [CI] = 1.296–3.292, P = 0.002) and RFS (HR = 1.844, 95% CI = 1.218–2.793, P = 0.004). Moreover, CXCL17 expression was associated with more CD68 and less CD4 cell infiltration (both P<0.05). The combination of CXCL17 density and immune infiltration could be used to further classify patients into subsets with different prognosis for RFS. Our results provide the first evidence that tumor-infiltrating CXCL17+ cell density is an independent prognostic factor that predicts both OS and RFS in HCC. CXCL17 production correlated with adverse immune infiltration and might be an important target for anti-HCC therapies. PMID:25303284

  19. Embryonic Morphogen Nodal Is Associated with Progression and Poor Prognosis of Hepatocellular Carcinoma

    PubMed Central

    Jia, Wei-Dong; Xu, Ge-Liang; Ma, Jin-Liang; Ren, Yun; Chen, Hao; Sun, Si-Nan; Huang, Mei; Li, Jian-Sheng

    2014-01-01

    Background Nodal, a TGF-β-related embryonic morphogen, is involved in multiple biologic processes. However, the expression of Nodal in hepatocellular carcinoma (HCC) and its correlation with tumor angiogenesis, epithelial-mesenchymal transition, and prognosis is unclear. Methods We used real-time PCR and Western blotting to investigate Nodal expression in 6 HCC cell lines and 1 normal liver cell line, 16 pairs of tumor and corresponding paracarcinomatous tissues from HCC patients. Immunohistochemistry was performed to examine Nodal expression in HCC and corresponding paracarcinomatous tissues from 96 patients. CD34 and Vimentin were only examined in HCC tissues of patients mentioned above. Nodal gene was silenced by shRNA in MHCC97H and HCCLM3 cell lines, and cell migration and invasion were detected. Statistical analyses were applied to evaluate the prognostic value and associations of Nodal expression with clinical parameters. Results Nodal expression was detected in HCC cell lines with high metastatic potential alone. Nodal expression is up-regulated in HCC tissues compared with paracarcinomatous and normal liver tissues. Nodal protein was expressed in 70 of the 96 (72.9%) HCC tumors, and was associated with vascular invasion (P = 0.000), status of metastasis (P = 0.004), AFP (P = 0.049), ICGR15 (indocyanine green retention rate at 15 min) (P = 0.010) and tumor size (P = 0.000). High Nodal expression was positively correlated with high MVD (microvessal density) (P = 0.006), but not with Vimentin expression (P = 0.053). Significantly fewer migrated and invaded cells were seen in shRNA group compared with blank group and negative control group (P<0.05). High Nodal expression was found to be an independent factor for predicting overall survival of HCC. Conclusions Our study demonstrated that Nodal expression is associated with aggressive characteristics of HCC. Its aberrant expression may be a predictive factor of unfavorable prognosis

  20. Increased Expression of CSF-1 Associates With Poor Prognosis of Patients With Gastric Cancer Undergoing Gastrectomy

    PubMed Central

    Liu, Hao; Zhang, Heng; Shen, Zhenbin; Lin, Chao; Wang, Xuefei; Qin, Jing; Qin, Xinyu; Xu, Jiejie; Sun, Yihong

    2016-01-01

    Abstract Clinical significance of diametrically polarized tumor-associated macrophages in gastric cancer has been elucidated in our previous study, whereas the role of cytokines that orchestrate tumor-associated macrophages polarization in gastric cancer remains elusive. The study aims to evaluate the prognostic value of colony-stimulating factor-1 expression in patients with gastric cancer. We examined the colony-stimulating factor-1 expression in tumor tissues by immunohistochemical staining in retrospectively enrolled 365 patients with gastric cancer undergoing gastrectomy at Zhongshan Hospital during 2008. Kaplan–Meier analysis and Cox regression models were used to evaluate the prognostic value of colony-stimulating factor-1 expression and its association with clinicopathological factors. A predictive nomogram by integrating colony-stimulating factor-1 expression with the TNM staging system was generated for overall survival evaluation of the patients. High colony-stimulating factor-1 expression predicted an unfavorable outcome in gastric cancer. The colony-stimulating factor-1 expression in tumor tissue could give a further discrimination for the prognosis of gastric cancer patients. Cox multivariate analysis identified the colony-stimulating factor-1 expression as an independent prognostic factor. The generated nomogram performed well in predicting the 3- and 5-year overall survival of gastric cancer patients. The colony-stimulating factor-1 is a potential independent adverse prognosticator for gastric cancer patients, which could be integrated with the tumor-associated macrophages staging system to improve the predictive accuracy for overall survival, especially in advanced tumors. PMID:26945355

  1. SOX4 is overexpressed in diffusely infiltrating astrocytoma and confers poor prognosis.

    PubMed

    Li, Ling; Li, Qiuyao; Chen, Xueqin; Xu, Miao; Li, Xinglan; Nie, Ling; Chen, Ni; Gong, Jing; Mao, Qing; Zhou, Qiao

    2015-12-01

    The SOX4 (sex-determining region Y-related high-mobility-group box transcription factor 4) gene plays critical roles in embryonic development and cell-fate determination. Recently, SOX4 overexpression has been found in various tumors. However, its expression status and prognostic significance in astrocytoma remain unknown. In this study, SOX4 expression in diffusely infiltrating astrocytoma (WHO grades II-IV) tissues (in comparison with pilocytic astrocytomas) was examined by immunohistochemistry, and its relevance with prognosis was analyzed. Our data showed that SOX4 was over-expressed in diffusely infiltrating astrocytomas and its expression was positively correlated with astrocytoma grade (WHO grades II-IV). Significantly, Kaplan-Meier analysis revealed that SOX4 nuclear overexpression (SOX4-N) was associated with poorer progression-free survival (PFS) and disease-specific survival (DSS) in diffusely infiltrating astrocytoma patients (P < 0.05). Cox regression analysis further showed that nuclear SOX4-N was a significant independent negative prognostic factor for these patients. PMID:26096696

  2. SOD2 deregulation enhances migration, invasion and has poor prognosis in salivary adenoid cystic carcinoma

    PubMed Central

    Chang, Boyang; Yang, Hang; Jiao, Yuan; Wang, Kefeng; Liu, Zhonghua; Wu, Peihong; Li, Su; Wang, Anxun

    2016-01-01

    This study aimed to investigate the role of SOD2 in the progression and metastasis of salivary adenoid cystic carcinoma (SACC). We analyzed the expression of SOD2 in 50 SACC patients. Then, the effects and mechanism of SOD2 on cell metastasis in a pair of different metastatic potential cell lines was investigated. SOD2 was deregulated in patients with SACC. Up-regulation of SOD2 was associated with distant metastasis and reduced overall survival and disease free - survival. Compared to SACC-83 cells (lower metastasis ability), SACC-LM cells (higher metastasis ability) had higher SOD2 activity and intracellular H2O2 concentrations, and protein levels of pERK1/2 and Slug, but had similar catalase protein level and activity. In SACC-LM, reducing the expression of SOD2 by SiRNA inhibited the metastasis ability and reduced the SOD2 activities, intracellular H2O2 concentrations, and protein levels of pERK1/2 and Slug. These effects were revised in SACC-83 after SOD2 overexpression. Moreover, in SACC-83, treated with H2O2, the metastasis was enhanced accompanied by increased protein levels of pERK1/2 and Slug. We confirmed that SOD2 play an important role in the development and prognosis of SACC and SOD2-dependent production of H2O2 contributes to metastasis of SACC through the ERK-Slug signaling pathway. PMID:27181103

  3. High expression of Sox10 correlates with tumor aggressiveness and poor prognosis in human nasopharyngeal carcinoma

    PubMed Central

    Zhao, Yu; Liu, Zhi-gang; Tang, Jiao; Zou, Ren-fang; Chen, Xiao-yan; Jiang, Guan-min; Qiu, Yan-fang; Wang, Hui

    2016-01-01

    Purpose The aim of the study was to detect the expression of Sox10 in human nasopharyngeal carcinoma (NPC) and investigate the relationship between its expression and the clinicopathological characteristics of NPC patients. Patients and methods Tumor specimens (n=105) were retrospectively collected from patients with NPC diagnosed between 2004 and 2005 who presented at Hunan Cancer Hospital. Immunohistochemistry analyses were performed to characterize the expression of Sox10 in NPC. Kaplan–Meier survival and Cox regression analyses were employed to evaluate the prognosis of 105 NPC patients. Results The results showed that Sox10 was markedly overexpressed in human NPC tissues. Analysis of clinicopathological parameters showed that high Sox10 expression was significantly correlated with the clinical stage (P=0.032), T classification (P=0.034), and lymph node metastasis (P=0.03). Cox regression analyses further showed that Sox10 expression was an independent prognostic factor for overall survival (P=0.005). This is the first time Sox10 has shown its importance in predicting NPC progressiveness and survival outcomes. Conclusion Sox10 serves as a potential biomarker for NPC patients. It may hopefully become a novel therapeutic target for NPC patients. PMID:27051302

  4. Overexpressed Rce1 is positively correlated with tumor progression and predicts poor prognosis in prostate cancer.

    PubMed

    Huang, Liangliang; Li, Meicai; Wang, Delin; He, Jiang; Wu, Wenqiang; Zeng, Qiangfeng; Li, Jianjun; Xiao, Maolin; Hu, Jie; He, Yunfeng; Li, Ying; Mai, Li; Liu, Wujiang

    2016-01-01

    Ras and a-factor-converting enzyme 1 (Rce1) have been reported to play a key role in the proteolysis processing of Ras proteins. The present study investigated the prognostic significance of Rce1 in patients with prostate cancer (PCa). The expressions of the mRNA and protein of Rce1 were analyzed in 12 pairs of PCa and benign prostatic hyperplasia (BPH) by quantitative real-time polymerase chain reaction and Western blotting, respectively. Immunohistochemistry was used to examine expression of Rce1 protein in 74 PCa tissues and 30 BPH tissues. The association between Rce1 expression and the specific clinicopathologic features was evaluated by χ(2) tests. Kaplan-Meier and Cox proportional hazards regression models were used to analyze the data. We found that expression of Rce1 mRNA and protein was markedly higher in PCa tissues than in paired BPH tissues. Expression of Rce1 in PCa was strongly associated with clinicopathologic features. It was detected in 69 (93.24%) of 74 PCa tissues by immunohistochemistry, and it was found to be associated with Gleason score (P = .013), T class (P = .015), and distant metastasis (P = .044). Patients with PCa having higher Rce1 expression had substantially shorter survival times than patients with lower Rce1 expression. Univariate and multivariate analysis revealed that Rce1 was an independent prognostic factor. In conclusion, our study suggests that expression of Rce1 can serve as an independent biomarker for the prognosis of PCa patients. PMID:26546252

  5. Axl Expression Stratifies Patients with Poor Prognosis after Hepatectomy for Hepatocellular Carcinoma

    PubMed Central

    Xia, Yong; Li, Jun; Shi, Lehua; Zou, Qifei; Wan, Xuying; Jiao, Binghua; Wang, Hongyang; Wu, Mengchao; Zhang, Yongjie; Shen, Feng

    2016-01-01

    Background Axl is a receptor tyrosine kinase which plays an important role in multiple human malignancies. Design The Axl expression was examined in several hepatocellular carcinoma(HCC) cell lines, paired tumor and nontumorous samples. Then, we examined cell growth curve, cell apoptosis and cell migration in SMMC-7721 cells over-expressed with Axl or siRNA against Axl, respectively. Finally, the prognostic value of Axl was investigated in a prospective cohort of 246 consecutive HCC patients undergoing curative hepatoectomy. Results We found Axl was positive in 22% of examined tumor tissues and all four cell lines. Over-expressing Axl in SMMC-7721 cells accelerated cell growth, cell migration and inhibited cell apoptosis, while knock-down of Axl exerted opposite effect. Axl expression was closely associated with serum AFP, multiple tumors, absence of encapsulation, microvascular invasion, and advanced BCLC or TNM stage. Patients with positive Axl staining had a higher 5-year recurrence rate (92% vs. 71%, P<0.001) and a lower 5-year survival rate (9% vs. 48%, P<0.001) than those with negative staining. The multivariate analyses showed that Axl expression was an independent factor for both tumor recurrence (HR: 1.725; 95% CI: 1.219–2.441) and survival (1.847; 1.291–2.642). Conclusion Axl expression suggests more aggressive tumor invasiveness and predicts worse prognosis for HCC patients undergoing resection. PMID:27182739

  6. Increased NUCKS expression is a risk factor for poor prognosis and recurrence in endometrial cancer

    PubMed Central

    Liu, Tianbo; Tan, Shu; Xu, Ye; Meng, Fanling; Yang, Chang; Lou, Ge

    2015-01-01

    Nuclear ubiquitous casein and cyclin-dependent kinases substrate (NUCKS) was reported to function as a potential biomarker in various tumors. Thus, we aimed to explore the expression of NUCKS in endometrial cancer (EC) and its clinical significance using quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC). qRT-PCR results showed that NUCKS mRNA expression gradually elevated from normal endometrium to atypical endometrial hyperplasia, and to EC (P < 0.05 between each group). NUCKS overexpression was strongly associated with FIGO stage (P = 0.002), histologic grade (P = 0.029), lympho-vascular space involvement (P = 0.014), lymph node metastasis (P = 0.019), and recurrence (P < 0.001). Cox multivariate analysis revealed that NUCKS overexpression was an independent factor for overall survival and recurrence-free survival (P < 0.001 for both). Multivariate logistic regression suggested that recurrence was independently correlated with NUCKS overexpresion (P = 0.039), FIGO stage (P = 0.002), and lymph node metastasis (P = 0.002). In summary, NUCKS overexpression may function as a potential biomarker for prognosis especially for recurrence in ECs. PMID:26885454

  7. Low level of 5-Hydroxymethylcytosine predicts poor prognosis in non-small cell lung cancer

    PubMed Central

    LIAO, YUNFEI; GU, JIE; WU, YONGBING; LONG, XIANG; GE, DI; XU, JIANJUN; DING, JIANYONG

    2016-01-01

    The loss of 5-hydroxymethylcytosine (5-hmC) has previously been demonstrated to be implicated in the initiation and progression of various tumors. However, its role in non-small cell lung cancer (NSCLC) remains unknown. The present study aimed to determine the level of 5-hmC in NSCLC and their adjacent normal lung tissues by immunohistochemistry and dot-blot analysis; then the relationship between 5-hmC level and the clinicopathological features of NSCLC and the prognostic significance of 5-hmC level in NSCLC patients were analyzed. By employing the dot-blot analysis, a significant reduction of 5-hmC level in NSCLC tissues compared with the adjacent normal tissues was detected, which were further verified by the immunohistochemistry results on tissue microarrays. Further analyses demonstrated that 65.38% (136/208) presented with low 5-hmC level, and low 5-hmC level was significantly associated with lymph node metastasis (P<0.001), histological type (P<0.001) and large tumor size (P=0.031). Notably, the 5-year overall survival rate of patients with low 5-hmC levels were significantly lower than patients with high 5-hmC levels (P<0.001). In addition, it was demonstrated that 5-hmC level was identified as independent prognostic factor in patients' overall survival. In conclusion, downregulation of 5-hmC may serve as a useful biomarker for NSCLC prognosis evaluation. PMID:27313688

  8. Overexpression of long noncoding RNA HOTTIP promotes tumor invasion and predicts poor prognosis in gastric cancer

    PubMed Central

    Ye, Heng; Liu, Kun; Qian, Keqing

    2016-01-01

    Purpose Long noncoding RNAs have been proved to play important roles in the tumorigenesis and development of human gastric cancer (GC). Our study aims to investigate the expression and function of Homeobox A transcript at the distal tip (HOTTIP) in GC. Methods HOTTIP expression was detected in GC tissues and cell lines by using quantitative reverse transcription polymerase chain reaction. Association between HOTTIP levels and clinicopathological factors and patient prognosis was also analyzed. MTT, flow cytometry, and transwell invasion and migration assays were used to investigate the role of HOTTIP in the regulation of biological behaviors of GC cells. Results HOTTIP expression was remarkably increased in GC tissues and cell lines compared with that in the normal control. Clinicopathologic analysis revealed that high HOTTIP expression correlated with larger tumor size, deeper invasion depth, positive lymph node metastasis, advanced TNM stage, and shorter overall survival. Multivariate regression analysis identified HOTTIP overexpression as an independent unfavorable prognostic factor in GC patients. Moreover, HOTTIP downregulation by si-HOTTIP transfection impaired GC cell proliferation, promoted cell apoptosis, and reduced cell invasion and migration. Conclusion These findings suggested that HOTTIP may contribute to GC initiation and progression, and would be not only a novel prognostic marker but also a potential therapeutic target for this disease. PMID:27103834

  9. SOD2 deregulation enhances migration, invasion and has poor prognosis in salivary adenoid cystic carcinoma.

    PubMed

    Chang, Boyang; Yang, Hang; Jiao, Yuan; Wang, Kefeng; Liu, Zhonghua; Wu, Peihong; Li, Su; Wang, Anxun

    2016-01-01

    This study aimed to investigate the role of SOD2 in the progression and metastasis of salivary adenoid cystic carcinoma (SACC). We analyzed the expression of SOD2 in 50 SACC patients. Then, the effects and mechanism of SOD2 on cell metastasis in a pair of different metastatic potential cell lines was investigated. SOD2 was deregulated in patients with SACC. Up-regulation of SOD2 was associated with distant metastasis and reduced overall survival and disease free - survival. Compared to SACC-83 cells (lower metastasis ability), SACC-LM cells (higher metastasis ability) had higher SOD2 activity and intracellular H2O2 concentrations, and protein levels of pERK1/2 and Slug, but had similar catalase protein level and activity. In SACC-LM, reducing the expression of SOD2 by SiRNA inhibited the metastasis ability and reduced the SOD2 activities, intracellular H2O2 concentrations, and protein levels of pERK1/2 and Slug. These effects were revised in SACC-83 after SOD2 overexpression. Moreover, in SACC-83, treated with H2O2, the metastasis was enhanced accompanied by increased protein levels of pERK1/2 and Slug. We confirmed that SOD2 play an important role in the development and prognosis of SACC and SOD2-dependent production of H2O2 contributes to metastasis of SACC through the ERK-Slug signaling pathway. PMID:27181103

  10. Low Level of Microsatellite Instability Correlates with Poor Clinical Prognosis in Stage II Colorectal Cancer Patients

    PubMed Central

    Mojarad, Ehsan Nazemalhosseini; Kashfi, Seyed Mohammad Hossein; Mirtalebi, Hanieh; Taleghani, Mohammad Yaghoob; Azimzadeh, Pedram; Savabkar, Sanaz; Pourhoseingholi, Mohammad Amin; Jalaeikhoo, Hasan; Asadzadeh Aghdaei, Hamid; Kuppen, Peter J. K.; Zali, Mohammad Reza

    2016-01-01

    The influence of microsatellite instability (MSI) on the prognosis of colorectal cancer (CRC) requires more investigation. We assessed the role of MSI status in survival of individuals diagnosed with primary colorectal cancer. In this retrospective cross-sectional study the MSI status was determined in 158 formalin-fixed paraffin-embedded tumors and their matched normal tissues from patients who underwent curative surgery. Cox proportional hazard modeling was performed to assess the clinical prognostic significance. In this study we found that MSI-H tumors were predominantly located in the colon versus rectum (p = 0.03), associated with poorer differentiation (p = 0.003) and TNM stage II/III of tumors (p = 0.02). In CRC patients with stage II, MSI-L cases showed significantly poorer survival compared with patients who had MSI-H or MSS tumors (p = 0.04). This study indicates that MSI-L tumors correlate with poorer clinical outcome in patients with stage II tumors (p = 0.04) or in tumors located in the colon (p = 0.02). MSI-L characterizes a distinct subgroup of CRC patients who have a poorer outcome. This study suggests that MSI status in CRC, as a clinical prognostic marker, is dependent on other factors, such as tumor stage and location. PMID:27429617

  11. High telomerase activity and long telomeres in advanced hepatocellular carcinomas with poor prognosis.

    PubMed

    Oh, Bong-Kyeong; Kim, Haeryoung; Park, Young Nyun; Yoo, Jeong Eun; Choi, Jinsub; Kim, Kyung-Sik; Lee, Jae Jung; Park, Chanil

    2008-02-01

    Telomerase reactivation and telomere maintenance are crucial in carcinogenesis and tumor progression. In this study, the relationships between telomere parameters, chromosomal instability and clinicopathological features were evaluated in hepatocellular carcinomas (HCCs). Telomere length (TL), telomerase activity (TA) and human telomerase reverse transcriptase (hTERT) mRNA levels were measured in 49 hepatitis B virus (HBV)-related HCCs and corresponding non-tumorous tissues. The results were compared with clinicopathological data, including differentiation, multipolar mitosis (MM), anaphase bridge, immunohistochemical stain results for cytokeratin 19 (CK19) and patient outcome. TL of HCCs ranged from 4.7 to 13.1 kb, and 44.4% of HCCs showed telomere lengthening. hTERT mRNA levels and TA were closely related (P=0.008), and were significantly higher in HCCs than non-tumorous tissues. TL was significantly higher in HCCs with strong TA (P=0.048), high hTERT mRNA levels (P=0.001) and poor differentiation (P=0.041). Frequent MM was associated with poor differentiation (P=0.007) and advanced stage (P<0.001). TA was positively correlated with MM, anaphase bridges and advanced stage (P=0.019, P=0.017 and P=0.029). Thirteen (28.3%) HCCs were CK19+ and demonstrated longer telomeres than CK19- HCCs (P=0.046). Overall survival was poor in HCCs with MM >0.4 per field (P=0.016), high TA (P=0.009) and high TL ratio (HCC/non-HCC) >0.8 (P=0.044). Our results show that long telomeres, high TA and high mitotic instability are poor prognostic markers for HBV-related HCCs and their close association suggests that telomere maintenance may be important for the progression of HCCs with high chromosomal instability to more aggressive ones. PMID:18158557

  12. Fertility treatment when the prognosis is very poor or futile: a committee opinion.

    PubMed

    2012-07-01

    The Ethics Committee recommends development of evidence-based policies that are patient-centered for each in vitro fertilization (IVF) center. In most cases, the provision of futile therapies is not ethically justifiable. For those treatments with very poor success rates, clinicians must be vigilant in their presentation of risks, benefits, and alternatives. This document was reviewed in January 2012. This version replaces the previous version of this document, published in 2009. PMID:22537382

  13. DNMT3A R882 Mutations Predict a Poor Prognosis in AML

    PubMed Central

    Yuan, Xiao-Qing; Peng, Li; Zeng, Wen-Jing; Jiang, Bin-Yuan; Li, Guan-Cheng; Chen, Xiao-Ping

    2016-01-01

    Abstract DNA (cytosine-5)-methyltransferase 3 alpha (DNMT3A) mutations were widely believed to be independently associated with inferior prognosis in acute myeloid leukemia (AML) patients. As dominant missense alterations in DNMT3A mutations, R882 mutations cause the focal hypomethylation phenotype. However, there remains debate on the influence of R882 mutations on AML prognosis. Thus, this meta-analysis aimed at further illustrating the prognostic power of DNMT3A R882 mutations in AML patients. Eligible studies were identified from 5 databases containing PubMed, Embase, Web of Science, Clinical Trials, and the Cochrane Library (up to October 25, 2015). Effects (hazard ratios [HRs] with 95% confidence interval [CI]) of relapse-free survival (RFS) and overall survival (OS) were pooled to estimate the prognostic power of mutant DNMT3A R882 in overall patients and subgroups of AML patients. Eight competent studies with 4474 AML patients including 694 with DNMT3A R882 mutations were included. AML patients with DNMT3A R882 mutations showed significant shorter RFS (HR = 1.40, 95% CI = 1.24–1.59, P < 0.001) and OS (HR = 1.47, 95% CI = 1.17–1.86, P = 0.001) in the overall population. DNMT3A R882 mutations predicted worse RFS and OS among the subgroups of patients under age 60 (RFS: HR = 1.44, 95% CI = 1.25–1.66, P < 0.001; OS: HR = 1.48, 95% CI = 1.15–1.90, P = 0.002), over age 60 (RFS: HR = 2.03, 95% CI = 1.40–2.93, P < 0.001; OS: HR = 1.85, 95% CI = 1.36–2.53, P < 0.001), cytogenetically normal (CN)-AML (RFS: HR = 1.52, 95% CI = 1.26–1.83, P < 0.001; OS: HR = 1.67, 95% CI = 1.16–2.41, P = 0.006), and non-CN-AML (RFS: HR = 1.96, 95% CI = 1.20–3.21, P = 0.006; OS: HR = 2.51, 95% CI = 1.52–4.15, P = 0.0038). DNMT3A R882 mutations possessed significant unfavorable prognostic influence on RFS and OS in AML patients. PMID:27149454

  14. Elevated Preoperative Serum Gamma-glutamyltranspeptidase Predicts Poor Prognosis for Hepatocellular Carcinoma after Liver Transplantation.

    PubMed

    Fu, Shun-Jun; Zhao, Qiang; Ji, Fei; Chen, Mao-Gen; Wu, Lin-Wei; Ren, Qing-Qi; Guo, Zhi-Yong; He, Xiao-Shun

    2016-01-01

    Gamma-glutamyltransferase (γ-GGT) is a membrane-bound enzyme that is involved in biotransformation, nucleic acid metabolism, and tumourigenesis. Elevated serum γ-GGT levels are related to an increased cancer risk and worse prognosis in many cancers. In the present study, we evaluated the prognostic value of preoperative serum γ-GGT in patients with hepatocellular carcinoma (HCC) who underwent liver transplantation (LT). A total of 130 HCC patients after LT were included in the study. The optimal cut-off value of γ-GGT was 128U/L by receiver operating characteristic analysis, with a sensitivity and specificity of 60.0% and 72.9%, respectively. Elevated preoperative serum γ-GGT was significantly associated with high alpha-fetoprotein (AFP), large tumor size, and macro- and micro-vascular invasion. The 1-, 3-, 5-year disease-free survival (DFS) and overall survival (OS) rates of HCC patients in the γ-GGT > 128U/L group were poorer than those in the γ-GGT ≤ 128U/L group. Stratification analysis revealed that γ-GGT exhibited a greater predictive value for DFS and OS in HCC patients beyond the Milan criteria and no macro-vascular invasion. In conclusion, elevated preoperative serum γ-GGT was significantly associated with advanced tumor stage and aggressive tumor behaviors, and serum γ-GGT can be considered as a prognostic factor for HCC patients after LT, especially for patients beyond the Milan criteria or without macro-vascular invasion. PMID:27381639

  15. High expression of WDR1 in primary glioblastoma is associated with poor prognosis

    PubMed Central

    Xu, Hanchong; Chen, Yihong; Tan, Cong; Xu, Tao; Yan, Yong; Qin, Rong; Huang, Qilin; Lu, Chengyin; Liang, Chun; Lu, Yicheng; Wang, Hongxiang; Chen, Juxiang

    2016-01-01

    Primary glioblastoma always has a fatal outcome despite maximal therapy. Identification and validation of prognostic biomarkers and novel therapeutics will be potentially powerful to transform the care of glioblastoma patients. In this study, we constructed Affymetrix gene microarrays with 14 glioma samples to screen for genes with potential prognostic value by hieratical clustering, and 83 genes including WD-repeat containing protein 1 (WDR1) were filtered out. WDR1 is a major co-factor collaborating with cofilin in actin cytoskeletal dynamics, which may play vital role in glioma proliferation and invasion. Further, The Cancer Genome Atlas (TCGA) database was utilizedto verify the expression of WDR1 and its prognostic implicationin 528 glioblastoma specimens. Survival and correlation analyses showed WDR1 expression was highly expressed and related to the prognosis of glioblastoma and the expression of signal transducer and activator of transcription 3 (STAT3), respectively (p<0.05). Finally, WDR1 expression was detected in our large cohort containing 258 glioma patients (including 100 primary glioblastomas).And univariate and multivariate analyses confirmed that high WDR1 expression was an independent prognostic factor for a shorter progression-free survival (PFS) and overall survival (OS) in primary glioblastoma patients at our center [hazard ratio (HR)=1.844, p=0.005 and HR=2.085, p=0.001, respectively]. Together, WDR1 is significantly over-expressed in primary glioblastoma. High expression of WDR1 can independently predict unfavorable clinical outcome for primary glioblastoma patients. This study identifies a novel prognostic biomarker and a potential therapeutic target for glioblastoma. PMID:27158412

  16. Decreased xanthine oxidoreductase is a predictor of poor prognosis in early‐stage gastric cancer

    PubMed Central

    Linder, N; Haglund, C; Lundin, M; Nordling, S; Ristimäki, A; Kokkola, A; Mrena, J; Wiksten, J‐P; Lundin, J

    2006-01-01

    Background Xanthine oxidoreductase (XOR) is a key enzyme in the degradation of DNA, RNA and high‐energy phosphates. About half of the patients with breast cancer have a decrease in XOR expression. Patients with breast cancer with unfavourable prognosis are independently identified by the loss of XOR. Aim To assess the clinical relevance of XOR expression in gastric cancer. Methods XOR levels were studied by immunohistochemistry in tissue microarray specimens of 337 patients with gastric cancer and the relation between XOR expression and a series of clinicopathological variables, as well as disease‐specific survival, was assessed. Results XOR was moderately decreased in 41% and was undetectable in another 14% of the tumours compared with the corresponding normal tissue. Decreased XOR was associated with advanced stage, deep tumour penetration, diffusely spread tumour location, positive lymph node status, large tumour size, non‐curative disease, cellular aneuploidy, high S‐phase fraction and high cyclooxygenase‐2 expression, but not with p53 expression or Borrmann classification. Down regulation of XOR was associated with unfavourable outcome, and the cumulative 5‐year gastric cancer‐specific survival in patients with strong XOR expression was 47%, compared with 22% in those with moderate to negative expression (p<0.001). This was also true in patients with stage I–II (p = 0.01) and lymph node‐negative (p = 0.02) disease, as well as in patients with smaller (⩽5 cm) tumours (p = 0.02). Conclusion XOR expression in gastric cancer may be a new marker for a more aggressive gastric cancer biology, similar to that previously reported for breast cancer. PMID:16935971

  17. Concurrent Expression of VEGF-C and Neuropilin-2 Is Correlated with Poor Prognosis in Glioblastoma.

    PubMed

    Zhao, Haiqing; Hou, Chunfeng; Hou, Aiwu; Zhu, Dongyuan

    2016-01-01

    Vascular endothelial growth factor-C (VEGF-C) is a secreted growth factor involved in many oncogenic processes, and neuropilin-2 (NRP2) is essential for neuronal guidance as a well-acknowledged co-receptor of VEGF receptors. The overexpression of NRP2 has been reported in many types of cancers, but the significance of NRP2 in glioblastoma is not elucidated. To investigate the clinical significance of VEGF-C and NRP2 in glioblastoma, we detected their expression in 86 cases of glioblastoma with immunohistochemistry and categorized our cohort into high- and low-expression groups according to the immunohistochemistry score, which was the product of the score of staining intensity multiplied by the score reflecting the percentage of positive cells. The proportion of glioblastoma with high VEGF-C expression was 34.9% (30/86), and that with high NRP2 expression was 37.2% (32/86). The proportion of glioblastoma with high expression of both VEGF-C and NRP2 was 15.1% (13/86). Moreover, the proportion of cases with high VEGF-C and low NRP2 was 19.7% (17/86), while the proportion of cases with low VEGF-C and high NRP2 was 22.1% (19/86). The high expression of both VEGF-C and NRP2 was associated with poorer survival rate (P = 0.023), and can be identified as an independent prognostic factor in glioblastoma (P = 0.030). Moreover, cases with low NRP2 expression are easier for complete tumor resection (P = 0.038). In conclusion, the concurrent high expression of VEGF-C and NRP2 is predictive of the unfavorable prognosis in glioblastoma, indicating that the VEGF-C-NRP2 signaling pathway is a potential and promising drug target in glioblastoma therapy. PMID:26753562

  18. Decreased expression of SOX17 is associated with tumor progression and poor prognosis in breast cancer.

    PubMed

    Fu, De-Yuan; Tan, Hao-Sheng; Wei, Jin-Li; Zhu, Chang-Ren; Jiang, Ji-Xin; Zhu, Yu-Xiang; Cai, Feng-Lin; Chong, Mei-Hong; Ren, Chuan-Li

    2015-09-01

    The SOX17 (SRY-related HMG-box) transcription factor is involved in a variety of biological processes and is related to the tumorigenesis and progression of multiple tumors. However, the clinical application of SOX17 for breast cancer prognosis is currently limited. The aim of this study was to investigate the clinicopathologic and prognostic significance of SOX17 expression in human breast cancer. qPCR and western blot assays were performed to measure the expression of SOX17 in breast cancer cell lines and 30 matched pairs of breast cancer and corresponding noncancerous tissues. A SOX17 overexpression cell model was used to examine changes in cell growth in vitro. Immunohistochemical analyses were performed to retrospectively examine the prognostic impact of SOX17 expression in 187 additional breast cancer patients. Our results showed that SOX17 expression was decreased at both the messenger RNA (mRNA) and protein levels in the breast cancer cell lines and tissues, and that SOX17 overexpression could strongly suppress cell growth in vitro. Furthermore, the lack of SOX17 protein expression was strongly correlated with higher tumor grade (P = 0.002), lymph node metastasis (P < 0.001), and tumor node metastasis (TNM) stage (P = 0.001) and had poorer disease-free survival (DFS) and overall survival (OS) compared to normal SOX17 expression (P = 0.002 and 0.001, respectively). Univariate and multivariate analyses indicated that lower SOX17 expression was an independent prognostic factor for DFS (P = 0.007; HR = 2.854; 95 % CI 1.326-6.147) and OS (P = 0.005; HR = 5.035; 95 % CI 1.648-15.385) for breast cancer. Our findings indicate that SOX17 expression is a useful prognostic biomarker for breast cancer. PMID:25971583

  19. Gastric-type Endocervical Adenocarcinoma: An Aggressive Tumor With Unusual Metastatic Patterns and Poor Prognosis.

    PubMed

    Karamurzin, Yevgeniy S; Kiyokawa, Takako; Parkash, Vinita; Jotwani, Anjali R; Patel, Prusha; Pike, Malcolm C; Soslow, Robert A; Park, Kay J

    2015-11-01

    Gastric-type adenocarcinoma of the uterine cervix (GAS) is a rare variant of mucinous endocervical adenocarcinoma not etiologically associated with human papillomavirus (HPV) infection, with minimal deviation adenocarcinoma (MDA) at the well-differentiated end of the morphologic spectrum. These tumors are reported to have worse prognosis than usual HPV associated endocervical adenocarcinoma (UEA). A retrospective review of GAS was performed from the pathology databases of 3 institutions spanning 20 years. Stage, metastatic patterns, and overall survival were documented. Forty GAS cases were identified, with clinical follow-up data available for 38. The tumors were subclassified as MDA (n=13) and non-MDA GAS (n=27). Two patients were syndromic (1 Li-Fraumeni, 1 Peutz-Jeghers). At presentation, 59% were advanced stage (FIGO II to IV), 50% had lymph node metastases, 35% had ovarian involvement, 20% had abdominal disease, 39% had at least 1 site of metastasis at the time of initial surgery, and 12% of patients experienced distant recurrence. The metastatic sites included lymph nodes, adnexa, omentum, bowel, peritoneum, diaphragm, abdominal wall, bladder, vagina, appendix, and brain. Follow-up ranged from 1.4 to 136.0 months (mean, 33.9 mo); 20/38 (52.6%) had no evidence of disease, 3/38 (7.9%) were alive with disease, and 15/38 (39.5%) died of disease. Disease-specific survival at 5 years was 42% for GAS versus 91% for UEA. There were no survival differences between MDA and non-MDA GAS. GAS represents a distinct, biologically aggressive type of endocervical adenocarcinoma. The majority of patients present at advanced stage and pelvic, abdominal, and distant metastases are not uncommon. PMID:26457350

  20. Overexpression of HOXB7 is associated with a poor prognosis in patients with gastric cancer

    PubMed Central

    TU, WEIWEI; ZHU, XINGWU; HAN, YANG; WEN, YUGANG; QIU, GUOQIANG; ZHOU, CHONGZHI

    2015-01-01

    Previous studies have indicated that the homeobox gene HOXB7 is overexpressed in certain cancers, which promotes tumorigenesis. However, less is known about the association between the HOXB7 gene and gastric cancer. The purpose of the present study was to investigate the association between the expression level of HOXB7 and gastric cancer. Reverse transcription-quantitative polymerase chain reaction and western blot analysis were used to detect the expression of the homeobox B7 (HOXB7) RNA and protein, respectively. In addition, the association between the expression of HOXB7 and the clinicopathological characteristics of gastric cancer was analyzed by immunohistochemistry. The Kaplan-Meier method was used to calculate the survival rates, and the COX proportional hazards model was used to investigate univariate and multivariate analyses. The expression level of HOXB7 RNA and protein was significantly elevated in cancerous tissues compared with the corresponding normal mucosa. Increased expression of HOXB7 was significantly associated with tumor size (P=0.01), T stage (P<0.001) and advanced Union for International Cancer Control stage (P=0.003). In addition, patients with positive HOXB7 expression possessed an evident lower overall survival and disease-free survival rate compared with patients with tumors that did not express HOXB7. Furthermore, univariate and multivariate analyses indicated that HOXB7 served as a significant independent prognostic factor for OS and DFS in patients with gastric cancer. The present data indicate that the HOXB7 gene may play an important role in the process of gastric tumorigenesis, and also indicate that HOXB7 may be an important determinant of patient prognosis in gastric cancer. PMID:26722273

  1. Elevated Preoperative Serum Gamma-glutamyltranspeptidase Predicts Poor Prognosis for Hepatocellular Carcinoma after Liver Transplantation

    PubMed Central

    Fu, Shun-Jun; Zhao, Qiang; Ji, Fei; Chen, Mao-Gen; Wu, Lin-Wei; Ren, Qing-Qi; Guo, Zhi-Yong; He, Xiao-Shun

    2016-01-01

    Gamma-glutamyltransferase (γ-GGT) is a membrane-bound enzyme that is involved in biotransformation, nucleic acid metabolism, and tumourigenesis. Elevated serum γ-GGT levels are related to an increased cancer risk and worse prognosis in many cancers. In the present study, we evaluated the prognostic value of preoperative serum γ-GGT in patients with hepatocellular carcinoma (HCC) who underwent liver transplantation (LT). A total of 130 HCC patients after LT were included in the study. The optimal cut-off value of γ-GGT was 128U/L by receiver operating characteristic analysis, with a sensitivity and specificity of 60.0% and 72.9%, respectively. Elevated preoperative serum γ-GGT was significantly associated with high alpha-fetoprotein (AFP), large tumor size, and macro- and micro-vascular invasion. The 1-, 3-, 5-year disease-free survival (DFS) and overall survival (OS) rates of HCC patients in the γ-GGT > 128U/L group were poorer than those in the γ-GGT ≤ 128U/L group. Stratification analysis revealed that γ-GGT exhibited a greater predictive value for DFS and OS in HCC patients beyond the Milan criteria and no macro-vascular invasion. In conclusion, elevated preoperative serum γ-GGT was significantly associated with advanced tumor stage and aggressive tumor behaviors, and serum γ-GGT can be considered as a prognostic factor for HCC patients after LT, especially for patients beyond the Milan criteria or without macro-vascular invasion. PMID:27381639

  2. High Expression of HULC Is Associated with Poor Prognosis in Osteosarcoma Patients

    PubMed Central

    Uzan, Vanessa Regina Maciel; Lengert, André van Helvoort; Boldrini, Érica; Penna, Valter; Scapulatempo-Neto, Cristovam; Scrideli, Carlos Alberto; Filho, Alberto Paiva de Moraes; Cavalcante, Carlos Eduardo Bezerra; de Oliveira, Cleyton Zanardo; Lopes, Luiz Fernando

    2016-01-01

    Osteosarcoma (OS) is the most common primary bone cancer in childhood. OS is an aggressive disease, and metastatic patients evolve with very poor clinical outcomes. Genetically, OSs are extremely complex tumors, and the related metastatic process is not well understood in terms of the biology of the disease. In this context, long non-coding RNAs (lncRNAs) have emerged as an important class of gene expression regulators that play key roles in the invasion and metastasis of several human tumors. Here, we evaluated the expression of HULC, which is an lncRNA that is associated with the tumor metastatic process, and assessed its potential role as a prognostic marker in OS. HULC expression was evaluated in primary OS samples using real-time RT-PCR. HULC expression status was determined by receiver operating characteristic (ROC) analysis, and its association with survival was assessed using the Kaplan-Meier method. The HULC expression level was not significantly associated with the clinicopathological characteristics of the OS patients. However, our data demonstrated that higher levels of expression of HULC were associated with lower survival rates in OS patients, both in terms of overall and event-free survival. Elevated HULC expression was associated with poor clinical outcomes among the OS patients, which suggests that HULC could be a potential prognostic biomarker in OS. PMID:27253450

  3. Cytokeratin 8/18 expression indicates a poor prognosis in squamous cell carcinomas of the oral cavity

    PubMed Central

    Fillies, Thomas; Werkmeister, Richard; Packeisen, Jens; Brandt, Burkhard; Morin, Philippe; Weingart, Dieter; Joos, Ulrich; Buerger, Horst

    2006-01-01

    Background Intermediary filaments are involved in cell motility and cancer progression. In a variety of organs, the expression of distinct intermediary filaments are associated with patient prognosis. In this study, we seeked to define the prognostic potential of cytokeratin and vimentin expression patterns in squamous cell carcinomas (SCC's) of the oral cavity. Methods 308 patients with histologically proven and surgically treated squamous cell carcinomas of the oral cavity were investigated for the immunohistochemical expression of a variety of intermediary filaments including high- and low-molecular weight cytokeratins (Ck's), such as Ck 5/6, Ck 8/18, Ck 1, CK 10, Ck 14, Ck 19 and vimentin, using the tissue microarray technique. Correlations between clinical features and the expression of Cytokeratins and vimentin were evaluated statistically by Kaplan-Meier curves and multivariate Cox regression analysis. Results The expression of Ck 8/18 and Ck 19 were overall significantly correlated with a poor clinical prognosis (Ck 8/18 p = 0.04; Ck19 p < 0.01). These findings could also be reproduced for Ck 8/18 in primary nodal-negative SCC's and held true in multivariate-analysis. No significant correlation with patient prognosis could be found for the expression of the other cytokeratins and for vimentin. Conclusion The expression of Ck 8/18 in SCC's of the oral cavity is an independent prognostic marker and indicates a decreased overall and progression free survival. These results provide an extended knowledge about the role of intermediary filament expression patterns in SCC's. PMID:16412231

  4. High-level expression of HOXB13 is closely associated with tumor angiogenesis and poor prognosis of hepatocellular carcinoma

    PubMed Central

    Zhu, Jian-Yu; Sun, Qi-Kai; Wang, Wei; Jia, Wei-Dong

    2014-01-01

    Homeobox B13 (HOXB13) is generally considered as a crucial regulator of terminal cellular differentiation. More recently, the absent or aberrant expression of HOXB13 has been increasingly implicated in cancer development and metastasis. However, the expression of HOXB13 in hepatocellular carcinoma (HCC) and its correlation with tumor angiogenesis and prognosis still remain unclear. The aim of the study was to evaluate the expression of HOXB13 in patients with HCC and explore the relationship of HOXB13 expression with clinicopathologic factors, tumor angiogenesis and prognosis. Immunohistochemistry was performed to determine the expression of HOXB13 in HCC and corresponding paracarcinomatous tissues from 72 patients. Vascular endothelial growth factor (VEGF) and CD31 were only examined in tissues of HCC patients mentioned above. The results showed that HOXB13 expression was significantly (P <0.001) higher in HCC (69.4%) than that in surrounding non-tumor tissues (26.4%), positively correlated with tumor VEGF (P <0.001) and microvessel density (MVD) (P = 0.013). Besides, it was associated with tumor capsula (P <0.001), vascular invasion (P <0.001), Edmondson grade (P <0.001), AFP (P = 0.007) and TNM stage (P <0.001). Univariate analysis showed poorer overall survival (OS) rate and disease free survival (DFS) rate in patients expressing higher levels of HOXB13. HOXB13 was also found to be an independent poor prognostic factor of OS and DFS in multivariate analysis. Taken together, our results suggest that increased HOXB13 expression is associated with tumor angiogenesis and progression in HCC and may function as a promising biomarker for unfavorable prognosis of HCC. PMID:25031711

  5. Genetic alterations in fatty acid transport and metabolism genes are associated with metastatic progression and poor prognosis of human cancers.

    PubMed

    Nath, Aritro; Chan, Christina

    2016-01-01

    Reprogramming of cellular metabolism is a hallmark feature of cancer cells. While a distinct set of processes drive metastasis when compared to tumorigenesis, it is yet unclear if genetic alterations in metabolic pathways are associated with metastatic progression of human cancers. Here, we analyzed the mutation, copy number variation and gene expression patterns of a literature-derived model of metabolic genes associated with glycolysis (Warburg effect), fatty acid metabolism (lipogenesis, oxidation, lipolysis, esterification) and fatty acid uptake in >9000 primary or metastatic tumor samples from the multi-cancer TCGA datasets. Our association analysis revealed a uniform pattern of Warburg effect mutations influencing prognosis across all tumor types, while copy number alterations in the electron transport chain gene SCO2, fatty acid uptake (CAV1, CD36) and lipogenesis (PPARA, PPARD, MLXIPL) genes were enriched in metastatic tumors. Using gene expression profiles, we established a gene-signature (CAV1, CD36, MLXIPL, CPT1C, CYP2E1) that strongly associated with epithelial-mesenchymal program across multiple cancers. Moreover, stratification of samples based on the copy number or expression profiles of the genes identified in our analysis revealed a significant effect on patient survival rates, thus confirming prominent roles of fatty acid uptake and metabolism in metastatic progression and poor prognosis of human cancers. PMID:26725848

  6. High ROR2 expression in tumor cells and stroma is correlated with poor prognosis in pancreatic ductal adenocarcinoma

    PubMed Central

    Huang, Jianfei; Fan, Xiangjun; Wang, Xudong; Lu, Yuhua; Zhu, Huijun; Wang, Wei; Zhang, Shu; Wang, Zhiwei

    2015-01-01

    RTK-like orphan receptor 2 (ROR2) is overexpressed in several cancers and has tumorigenic activity. However, the expression of ROR2 and its functional and prognostic significance have yet to be evaluated in pancreatic ductal adenocarcinoma (PDAC). Quantitative real-time polymerase chain reaction was used to characterize the expression of ROR2 mRNA in PDAC, corresponding peritumoral tissues, and PDAC cell lines. Immunohistochemical analysis with tissue microarrays was used to evaluate ROR2 expression in PDAC and to investigate the relationship of this expression to clinicopathological factors and prognosis. The expression of ROR2 mRNA and protein was significantly higher in PDAC than in normal pancreatic tissues. High cytoplasmic ROR2 expression in cancer cells was significantly associated with a primary tumor, distant metastasis, and TNM stage, and high stromal ROR2 expression was significantly associated with regional lymph node metastasis and TNM stage. The Kaplan–Meier method and Cox regression analyses showed that high ROR2 expression in tumor cytoplasm or stromal cells was significantly associated with malignant attributes and reduced survival in PDAC. We present strong evidence that ROR2 could be used as an indicator of poor prognosis and could represent a novel therapeutic target for PDAC. PMID:26259918

  7. Upregulated expression of polycomb protein Ring1 contributes to poor prognosis and accelerated proliferation in human hepatocellular carcinoma.

    PubMed

    Xiong, Yicheng; Hu, Baoying; Wei, Lixian; Jiang, Dawei; Zhu, Mingyan

    2015-12-01

    Ring finger protein 1 (Ring1) have recently been reported to be closely related to aggressive tumor features in multiple cancer types, including prostate cancer, non-small-cell lung cancer, and bladder cancer. However, the role of Ring1 in human hepatocarcinogenesis remains unclear. In this study, we aimed at investigating the latent role of Ring1 in hepatocellular carcinoma (HCC) development. The expression of Ring1 was evaluated using Western blot analysis in 8 paired fresh HCC tissues and immunohistochemistry on 98 paraffin-embedded sections from 2005 to 2008. Moreover, RNA interference, CCK-8, colony formation, and flow-cytometry analyses were performed to investigate the role of Ring1 in the regulation of HCC cell proliferation. Compared with adjacent normal tissues, the level of Ring1 was significantly increased in HCC specimens. High expression of Ring1 was associated with histological grade (P = 0.011) and tumor size (P = 0.004), and Ring1 expression was positively related with the proliferation marker Ki-67 (P < 0.001). Moreover, knocking down Ring1 induced growth impairment and G1/S cell cycle arrest in HCC cells. Kaplan-Meier survival curves showed that high expression of Ring1 indicated poor prognosis of HCC (P = 0.03). On the basis of these results, we proposed that the expression of Ring1 protein may be a novel indicator of HCC prognosis. PMID:26141041

  8. Downregulation of the long non-coding RNA TUSC7 promotes NSCLC cell proliferation and correlates with poor prognosis

    PubMed Central

    Wang, Zhongwei; Jin, Yingying; Ren, Hongtao; Ma, Xiulong; Wang, Baofeng; Wang, Yali

    2016-01-01

    Background: Emerging evidence indicated that dysregulated long non-coding RNAs (lncRNAs) was implicated in the tumorigenesis and progression. LncRNA TUSC7 was involved in various malignancies. However, the role of TUSC7 in human non-small-cell lung cancer (NSCLC) remains unclear. Methods: Expression of TUSC7 was analyzed in 112 cases of NSCLC tissues and six lung cancer cell lines by quantitative real-time PCR (qRT-PCR). Then the correlation of TUSC7 expression with clinicopathological features and prognosis was aslo studied. Furthermore, overexpression of TUSC7 was performed and its role in tumor progression was explored. Results: The expression level of TUSC7 was lower in NSCLC tissues and lung cancer cells compared with their normal counterparts. Lower expression of TUSC7 in NSCLC tissues was associated with larger tumor size and higher TNM stage. Patients with lower TUSC7 expression had worse overall survival compared with the high expression cases. Univariate and multivariate analyses suggested that low expression of TUSC7 was an independent poor prognostic indicator for NSCLC patients. Moreover, upregulation of TUSC7 expression could inhibit proliferation of lung cancer cell in vitro. Conclusions: Our results suggested that TUSC7 was a potential biomarker for NSCLC prognosis, and the dysregulation of TUSC7 may play an important role in the NSCLC progression. PMID:27158360

  9. Genetic alterations in fatty acid transport and metabolism genes are associated with metastatic progression and poor prognosis of human cancers

    PubMed Central

    Nath, Aritro; Chan, Christina

    2016-01-01

    Reprogramming of cellular metabolism is a hallmark feature of cancer cells. While a distinct set of processes drive metastasis when compared to tumorigenesis, it is yet unclear if genetic alterations in metabolic pathways are associated with metastatic progression of human cancers. Here, we analyzed the mutation, copy number variation and gene expression patterns of a literature-derived model of metabolic genes associated with glycolysis (Warburg effect), fatty acid metabolism (lipogenesis, oxidation, lipolysis, esterification) and fatty acid uptake in >9000 primary or metastatic tumor samples from the multi-cancer TCGA datasets. Our association analysis revealed a uniform pattern of Warburg effect mutations influencing prognosis across all tumor types, while copy number alterations in the electron transport chain gene SCO2, fatty acid uptake (CAV1, CD36) and lipogenesis (PPARA, PPARD, MLXIPL) genes were enriched in metastatic tumors. Using gene expression profiles, we established a gene-signature (CAV1, CD36, MLXIPL, CPT1C, CYP2E1) that strongly associated with epithelial-mesenchymal program across multiple cancers. Moreover, stratification of samples based on the copy number or expression profiles of the genes identified in our analysis revealed a significant effect on patient survival rates, thus confirming prominent roles of fatty acid uptake and metabolism in metastatic progression and poor prognosis of human cancers. PMID:26725848

  10. APACHE II Score, Rather Than Cardiac Function, May Predict Poor Prognosis in Patients With Stress-Induced Cardiomyopathy

    PubMed Central

    Joe, Byung-Hyun; Jo, Uk; Kim, Hyun-Soo; Park, Chang-Bum; Hwang, Hui-Jeong; Sohn, Il-Suk; Jin, Eun-Sun; Cho, Jin-Man; Park, Jeong-Hwan

    2012-01-01

    While the disease course of stress-induced cardiomyopathy (SIC) is usually benign, it can be fatal. The prognostic factors to predict poorer outcome are not well established, however. We analyzed the Acute Physiology And Chronic Health Evaluation (APACHE) II score to assess its value for predicting poor prognosis in patients with SIC. Thirty-seven consecutive patients with SIC were followed prospectively during their hospitalization. Clinical factors, including APACHE II score, coronary angiogram, echocardiography and cardiac enzymes at presentation were analyzed. Of the 37 patients, 27 patients (73%) were women. The mean age was 66.1 ± 15.6 yr, and the most common presentation was chest pain (38%). Initial echocardiographic left ventricular ejection fraction (EF) was 42.5% ± 9.3%, and the wall motion score index (WMSI) was 1.9 ± 0.3. Six patients (16%) expired during the follow-up period of hospitalization. Based on the analysis of characteristics and clinical factors, the only predictable variable in prognosis was APACHE II score. The patients with APACHE II score greater than 20 had tendency to expire than the others (P = 0.001). Based on present study, APACHE II score more than 20, rather than cardiac function, is associated with mortality in patients with SIC. PMID:22219614

  11. Co-expression of LASS2 and TGF-β1 predicts poor prognosis in hepatocellular carcinoma

    PubMed Central

    Ruan, Haoyu; Wang, Ting; Yang, Chen; Jin, Guangzhi; Gu, Dishui; Deng, Xuan; Wang, Cun; Qin, Wenxin; Jin, Haojie

    2016-01-01

    Longevity assurance homolog 2 of yeast LAG1 (LASS2) has been reported to act as an important tumor suppressor in the development of human cancers. However, little is known about the prognostic value of LASS2 in hepatocellular carcinoma (HCC) . In the present study, we analyzed correlation between LASS2 and TGF-β1 levels, and evaluated their prognostic values in HCC patients. We first analyzed the expression of LASS2 and TGF-β1 in two independent cohorts (test cohort: 184 HCC patients; validation cohort: 118 HCC patients) using immunohistochemistry (IHC). Kaplan-Meier survival and Cox regression analyses were executed to evaluate the prognosis of HCC. The results of IHC analysis revealed a positive correlation between the expression of LASS2 and TGF-β1. HCC Patients with low expression of LASS2 and TGF-β1 had shorter overall survival (OS) and time to recurrence (TTR) than patients with high expression of LASS2 and TGF-β1. Furthermore, combination of LASS2 and TGF-β1 was an independent and significant risk factor for OS and TTR. In conclusion, low expression of LASS2 and TGF-β1 contributes to the aggressiveness and poor prognosis of HCC, and may represent a novel prognostic biomarker for HCC patients. PMID:27581744

  12. High expression of myofibrillogenesis regulator-1 predicts poor prognosis for patients with hepatocellular carcinoma after curative hepatectomy

    PubMed Central

    Wang, Chunwei; Xiang, Hua; Si, Huiyuan; Guo, Dandan; Sun, Mei

    2015-01-01

    Myofibrillogenesis regulator (MR-1) is overexpressed in human cancer cells and plays an essential role in cancer cell growth. However, its role in hepatocellular carcinoma (HCC) has not yet been explored. The aim of this study was to investigate the association of MR-1 expression with clinicopathologic features and prognosis in patients with HCC. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) was used to detect MR-1 mRNA levels in tissues samples from 120 HCC patients. Results showed that MR-1 expression was significantly higher in HCC tissues when compared with matched adjacent normal tissues (P=0.004). In HCC cancerous tissues, it was also significantly associated with tumor size (P=0.024) and serum AFP level (P=0.003). Moreover, Kaplan-Meier analysis showed that HCC patients with high MR-1 expression had shorter overall survival time than those with low MR-1 expression (P=0.009). When analyzed with a multivariate Cox regression model, MR-1 was identified as an independent prognostic factor for overall survival. Furthermore, when combined with serum AFP level, the median survival time significantly differed between patients with baseline high serum AFP and high MR-1 expression levels and those with normal AFP and low MR-1 levels (P=0.007). Taken together, our results suggest that high expression of MR-1 is involved in HCC progression and could be a novel biomarker of poor prognosis in patients with HCC. PMID:26823810

  13. Co-expression of LASS2 and TGF-β1 predicts poor prognosis in hepatocellular carcinoma.

    PubMed

    Ruan, Haoyu; Wang, Ting; Yang, Chen; Jin, Guangzhi; Gu, Dishui; Deng, Xuan; Wang, Cun; Qin, Wenxin; Jin, Haojie

    2016-01-01

    Longevity assurance homolog 2 of yeast LAG1 (LASS2) has been reported to act as an important tumor suppressor in the development of human cancers. However, little is known about the prognostic value of LASS2 in hepatocellular carcinoma (HCC) . In the present study, we analyzed correlation between LASS2 and TGF-β1 levels, and evaluated their prognostic values in HCC patients. We first analyzed the expression of LASS2 and TGF-β1 in two independent cohorts (test cohort: 184 HCC patients; validation cohort: 118 HCC patients) using immunohistochemistry (IHC). Kaplan-Meier survival and Cox regression analyses were executed to evaluate the prognosis of HCC. The results of IHC analysis revealed a positive correlation between the expression of LASS2 and TGF-β1. HCC Patients with low expression of LASS2 and TGF-β1 had shorter overall survival (OS) and time to recurrence (TTR) than patients with high expression of LASS2 and TGF-β1. Furthermore, combination of LASS2 and TGF-β1 was an independent and significant risk factor for OS and TTR. In conclusion, low expression of LASS2 and TGF-β1 contributes to the aggressiveness and poor prognosis of HCC, and may represent a novel prognostic biomarker for HCC patients. PMID:27581744

  14. Oncogene mutation profiling reveals poor prognosis associated with FGFR1/3 mutation in liposarcoma.

    PubMed

    Li, Chengfang; Shen, Yaoyuan; Ren, Yan; Liu, Wei; Li, Man; Liang, Weihua; Liu, Chunxia; Li, Feng

    2016-09-01

    Liposarcoma (LPS) is one of the most prevalent soft tissue sarcomas. LPS shows a poor response to radiation and chemotherapy. The causes of death in patients with LPS include locally recurrent and metastatic disease. We sought to examine novel gene mutations and pathways in primary and matched recurrent LPSs to identify potential therapeutic targets. We conducted a high-throughput analysis of 238 known mutations in 19 oncogenes using Sequenom MassARRAY technology. Nucleic acids were extracted from 19 primary and recurrent LPS samples, encompassing 9 dedifferentiated LPSs (DDLPS), 9 myxoid/round cell LPSs, and 1 pleomorphic LPS. Mutation screening revealed missense mutations in 21.1% (4/19) of the LPS specimens, including 4 different genes (FGFR1, FGFR3, PIK3CA, and KIT). Based on histologic subtypes, 22.2% DDLPS (2/9) and 22.2% myxoid cell LPS (2/9) contained gene mutations. Specifically, 3 (23.1%) of 13 primary tumors harbored mutations. Furthermore, although gene mutations were identified in 1 (11.1%) of 9 recurrent LPS samples, the difference between the primary and the recurrence was not statistically significant. Analysis of patient survival data indicated that patients harboring FGFR1/3 mutations experienced reduced overall survival (P<.05). Despite the limited number of samples, our findings provide the first evidence of FGFR1/3 mutations in DDLPS, which were associated with poor clinical outcomes. The FGFR pathway may play an important role in the development and progression of DDLPS and warrants further investigation; moreover, PIK3CA mutation is a common event (11.1%) in myxoid cell LPS. PMID:27237367

  15. Decreased apolipoprotein A-I level indicates poor prognosis in extranodal natural killer/T-cell lymphoma, nasal type

    PubMed Central

    Quan, Qi; Chen, Qi; Chen, Ping; Jiang, Li; Li, Tingwei; Qiu, Huijuan; Zhang, Bei

    2016-01-01

    Background Extranodal natural killer (NK)/T-cell lymphoma, nasal type (ENKTL) is an invasive lymphoid malignancy with unfavorable survival, for which a prognostic model has not yet been validated. We hypothesized that serum apolipoprotein A-I (ApoA-I) may serve as a novel prognostic marker for ENKTL. Patients and methods A total of 236 newly diagnosed cases of ENKTL were analyzed retrospectively. Results The optimal cutoff value for the serum ApoA-I level was determined to be 0.95 g/L. A total of 154 and 82 cases were assigned to the high and low ApoA-I groups, respectively. Patients in the low ApoA-I group tended to present with poorer clinical features, a lower complete remission rate (P=0.001), and poor median progression-free survival (P<0.001) and overall survival (P<0.001). Multivariate analysis using Cox model showed that the serum ApoA-I level was an independent prognostic marker of overall survival (P<0.001) and progression-free survival (P<0.001) for ENKTL patients. For cases in the low-risk group, as assessed by International Prognostic Index, Prognosis Index for peripheral T-cell lymphoma, unspecified, and Korean Prognostic Index, the serum ApoA-I level was able to differentiate cases with poor outcomes from cases with good outcomes. Conclusion Our results showed that the baseline serum ApoA-I level was helpful for predicting ENKTL prognosis. PMID:27051293

  16. Decreased expression of RNA-binding motif protein 3 correlates with tumour progression and poor prognosis in urothelial bladder cancer

    PubMed Central

    2013-01-01

    Background Low nuclear expression of the RNA-binding motif protein 3 (RBM3) has previously been found to be associated with poor prognosis in several cancer forms e.g. breast, ovarian, colorectal, prostate cancer and malignant melanoma. The aim of this study was to examine the prognostic impact of RBM3 expression in urinary bladder cancer. Methods Immunohistochemical RBM3 expression was examined in tumours from 343 patients with urothelial bladder cancer. Chi-square and Spearman’s correlation tests were applied to explore associations between RBM3 expression and clinicopathological characteristics. The impact of RBM3 expression on disease-specific survival (DSS), 5-year overall survival (OS) and progression-free survival (PFS) was assessed by Kaplan-Meier analysis and Cox proportional hazards modelling. Results Reduced nuclear RBM3 expression was significantly associated with more advanced tumour (T) stage (p <0.001) and high grade tumours (p=0.004). Negative RBM3 expression was associated with a significantly shorter DSS (HR=2.55; 95% CI 1.68-3.86)) and 5-year OS (HR=2.10; 95% CI 1.56-2.82), also in multivariable analysis (HR=1.65; 95% CI 1.07-2.53 for DSS and HR=1.54; 95% CI 1.13-2.10 for 5-year OS). In patients with Ta and T1 tumours expressing reduced RBM3 levels, Kaplan-Meier analysis revealed a significantly shorter PFS (p=0.048) and 5-year OS (p=0.006). Conclusion Loss of RBM3 expression is associated with clinically more aggressive tumours and an independent factor of poor prognosis in patients with urothelial bladder cancer and a potentially useful biomarker for treatment stratification and surveillance of disease progression. PMID:23565664

  17. Increased Expression of SETD7 Promotes Cell Proliferation by Regulating Cell Cycle and Indicates Poor Prognosis in Hepatocellular Carcinoma

    PubMed Central

    Hu, Jiewei; Yu, Chaoqin; He, Miaoxia; Cai, Zailong

    2016-01-01

    Purpose To investigate the role of SET domain containing 7 (SETD7) in hepatocellular carcinoma (HCC) and determine whether SETD7 can be used as a predictor of overall survival in HCC patients. Methods mRNAs and proteins of SETD7 and related genes in HCC tumor samples and paired adjacent non-tumorous liver tissues (ANLTs) (n = 20) or culture cells were determined by quantitative real-time PCR and Western blot. Cell proliferation and apoptosis with SETD7 knockdown SMMC-7721 cells or SETD7 overexpressed HepG2 cells were analyzed by CCK8 assay or flow cytometry. Gene expression alterations in SETD7 knockdown of SMMC-7721 cells were determined by digital gene expression (DGE) profiling. Defined data on patients (n = 225) with HCC were retrieved for the further study. Tissue microarrays (TMAs) were performed using paraffin tissues with tumor and ANLTs. SETD7 and related proteins were determined by TMAs immunohistochemistry. Statistical analyses were conducted to associate SETD7 expression with tumor features and patient outcomes, as well as related proteins expression. Results SETD7 expression was significantly higher in HCC tumor tissues than in ANLTs. SETD7 overexpression in vitro can promote HepG2 cell proliferation, whereas SETD7 knockdown can inhibit SMMC-7721 cell proliferation by regulating the cell cycle. SETD7 expression was significantly correlated with five genes expression. Increased SETD7 is associated with metastasis, recurrence, large tumor size, and poor tumor differentiation, and indicates poor prognosis in HCC patients. Conclusions SETD7 plays a critical role in HCC, and its immunohistochemistry signature provides potential clinical significance for personalized prediction of HCC prognosis. PMID:27183310

  18. ATAD2 Overexpression Identifies Colorectal Cancer Patients with Poor Prognosis and Drives Proliferation of Cancer Cells

    PubMed Central

    Luo, Yang; Ye, Guang-Yao; Qin, Shao-Lan; Yu, Min-Hao; Mu, Yi-Fei; Zhong, Ming

    2015-01-01

    ATPase family AAA domain-containing 2 (ATAD2) has been identified as a critical modulator involved in cell proliferation and invasion. The purpose of this study was to explore the expression of ATAD2 in CRC tissues as well as its relationship with degree of malignancy. Data containing three independent investigations from Oncomine database demonstrated that ATAD2 is overexpressed in CRC compared with normal tissue, and similar result was also found in 32 pairs of CRC tissues by qPCR. The protein expression of ATAD2 was examined in six CRC cell lines and 300 CRC specimens. The results showed that high expression of ATAD2 was significantly correlated with tumor size (P < 0.001), serum CEA (P = 0.012), lymph node metastasis (P = 0.018), liver metastasis (P = 0.025), and clinical stage (P = 0.004). Kaplan-Meier method suggested that higher ATAD2 protein expression significantly associated with the overall survival (OS) of CRC patients (P < 0.001) and was an independent predictor of poor OS. Functional studies showed that suppression of ATAD2 expression with siRNA could significantly inhibit the growth in SW480 and HCT116 cells. These results indicated that ATAD2 could serve as a prognostic marker and a therapeutic target for CRC. PMID:26697062

  19. MicroRNA-139-3p indicates a poor prognosis of colon cancer

    PubMed Central

    Liu, Xiaojing; Duan, Bensong; Dong, Yuanyuan; He, Chengzhi; Zhou, Hongmei; Sheng, Haihui; Gao, Hengjun; Zhang, Xizhi

    2014-01-01

    MicroRNAs (miRNAs) play an important role in the regulation of gene expression and are involved in almost biological procession. Recently, miR-139-5p has been reported to be downregulated in some types of cancer, and inhibits cancer cell invasion and metastasis. However, there are few reports on the role of miR-139-3p in cancer. In this study, we examined the expression level of miR-139-3p in 63 pairs of colon cancer and adjacent paracancerous tissues using quantitative reverse transcription PCR. The levels of miR-139-3p in colon cancer tissues were significantly lower than those in adjacent noncancerous tissues. There was an inverse correlation between the level of miR-139-3p and patient’s age. Lower level of miR-139-3p was significantly associated with poor overall survival, especially in patients with TNM stages I and II. In conclusion, miR-139-3p has potential as a prognostic biomarker for colon cancer. Further prospective studies are required to validate this result. PMID:25550849

  20. CD73 as a novel marker for poor prognosis of oral squamous cell carcinoma

    PubMed Central

    REN, ZHEN-HU; YUAN, YONG-XIANG; JI, TONG; ZHANG, CHEN-PING

    2016-01-01

    Ecto-5′-nucleotidase [cluster of differentiation (CD)73] has important functions in several types of cancer, however, its expression in squamous cell carcinoma (SCC) remains unknown. The present study was designed to investigate CD73 expression in SCC. CD73 expression was assessed by immunohistochemistry in 113 patients with oral SCC (OSCC). The association between CD73 expression and clinicopathological features, overall survival (OS) and disease-free survival (DFS) times of patients were statistically analyzed. CD73 expression was detected in 58.4% (66/113) of OSCC patients, with the immunostaining predominantly localized in the cytomembrane and a little in the cytoplasm. Statistical analysis revealed that CD73 expression was more frequently detected in patients with larger tumors (P=0.021). The overexpression of CD73 was significantly associated with clinical stage (P=0.047). Furthermore, immunohistochemical staining showed that overexpression of CD73 was inversely correlated with DFS (P=0.002) and OS (P=0.002) times. Multivariate Cox regression analysis revealed that CD73 expression was an independent prognostic factor for poor DFS (P=0.018) and OS (P=0.021). The current study is the first to evaluate the clinical significance and prognostic value of CD73 in patients with OSCC. The findings suggest that CD73 is a potential prognostic marker for OSCC. PMID:27347180

  1. Identification of SPHK1 as a therapeutic target and marker of poor prognosis in cholangiocarcinoma

    PubMed Central

    Chen, Ming-Huang; Yen, Chueh-Chuan; Cheng, Chi-Tung; Wu, Ren-Chin; Huang, Shih-Chiang; Yu, Chung-Shan; Chung, Yi-Hsiu; Liu, Chun-Yu; Chang, Peter Mu-Hsin; Chao, Yee; Chen, Ming-Han; Chen, Yu-Fen; Chiang, Kun-Chun; Yeh, Ta-Sen; Chen, Tzu Chi; Huang, Chi-Ying F.; Yeh, Chun-Nan

    2015-01-01

    Cholangiocarcinoma (CCA) is characterized by a uniquely aggressive behavior and lack of effective targeted therapies. After analyzing the gene expression profiles of seven paired intrahepatic CCA microarrays, a novel sphingosine kinase 1 (SPHK1)/sphingosine-1-phosphate (S1P) pathway and a novel target gene, SPHK1, were identified. We hypothesized that therapeutic targeting of this pathway can be used to kill intrahepatic cholangiocarcinoma (CCA) cells. High levels of SPHK1 protein expression, which was evaluated by immunohistochemical staining of samples from 96 patients with intrahepatic CCA, correlated with poor overall survival. The SPHK1 inhibitor SK1-I demonstrated potent antiproliferative activity in vitro and in vivo. SK1-I modulated the balance of ceramide-sphinogosine-S1P and induced CCA apoptosis. Furthermore, SK1-I combined with JTE013, an antagonist of the predominant S1P receptor S1PR2, inhibited the AKT and ERK signaling pathways in CCA cells. Our preclinical data suggest SPHK1/S1P pathway targeting may be an effective treatment option for patients with CCA. PMID:26090720

  2. Heterogeneous nuclear ribonucleoprotein K is overexpressed and associated with poor prognosis in gastric cancer.

    PubMed

    Yang, Ruirui; Zeng, Ying; Xu, Haifan; Chen, Zhuo; Xiang, Mengqin; Fu, Yun; Yin, Yufang; Zhong, Jing; Zeng, Min; Wang, Peihua; You, Qin; Zeng, Xi

    2016-08-01

    Heterogeneous nuclear ribonucleoprotein K (hnRNP K) is one of the major pre-mRNA-binding proteins, that is involved in translational modifications. In our previous studies, we found that hnRNP K is associated with human gastric cancer. The protein levels of hnRNP K were detected in cell lines and tissue microarrays. The correlation between hnRNP K expression and patient survival rate was evaluated by Kaplan-Meier survival analysis. In addition, we also detected hnRNP K expression in preoperative and postoperative serum samples from patients with gastric cancer, and serum samples from healthy volunteers. We found that hnRNP K was overexpressed in the gastric cancer cell lines. The levels of hnRNP K were significantly elevated in the gastric cancer tissues compared with that noted in the tumor-adjacent gastric mucosal and normal gastric mucosal sampes, and hnRNP K expression was found to correlate with tumor stage and lymph node metastasis. However, the level of serum hnRNP K did not differ significantly between gastric cancer patients and healthy volunteers. We also found that patients whose tumors showed elevated expression of hnRNP K had poor survival. The present study suggests that hnRNP K is a promising tissue biomarker for diagnosing gastric cancer and is a prognostic indicator for patients with gastric cancer. PMID:27278897

  3. ZNF217 is associated with poor prognosis and enhances proliferation and metastasis in ovarian cancer.

    PubMed

    Li, Jing; Song, Lanlin; Qiu, Yuwen; Yin, Ailan; Zhong, Mei

    2014-01-01

    ZNF217 is an alternatively spliced Kruppel-like transcription factor that has recently been implicated to play a role in human carcinogenesis. Here, we used immunohistochemistry (IHC) to show that ZNF217 protein is overexpressed in nearly 60% of ovarian tumor samples. The disease-free survival time was shorter in patients with positive ZNF217 expression than in ZNF217-negative patients (P=0.042). Fluorescence in situ hybridization (FISH) analysis showed ZNF217 genomic amplification in the poorly differentiated tumors, suggesting that ZNF217 is associated with the progression of ovarian cancer. Invasion was enhanced in HO-8910 cells stably transfected with constructs carrying full-length ZNF217 relative to cells transfected with the empty vector. To confirm our findings in vivo, we performed a tumorigenicity assay in nude mice inoculated with the HO-8910 overexpressing ZNF217 cells. As expected, tumors grown in the ZNF217 group were more invasive and prone to metastasis than those formed control groups. Based on these clinical and laboratory observations, we conclude that ZNF217 may contribute to ovarian cancer invasion and metastasis, and associated with worse clinical outcomes. PMID:25031722

  4. RALY RNA binding protein-like reduced expression is associated with poor prognosis in clear cell renal cell carcinoma.

    PubMed

    Cui, Zhi-Wen; Xia, Ye; Ye, Yi-Wang; Jiang, Zhi-Mao; Wang, Ya-Dong; Wu, Jian-Ting; Sun, Liang; Zhao, Jun; Fa, Ping-Ping; Sun, Xiao-Juan; Gui, Yao-Ting; Cai, Zhi-Mingn

    2012-01-01

    The molecular mechanisms involved in the progression of clear cell renal cell carcinomas (ccRCCs) are still unclear. The aim of this study was to analyse the relationships between expression of RALYL and clinical characteristics. In 41 paired samples of ccRCCs and adjacent normal tissues, we used real-time qPCR to evaluate the expression of RALYL mRNA. RALYL protein levels were determined in 146 samples of ccRCC and 37 adjacent normal tissues by immunohistochemistry. Statistical analysis was used to explore the relationships between expression of RALYL and the clinical characteristics (gender, age, tumor size, T stage, N stage, M stage, survival times and survival outcome) in ccRCC. In addition, these patients were follow-up period 64 months (range: 4~116 months) to investigate the influence on prognosis. We found significantly differences between ccRCC tissues and normal tissues (p<0.001, paired-sample t test) in mRNA levels of RALYL. Immunohistochemistry analyses in 146 ccRCC samples and 37 adjacent normal tissues showed significantly lower RALYL protein levels in ccRCC samples (χ2-test, p<0.001), inversely correlating with tumour size (p=0.024), T stage (0.005), N stage (p<0.001) as well as M stage (p=0.019), but not age (p=0.357) and gender (p=0.348). Kaplan-Meier survival analysis demonstrated that people with lower level of RALYL expression had a poorer survival rate than those with a higher level of RALYL expression, significantly different by the log-rank test (p=0.011). Cox regression analysis indicated that RALYL expression (p=0.039), N stage (p=0.008) and distant metastasis (p<0.001) were independent prognosis factors for the overall survival of ccRCC patients. We demonstrated that the expression of RALYL was significantly low in ccRCC and correlated with a poor prognosis in a large number of clinical samples. Our findings showed that RALYL may be a potential therapeutic target as well as a poor prognostic factor. PMID:22994768

  5. Pyruvate kinase M2 overexpression and poor prognosis in solid tumors of digestive system: evidence from 16 cohort studies

    PubMed Central

    Wu, Jiayuan; Hu, Liren; Chen, Manyu; Cao, Wenjun; Chen, Haicong; He, Taiping

    2016-01-01

    Purpose The expression of pyruvate kinase M2 (PKM2) has been linked to tumor formation and invasion. Specifically, the relationship between high PKM2 expression and prognosis has been evaluated in solid tumors of digestive system. However, the prognostic value of PKM2 remains controversial. Methods A literature search of PubMed, Embase, and Cochrane databases was conducted until October 2015. The end point focused on overall survival (OS). The pooled hazard ratio (HR) or odds ratio and the 95% confidence intervals were calculated to correlate PKM2 overexpression with OS and clinicopathological characteristics by employing fixed- or random-effects models, depending on the heterogeneity of the included studies. Results We identified 18 cohorts in 16 studies involving 2,812 patients for this meta-analysis. Overall, the combined HR for OS in all tumor types was 1.74 (1.44–2.11; P<0.001). When stratified by tumor type, the influence of PKM2 expression on poor prognosis was also found in gastric cancer (HR =1.54 [1.08–2.21], P=0.018), esophageal squamous cell carcinoma (HR =1.71 [1.38–2.12], P<0.001), hepatocellular cancer (HR =1.92 [1.52–2.42], P<0.001), biliary cancer (HR =2.11 [1.50–2.95], P<0.001), and oral cancer (HR =3.49 [1.97–6.18], P<0.001), but not in pancreatic ductal adenocarcinoma (HR =1.03 [0.28–3.76], P=0.968). Furthermore, PKM2 overexpression had a negative effect on the late clinical stage of all tumor types except for pancreatic ductal adenocarcinoma. The high density of PKM2 overexpression was significantly associated with some clinical characteristics in different cancer types, such as tumor stage, modal metastasis, and tumor size. Conclusion Our findings revealed significant association of PKM2 overexpression with OS and certain clinicopathological features in solid tumors of digestive system, thereby suggesting that PKM2 might be an indicator of poor prognosis in digestive system cancers. PMID:27478385

  6. Association between cytoplasmic CRABP2, altered retinoic acid signaling, and poor prognosis in glioblastoma.

    PubMed

    Liu, Rong-Zong; Li, Shuai; Garcia, Elizabeth; Glubrecht, Darryl D; Yin Poon, Ho; Easaw, Jacob C; Godbout, Roseline

    2016-06-01

    Retinoic acid (RA), a metabolite of vitamin A, is required for the regulation of growth and development. Aberrant expression of molecules involved in RA signaling has been reported in various cancer types including glioblastoma multiforme (GBM). Cellular retinoic acid-binding protein 2 (CRABP2) has previously been shown to play a key role in the transport of RA to retinoic acid receptors (RARs) to activate their transcription regulatory activity. Here, we demonstrate that CRABP2 is predominantly located in the cytoplasm of GBM tumors. Cytoplasmic, but not nuclear, CRABP2 levels in GBM tumors are associated with poor patient survival. Treatment of malignant glioma cell lines with RA results in a dose-dependent increase in accumulation of CRABP2 in the cytoplasm. CRABP2 knockdown reduces proliferation rates of malignant glioma cells, and enhances RA-induced RAR activation. Levels of CRYAB, a small heat shock protein with anti-apoptotic activity, and GFAP, an astrocyte-specific intermediate filament protein, are greatly reduced in CRABP2-depleted cells. Restoration of CRYAB expression partially but significantly reversed the effect of CRABP2 depletion on RAR activation. Our combined in vivo and in vitro data indicate that: (i) CRABP2 is an important determinant of clinical outcome in GBM patients, and (ii) the mechanism of action of CRABP2 in GBM involves sequestration of RA in the cytoplasm and activation of an anti-apoptotic pathway, thereby enhancing proliferation and preventing RA-mediated cell death and differentiation. We propose that reducing CRABP2 levels may enhance the therapeutic index of RA in GBM patients. GLIA 2016;64:963-976. PMID:26893190

  7. Peripheral blood involvement in patients with follicular lymphoma: a rare disease manifestation associated with poor prognosis.

    PubMed

    Sarkozy, Clémentine; Baseggio, Lucile; Feugier, Pierre; Callet-Bauchu, Evelyne; Karlin, Lionel; Seymour, John F; Lebras, Laure; Michallet, Anne-Sophie; Offner, Fritz; Dumas, Olivier; Traverse-Glehen, Alexandra; Ffrench, Martine; Lopez-Guillermo, Armando; Berger, Françoise; Coiffier, Bertrand; Felman, Pascale; Salles, Gilles

    2014-03-01

    Follicular Lymphoma (FL) is the second most common non-Hodgkin lymphoma (NHL) subtype and its course is heterogeneous. At diagnosis, some patients with FL manifest a detectable leukaemic phase (FL-LP), but this feature has been seldom described and is poorly characterized. Among 499 patients diagnosed with FL in Lyon-Sud hospital, 37 (7·4%) had characteristic FL-LP (by cytological blood smears and flow cytometric analysis). In addition, 91/1135 FL patients from the PRIMA study presented FL-LP at study entry. In order to evaluate the outcome of this Lyon-Sud cohort, FL-LP patients were matched with 111 newly diagnosed FL without LP according to the Follicular Lymphoma International Prognostic Index (FLIPI) score, age and treatment. Presence of FL-LP was associated with shorter progression-free survival (PFS) and overall survival (OS) (P = 0·004 and P = 0·031, respectively). Presence of FL-LP and high FLIPI score remained independent prognostic factors in a Cox model for time to progression (TTP). A number of circulating lymphoma cells (CLC) >4 × 10(9) /l was the most significant predictor for a shorter TTP in this Cox model. The prognostic impact of FL-LP on TTP was validated in the PRIMA cohort (P = 0·0004). In conclusion, FL-LP is a rare event associated with shorter PFS and patients with CLC >4 × 10(9) /l have a poorer outcome. These patients should be monitored carefully to consider alternative therapeutic options. PMID:24274024

  8. A Long Noncoding RNA ZEB1-AS1 Promotes Tumorigenesis and Predicts Poor Prognosis in Glioma.

    PubMed

    Lv, Qiao-Li; Hu, Lei; Chen, Shu-Hui; Sun, Bao; Fu, Meng-Long; Qin, Chong-Zhen; Qu, Qiang; Wang, Gui-Hua; He, Chen-Jie; Zhou, Hong-Hao

    2016-01-01

    Emerging studies show that long noncoding RNAs (lncRNAs) have important roles in carcinogenesis. lncRNA ZEB1 antisense 1 (ZEB1-AS1) is a novel lncRNA, whose clinical significance, biological function, and underlying mechanism remains unclear in glioma. Here, we found that ZEB1-AS1 was highly expressed in glioma tissues, being closely related to clinical stage of glioma. Moreover, patients with high ZEB1-AS1 levels had poor prognoses, with the evidence provided by multivariate Cox regression analysis indicating that ZEB1-AS1 expression could serve as an independent prognostic factor in glioma patients. Functionally, silencing of ZEB1-AS1 could significantly inhibit cell proliferation, migration, and invasion, as well as promote apoptosis. Knockdown of ZEB1-AS1 significantly induced the G0/G1 phase arrest and correspondingly decreased the percentage of S phase cells. Further analysis indicated that ZEB1-AS1 could regulate the cell cycle by inhibiting the expression of G1/S transition key regulators, such as Cyclin D1 and CDK2. Furthermore, ZEB1-AS1 functioned as an important regulator of migration and invasion via activating epithelial to mesenchymal transition (EMT) through up-regulating the expression of ZEB1, MMP2, MMP9, N-cadherin, and Integrin-β1 as well as decreasing E-cadherin levels in the metastatic progression of glioma. Additionally, forced down-regulation of ZEB1-AS1 could dramatically promote apoptosis by increasing the expression level of Bax and reducing Bcl-2 expression in glioma. Taken together, our data suggest that ZEB1-AS1 may serve as a new prognostic biomarker and therapeutic target of glioma. PMID:27589728

  9. Association of pancreatic adenocarcinoma up-regulated factor expression in ovarian mucinous adenocarcinoma with poor prognosis.

    PubMed

    Kim, Sang Kyum; Song, Si Young; Kim, Sunghoon; Cho, Nam Hoon; Yim, Ga Won; Kim, Sang Wun; Kim, Young Tae; Nam, Eun Ji

    2014-01-01

    Pancreatic adenocarcinoma up-regulated factor (PAUF) expression is elevated in both ovarian tumors and pancreatic adenocarcinoma. However, PAUF expression in ovarian tumors according to histologic subtype and grade has not been investigated. In this study, we examined various clinicopathologic features of 24 patients with mucinous cystadenoma (MCA), 36 with mucinous borderline tumors (MBTs), and 46 with mucinous adenocarcinomas (MACs) according to PAUF expression status assessed using immunohistochemistry. We found that MACs more frequently stained positive for PAUF than did MCAs and MBTs (P < 0.0001). Although there was no significant differences with respect to other clinicopathologic characteristics of MACs according to PAUF expression status, patients with PAUF-weakly positive and PAUF-strongly positive MACs tended to have a shorter overall survival (OS) than those with PAUF-negative MAC, determined using a Kaplan-Meier analysis (P = 0.1885). After adjusting for various clinicopathologic parameters, PAUF positivity of MACs was a significant predictive factor for disease-free survival (DFS) (negative vs. weakly positive: P = 0.045, hazard ratio [HR] = 57.406, 95% confidence interval [CI]: 1.090-3022.596; and negative vs. strongly positive: P = 0.034, HR = 97.890, 95% CI: 1.412-6785.925). In conclusion, PAUF was more frequently expressed in MAC than in its benign and borderline counterparts, and was associated with a poor OS and DFS in MAC patients. Therefore, we suggest that PAUF may be a practical biomarker for histopathological categorization and a prognostic marker for patients with an ovarian mucinous tumor. PMID:25197383

  10. Osteopontin Involves Cisplatin Resistance and Poor Prognosis in Oral Squamous Cell Carcinoma

    PubMed Central

    Luo, Sheng-Dean; Chen, Yi-Ju; Liu, Chien-Ting; Rau, Kun-Ming; Chen, Yi-Ching; Tsai, Hsin-Ting; Chen, Chang-Han; Chiu, Tai-Jan

    2015-01-01

    Background. Osteopontin (OPN) is a multifunctional cytokine involved in cell survival, migration, and adhesion. However, its role in chemosensitivity in locally advanced oral squamous cell carcinoma (OSCC) in humans has not yet been investigated. Methods. We enrolled 121 patients with locally advanced stage IVA/B OSCC receiving cisplatin-based IC followed by CCRT from January 1, 2006, through January 1, 2012. Immunohistochemistry was used to assess OPN expression in OSCC patients' biopsy specimens from paraffin blocks before treatment. In addition, MTT/colony formation assay was used to estimate the influence of OPN in an oral cancer cell line treated with cisplatin. Results. Of the 121 patients, 94 had positive OPN findings and 52 responded to IC followed by CCRT. Positive osteopontin immunostaining also correlated significantly with positive N status/TNM stage/male gender and smoking. Univariate analyses showed that patients whose tumors had a low expression of OPN were more likely to respond to chemotherapy and have a significantly better OS than those whose tumors had a high expression of OPN. Multivariate analysis revealed that prolonged survival was independently predicted for patients with stage IVA disease, negative lymph nodes, and negative expressions of OPN and for those who received chemotherapy with Docetaxel/cisplatin/fluorouracil (TPF). An oral cancer line stimulated with OPN exhibited a dose-dependent resistance to cisplatin treatment. Conversely, endogenous OPN depletion by OPN-mediated shRNA increased sensitivity to cisplatin. Conclusions. A positive expression of OPN predicts a poor response and survival in patients with locally advanced stage IVA/B OSCC treated with cisplatin-based IC followed by CCRT. PMID:26491674

  11. RRAD inhibits aerobic glycolysis, invasion, and migration and is associated with poor prognosis in hepatocellular carcinoma.

    PubMed

    Shang, Runze; Wang, Jianlin; Sun, Wei; Dai, Bin; Ruan, Bai; Zhang, Zhuochao; Yang, Xisheng; Gao, Yuan; Qu, Shibin; Lv, Xing; Tao, Kaishan; Wang, Lin; Dou, Kefeng; Wang, Desheng

    2016-04-01

    Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal cancer worldwide. However, the mechanism underlying the HCC development remains unclear. Ras-related associated with diabetes (RRAD) is a small Ras-related GTPase which has been implicated in metabolic disease and several types of cancer, yet its functions in HCC remain unknown. A tissue microarray constructed by 90 paired HCC tissues and adjacent non-cancerous liver tissues was used to examine the protein levels of RRAD, and the messenger RNA (mRNA) expression of RRAD was also detected in a subset of this cohort. The prognostic significance of RRAD was estimated by the Kaplan-Meier analysis and Cox regression. The glucose utilization assay and lactate production assay were performed to measure the role of RRAD in HCC glycolysis. The effect of RRAD in HCC invasion and metastasis was analyzed by transwell assays. Our results suggested that the expression of RRAD was downregulated in HCC tissues compared to the adjacent non-tumorous liver tissues both in mRNA and protein levels and lower RRAD expression served as an independent prognostic indicator for the survival of HCC patients. Moreover, RRAD inhibited hepatoma cell aerobic glycolysis by negatively regulating the expression of glucose transporter 1 (GLUT1) and hexokinase II (HK-II). In addition, RRAD inhibition dramatically increased hepatoma cell invasion and metastasis. In conclusion, our study revealed that RRAD expression was decreased in HCC tumor tissues and predicted poor clinical outcome for HCC patients and played an important role in regulating aerobic glycolysis and cell invasion and metastasis and may represent potential targets for improving the treatment of HCC. PMID:26546438

  12. Lost expression of ADAMTS5 protein associates with progression and poor prognosis of hepatocellular carcinoma

    PubMed Central

    Li, Chongyi; Xiong, Yanli; Yang, Xueqin; Wang, Lin’ang; Zhang, Shiheng; Dai, Nan; Li, Mengxia; Ren, Tao; Yang, Yuxin; Zhou, Shu-Feng; Gan, Lixia; Wang, Dong

    2015-01-01

    Altered expression of ADAMTS5 is associated with human carcinogenesis and tumor progression. However, the role of ADAMTS5 in hepatocellular carcinoma (HCC) is unclear. This study analyzed ADAMTS5 expression in HCC tissues and tested for association with clinicopathological and survival data from HCC patients and then explored the role of ADAMTS5 in HCC cells in vitro. Paraffin blocks from 48 HCC patients were used to detect ADAMTS5 and vascular endothelial growth factor (VEGF) expression and microvessel density (MVD). A normal liver cell line and HCC cell lines were used to detect ADAMTS5 expression and for ADAMTS5 manipulation. ADAMTS5 cDNA was stably transfected into HCC cells and ADAMTS5 expression assessed by Western blot analysis. Tumor cell-conditioned growth medium was used to assess human umbilical vein endothelial cell migration and Matrigel tube formation. Xenograft assay was performed to determine the role of ADAMTS5 in vivo. The data showed that the expression of ADAMTS5 was reduced in HCC, which was inversely associated with VEGF expression, MVD, and tumor size and associated with poor overall survival of HCC patients. Lentivirus-mediated ADAMTS5 expression significantly inhibited tumor angiogenesis by downregulating in vitro expression of VEGF and inhibiting migration and tube formations, and also inhibited tumor growth and VEGF expression and reduced MVD in vivo in a mouse xenograft model. Taken together, these results suggest that ADAMTS5 plays a role in suppression of HCC progression, which could be further studied as a promising novel therapeutic target and a potential prognostic marker in HCC. PMID:25848214

  13. B7-H4 expression indicates poor prognosis of oral squamous cell carcinoma.

    PubMed

    Wu, Lei; Deng, Wei-Wei; Yu, Guang-Tao; Mao, Liang; Bu, Lin-Lin; Ma, Si-Rui; Liu, Bing; Zhang, Wen-Feng; Sun, Zhi-Jun

    2016-09-01

    Checkpoint blockade therapy utilizing monoclonal antibodies to reactivate T cells and recover their antitumor activity makes an epoch in cancer immunotherapy. The role of B7-H4, a novel negative immune checkpoint, in oral squamous cell carcinoma (OSCC) has still not been elucidated. In this study, tissue samples from human OSCC, which contains 165 primary OSCC, 48 oral epithelial dysplasia and 43 normal oral mucosa specimens, and Tgfbr1/Pten 2cKO mice OSCC model were stained with B7-H4 antibody to analyze the correlations between B7-H4 expression and clinicopathological characteristics. Kaplan-Meier analysis was used to compare the survival of patients with high B7-H4 expression and patients with low B7-H4 expression. We found B7-H4 is highly expressed in human OSCC tissue, and the B7-H4 expression level was associated with the clinicopathological parameters containing pathological grade and lymph node status. Moreover, we confirmed that B7-H4 was overexpressed in Tgfbr1/Pten 2cKO mice OSCC model. Our data also indicated that patients with high B7-H4 expression had poor overall survival compared with those with low B7-H4 expression. Furthermore, this study demonstrated that B7-H4 was positively associated with PD-L1, CD11b, CD33, PI3Kα p110, and p-S6 (S235/236). Taken together, these findings suggest B7-H4 is a potential target in the treatment of OSCC. PMID:27383830

  14. Overexpression of interleukins IL-17 and IL-8 with poor prognosis in colorectal cancer induces metastasis.

    PubMed

    Mohammadi, Mohsen; Kaghazian, Maria; Rahmani, Omid; Ahmadi, Koorosh; Hatami, Elham; Ziari, Katayoun; Talebreza, Amir

    2016-06-01

    Current evidences indicated that a group of soluble mediators called chemokines is involved in tumor growth and metastasis. The association of IL-8 with tumor cell migration was previously found, and its expression was related to angiogenesis, tumor progression, and metastasis in many kinds of carcinomas in human and animal models. Furthermore, it has been showed that IL-17 plays its role as either a proteome of tumor progression or antitumor indifferent cancer models. To investigate the messenger RNA (mRNA) expressions of IL-8 and IL-17 in patients with colorectal cancer (CRC) and non-tumor tissue, quantitative real-time PCR was used in the study. Our results showed that expression of IL-8 mRNA was significantly increased in tumor tissues (mean ± SD 3.84 ± 0.08) compared with adjacent normal mucosa (mean ± SD 1.17 ± 0.75, P = 0.001). Furthermore, a higher expression of IL-17 mRNA was found in tumor tissues (mean ± SD 2.73 ± 0.69) when compared with normal tissues (mean ± SD 1.06 ± 0.07, P = 0.001). Our findings indicated that advanced tumor-node-metastasis (TNM) stage (P = 0.024) and histological grade (poorly differentiated, P = 0.013) and distant metastasis (P = 0.001) were correlated with expression of IL-8. Moreover, high expression of IL-17 showed significant association with early stage CRC (TNM) (P = 0.038). In conclusion, the expression of IL-8 and IL-17 mRNAs was significantly increased in tumor tissues compared with adjacent normal tissues. We found that advanced TNM stage and histological grade and distant metastasis were correlated with expression of IL-8, while high expression of IL-17 showed significant association with early stage CRC (TNM) stage and overexpression of IL-8 may be associated with progression of CRC. PMID:26678893

  15. Increased programmed death ligand-1 expression predicts poor prognosis in hepatocellular carcinoma patients

    PubMed Central

    Gu, Xiaobin; Gao, Xian-Shu; Xiong, Wei; Guo, Wei; Han, Linjun; Bai, Yun; Peng, Chuan; Cui, Ming; Xie, Mu

    2016-01-01

    Purpose Accumulating studies have investigated the prognostic and clinical significance of programmed death ligand-1 (PD-L1) expression in patients with hepatocellular carcinoma (HCC); however, the results were conflicting and inconclusive. We conducted a meta-analysis to combine controversial data to precisely evaluate this issue. Methods Relevant studies were thoroughly searched on PubMed, Web of Science, and Embase until April 2016. Eligible studies were evaluated by selection criteria. Hazard ratio (HR) with 95% confidence interval (CI) was used to estimate the prognostic role of PD-L1 for overall survival (OS) and disease-free survival (DFS)/recurrence-free survival (RFS). Odds ratio (OR) with 95% CI were selected to assess the relationship between PD-L1 and clinicopathological features of HCC patients. Publication bias was tested using Begg’s funnel plot. Results A total of seven studies published from 2009 to 2016 were included for meta-analysis. The data showed that high PD-L1 expression was correlated to shorter OS (HR =2.09, 95% CI: 1.66–2.64, P<0.001) as well as poor DFS/RFS (HR =2.3, 95% CI: 1.46–3.62, P<0.001). In addition, increased PD-L1 expression was also associated with tumor differentiation (HR =1.51, 95% CI: 1–2.29, P=0.05), vascular invasion (HR =2.16, 95% CI: 1.43–3.27, P<0.001), and α-fetoprotein (AFP; HR =1.46, 95% CI: 1–2.14, P=0.05), but had no association with tumor stage, tumor size, hepatitis history, sex, age, or tumor multiplicity. No publication bias was found for all analyses. Conclusion This meta-analysis revealed that overexpression of PD-L1 was predictive for shortened OS and DFS/RFS in HCC. Furthermore, increased PD-L1 expression was associated with less differentiation, vascular invasion, and AFP elevation. PMID:27536144

  16. Vasculogenic mimicry is a major feature and novel predictor of poor prognosis in patients with orbital rhabdomyosarcoma

    PubMed Central

    CHEN, LUXIA; HE, YANJIN; SUN, SHIZHEN; SUN, BAOCUN; TANG, XIN

    2015-01-01

    Vasculogenic mimicry (VM) is a key developmental program, frequently activated during cancer invasion and metastasis. The aim of the present study was to evaluate the role of VM in orbital rhabdomyosarcoma (RMS), the correlation between VM and tumor differentiation, recurrence and survival duration, as well as the contribution of epithelial cell kinase (EphA2) and matrix metalloproteinase-2 (MMP-2) in VM initiation. A total of 32 patients were enrolled to investigate the associations between VM in orbital RMS tumors and clinical characteristics, as well as its impact on overall survival. VM was identified and confirmed by CD31/periodic acid-Schiff double staining, while the presence of EphA2 and MMP-2 were examined by immunohistochemical analysis. VM was identified in eleven patients, particularly those with poorly differentiated orbital RMS (P=0.001). Patients with VM exhibited significantly worse survival rates (P=0.001, log-rank test), a significantly increased risk of mortality (P=0.008) and EphA2 and MMP-2 expression levels were enhanced (P=0.005 and 0.001, respectively). The VM and mitotic rate were independent predictors of poor prognosis (P=0.001 and 0.004, respectively), indicated by multivariate Cox proportional hazards models. These results demonstrated that VM is present in orbital RMS and represents an independent prognostic factor for overall survival. In addition, overexpression of EphA2 and MMP-2 may promote VM formation in orbital RMS. PMID:26622724

  17. Decreased long noncoding RNA MIR31HG is correlated with poor prognosis and contributes to cell proliferation in gastric cancer.

    PubMed

    Nie, Feng-Qi; Ma, Shijie; Xie, Min; Liu, Yan-Wen; De, Wei; Liu, Xiang-Hua

    2016-06-01

    Long noncoding RNAs (lncRNAs) are emerging as key regulators governing fundamental biological processes, and their disorder expression involves in the development of several human cancers. MIR31HG, an lncRNA located in 9p21.3 and 2166 bp in length, has been found to be upregulated in breast cancer and contributes to cell proliferation and invasion. However, the expression pattern and biological function of MIR31HG in gastric cancer are still not well documented. In this study, we found that MIR31HG expression is decreased in gastric cancer tissues and associated with larger tumor size and advanced pathological stage. Patients with lower MIR31HG expression had a relatively poor prognosis. Furthermore, ectopic over-expression of MIR31HG could inhibit gastric cancer (GC) cell proliferation both in vitro and in vivo, while knockdown of MIR31HG by small interfering RNA (siRNA) promoted cell proliferation in GC cells partly via regulating E2F1 and p21 expression. Our findings present that decreased MIR31HG is involved in GC development and could be identified as a poor prognostic biomarker in GC patients. PMID:26692098

  18. Physician’s Undecided Attitudes towards Posthumous Reproduction: Fertility Preservation in Cancer Patients with a Poor Prognosis

    PubMed Central

    Quinn, Gwendolyn P.; Knapp, Caprice; Malo, Teri; McIntyre, Jessica; Jacobsen, Paul; Vadaparampil, Susan T.

    2015-01-01

    Background The American Society for Clinical Oncology (ASCO) established guidelines for fertility preservation for cancer patients. In a national study of US oncologists, we examined attitudes towards the use of fertility preservation among patients with a poor prognosis, focusing on attitudes towards posthumous reproduction. Method A cross-sectional survey was administered via mail and Internet to a stratified random sample of US oncologists and measured demographics, knowledge, attitude, and practice behaviors regarding posthumous reproduction and fertility preservation with cancer patients of childbearing age. Results Only 16.2% supported posthumous parenting, while the majority (51.5%) did not have an opinion. ANOVA analyses indicated attitudes towards posthumous reproduction were significantly related to physician practice behaviors and dependent on oncologists’ knowledge of ASCO guidelines. Conclusions Physician attitudes may conflict with following recommended guidelines and may reduce the likelihood that some patients receive information about fertility preservation. Further education may raise physicians’ awareness of poor prognostic patients’ interest in pursuing this technology. PMID:22266153

  19. Decreased expression of PBLD correlates with poor prognosis and functions as a tumor suppressor in human hepatocellular carcinoma

    PubMed Central

    Zhong, Jietao; Yang, Haiyun; Feng, Zhiqiang; Du, Yanlei; Wang, Yadong; Wang, Zenan; Wang, Hong; Zhou, Yongjian; Liu, Side; Nie, Yuqiang

    2016-01-01

    Recent accumulating genomic and proteomic data suggested that decreased expression of phenazine biosynthesis-like domain-containing protein (PBLD) was frequently involved in hepatocellular carcinoma (HCC). However, there is lack of systematical investigation focusing on its expression pattern, clinical relevance, and biological function. Here, we found that PBLD was frequently decreased in HCC tissues relative to adjacent non-tumorigenic liver tissues. This decreased expression was significantly associated with poor tumor differentiation and advanced tumor stage. Kaplan–Meier analysis further showed that recurrence-free survival and overall survival were significantly worse among patients with low PBLD expression. Moreover, multivariate analyses revealed that PBLD was an independent predictor of OS and RFS. This prognostic value of PBLD was further validated in another independent cohort. We also found PBLD inhibited HCC cell growth and invasion in vitro and tumor growth in vivo. Furthermore, forced expression of PBLD influenced multiple downstream genes related to MAPK, NF-κB, EMT, and angiogenesis signaling pathways. PBLD deletion was an independent predictor of poor prognosis in patients with HCC. Elevated PBLD expression may reduce HCC cell growth and invasion via inactivation of several tumorigenesis-related signaling pathways. PMID:26594798

  20. Elevated ASCL2 expression is associated with metastasis of osteosarcoma and predicts poor prognosis of the patients.

    PubMed

    Liu, Ming-Han; Cui, You-Hong; Guo, Qiao-Nan; Zhou, Yue

    2016-01-01

    Achaetescute-like 2 (ASCL2), a basic helix-loop-helix (bHLH) transcription factor, plays an important role in the determination of neuronal precursors in the central and peripheral nervous system and involves in tumor progression. However, the role of ASCL2 expression in the osteosarcoma prognosis has not been elaborated. This study aimed to evaluate ASCL2 expression level in osteosarcoma and assess its prognostic value for patients. ASCL2 protein expression was detected by immunohistochemistry (IHC) in 73 cases of osteosarcoma. Kaplan-Meier analysis and Cox regression analysis were performed to evaluate the prognostic significance of ASCL2. Immunohistochemistry analysis showed that the overall survival and metastasis-free survival of patients with positive ASCL2 expression were significantly shorter than patients with negative expression (both P<0.01). Multivariate Cox analysis identified ASCL2 expression as an independent prognostic factor to predict poor overall survival and metastasis-free survival (both P<0.01). Overexpression of ASCL2 expression greatly promoted cell proliferation and enhanced migration and invasion in vitro. This study indicates that increased expression of ASCL2 in primary osteosarcoma is a novel biomarker for predicting the development of metastases and poor outcomes of the patients. PMID:27429855

  1. Lung cancer diagnosed in the young is associated with enrichment for targetable genomic alterations and poor prognosis

    PubMed Central

    Sacher, Adrian G.; Dahlberg, Suzanne E.; Heng, Jennifer; Mach, Stacy; Jänne, Pasi A.; Oxnard, Geoffrey R.

    2016-01-01

    Importance NSCLC in the young is a rare entity and the genomics and clinical characteristics of this disease are poorly understood. In contrast, young age at diagnosis has been demonstrated to define unique disease biology in other cancers. Here we report on the association of young age with targetable genomic alterations and prognosis in a large cohort of NSCLC patients. Objective To determine the relationship between young age at diagnosis and both the presence of a potentially targetable genomic alteration as well as prognosis and natural history. Design All patients with NSCLC genotyped at the Dana-Farber Cancer Institute between 2002–2014 were identified. Tumor genotype, patient characteristics and clinical outcomes were collected. Multivariate logistic regression was used to analyze the relationship between age and mutation status. Multivariate Cox proportional hazard models were fitted for survival analysis. Setting A National Cancer Institute (NCI) designated comprehensive cancer center. Participants All patients with NSCLC seen at the Dana-Farber Cancer Institute between 2002–2014 who underwent tumor genotyping. Main Outcome Measure The frequency of targetable genomic alterations by defined age categories as well as the association of these age groups with survival. Results 2237 patients with NSCLC were studied. EGFR (p=0.02) and ALK (P<0.01) were associated with younger age, and a similar trend existed for HER2 (p=0.15) and ROS1 (p=0.1) but not BRAF V600E (p=0.43). Amongst patients tested for all 5 targetable genomic alterations, younger age was associated with an increased frequency of a targetable genotype (p<0.01). Those diagnosed at age 50 or younger have a 59% increased likelihood of harboring a targetable genotype. While presence of a potentially targetable genomic alteration treated with a targeted agent was associated with improved survival, the youngest and oldest age groupings had similarly poor outcomes even when a targetable genotype was

  2. Loss of autophagy-related protein Beclin 1 may define poor prognosis in ovarian clear cell carcinomas

    PubMed Central

    KATAGIRI, HIROSHI; NAKAYAMA, KENTARO; RAZIA, SULTANA; NAKAMURA, KOHEI; SATO, EMI; ISHIBASHI, TOMOKA; ISHIKAWA, MASAKO; IIDA, KOUJI; ISHIKAWA, NORIYOSHI; OTSUKI, YOSHIRO; NAKAYAMA, SATORU; KYO, SATORU

    2015-01-01

    The aim of the present study was to clarify the role of autophagy in cisplatin (CDDP) sensitivity in OCCCs and the role of Beclin 1 in OCCC progression. Autophagy was measured using: i) western blot analysis of LC3 and p62 and ii) microscopic observation of GFP-LC3 puncta. Autophagy was suppressed using chloroquine and Beclin 1 siRNA. Surgical specimens were examined for Beclin 1 protein expression by immunohistochemistry. The correlations between the loss of Beclin 1 expression and clinicopathological characteristics, prognosis and chemosensitivity were investigated. Inhibition of autophagy by chloroquine or Beclin 1 siRNA did not enhance the sensitivity of the ES2 and TOV-21G OCCC cell lines to CDDP. Loss of Beclin 1 expression was observed in 38.3% (23/60) of the analyzed tumors. There was no significant correlation between loss of Beclin 1 expression and FIGO stage, CA125 levels, patient age, status of endometriosis, Ki-67 labeling index, chemotherapy regimen or status of residual tumor. However, negative expression of Beclin 1 was associated with a shorter progression-free survival in comparison to positive Beclin 1 expression in OCCC who received cytoreductive surgery, followed by a standard platinum-based chemotherapy regimen (P=0.027, log-rank test). Beclin 1-negative tumors were no more resistant to primary adjuvant chemotherapy than were Beclin 1-positive tumors (50.0 vs. 66.7%, P=0.937). Beclin 1 knockdown using siRNA increased cell growth but not cell migration and invasion in ES2 and TOV-21G OCCC cell lines. Autophagy defects caused by loss of Beclin 1 are not related to chemoresistance and metastasis, but may be associated with malignant phenotype and poor prognosis of OCCC. PMID:26458502

  3. High PD-L1 Expression Correlates with Metastasis and Poor Prognosis in Oral Squamous Cell Carcinoma

    PubMed Central

    Hsieh, Ming-Ju; Tsai, Shih-Chen; Lai, Hung-Wen; Yang, Shu-Mei; Shen, Ko-Hong; Chen, Mu-Kuan; Lee, Huei; Yeh, Kun-Tu; Chen, Chih-Jung

    2015-01-01

    PD-L1 has been widely demonstrated to contribute to failed antitumor immunity. Blockade of PD-L1 with monoclonal antibody could modulate the tumor immune environment to augment immunotherapy. PD-L1 expression is also detected in several types of cancer and is associated with poor prognosis. However, the prognostic role of PD-L1 in oral squamous cell carcinoma (OSCC) is still controversial. Our aim was to determine the role of PD-L1 in the prognosis of OSCC patients to identify its potential therapeutic relevance. PD-L1 immunoreactivity was analyzed by immunohistochemistry in 305 cancer specimens from primary OSCC patients. The medium follow-up time after surgery was 3.8 years (range from 0.1 to 11.1 years). The prognostic value of PD-L1 on overall survival was determined by Kaplan-Meier analysis and Cox proportional hazard models. Higher PD-L1 expression is more likely in tumor tissues of female than male OSCC patients (P = 0.0062). Patients with distant metastasis also had high PD-L1 expression (P = 0.0103). Multivariate analysis identified high PD-L1 expression as an independent risk factor in males and smokers (males: hazard ratio = 1.556, P = 0.0077; smokers: hazard ratio = 2.058, P = 0.0004). We suggest that PD-L1 expression, determined by IHC staining, could be an independent prognostic marker for OSCC patients who are male or who have a smoking habit. PMID:26562534

  4. Loss of 11βHSD1 enhances glycolysis, facilitates intrahepatic metastasis, and indicates poor prognosis in hepatocellular carcinoma

    PubMed Central

    Liu, Xu; Tan, Xiao-long; Xia, Meng; Wu, Chao; Song, Jia; Wu, Jing-jing; Laurence, Arian; Xie, Qing-guo; Zhang, Ming-zhi

    2016-01-01

    11Beta-hydroxysteroid dehydrogenase type 1 (11βHSD1), converting glucocorticoids from hormonally inactive cortisone to active cortisol, plays an essential role in glucose homeostasis. Accumulating evidence suggests that enhanced glycolytic activity is closely associated with postoperative recurrence and prognosis of hepatocellular carcinoma (HCC). Whether 11βHSD1 contributes to HCC metastasis and recurrence remains unclear. Here we found that expression of 11βHSD1 in human HCC (310 pairs) was frequently decreased compared to the adjacent non-neoplastic liver tissues (ANT), which correlated well with the intrahepatic-metastatic index, serum glycemia, and other malignant clinicopathological characteristics of HCC and predicted poor prognosis. Knockdown of 11βHSD1 in BEL-7402 cells drastically reduced the pH of culture medium and induced cell death. Meanwhile, overexpression of 11βHSD1 in SMMC-7721 HCC cells resulted in repression of cell migration, invasion, angiogenesis, and proliferation in vitro. When transferred into BALB/c nude mice, 11βHSD1 overexpression resulted in decreased intrahepatic metastasis, angiogenesis, and tumor size. F-18-2-fluoro-2-deoxyglucose accumulation assay measured by positron emission tomography elucidated that 11βHSD1 reduced glucose uptake and glycolysis in SMMC-7721 cells in vitro, and intrahepatic metastasis foci and subcutaneous tumor growth in vivo. We showed that 11βHSD1 repressed cell metastasis, angiogenesis and proliferation of HCC by causing disruption of glycolysis via the HIF-1α and c-MYC pathways. In conclusion, 11βHSD1 inhibits the intrahepatic metastasis of HCC via restriction of tumor glycolysis activity and may serve as a prognostic biomarker for patients. PMID:26700460

  5. Overexpression of long noncoding RNA PCAT-1 is a novel biomarker of poor prognosis in patients with colorectal cancer.

    PubMed

    Ge, Xiaosong; Chen, Yuanbin; Liao, Xiaoyu; Liu, Deqing; Li, Fangfang; Ruan, Honglian; Jia, Weihua

    2013-01-01

    Long noncoding RNAs (lncRNA) are emerging as key molecules in human cancer. Prostate cancer-associated ncRNA transcripts 1 (PCAT-1), a lncRNA, has been recently revealed involving in human prostate cancer progression. However, whether PCAT-1 could serve as novel biomarker to predict prognosis in colorectal cancer (CRC) or not is unknown. We therefore carried out the present study to explore the correlation between PCAT-1 expression and the progression of CRC. In this study, the expression of PCAT-1 in 108 cases of CRC tissues and matched 81 adjacent normal tissues were determined by quantitative real-time PCR. Furthermore, the copy number variation of PCAT-1 was also measured in 17 tumor tissues and matched normal tissues. Our results showed that PCAT-1 expression in CRC tissues was significantly upregulated compared with the matched normal tissues (p < 0.001) and the overexpression of PCAT-1(upregulated by more than 50 %) was found in 64 % (62/81) of CRC. Moreover, PCAT-1 gene copy number variation explains only a few percent of observed overexpression. In addition, there was a significant association between PCAT-1 expression and distant metastasis (p = 0.04), but not other clinical characteristics. More important, CRC patients with PCAT-1 higher expression have shown significantly poorer overall survival than those with lower PCAT-1 expression (p < 0.001). Also, multivariable Cox regression analysis identified PCAT-1 overexpression as an independent prognostic factor for CRC (p = 0.007, HR = 3.12 95 %CI = 1.355-7.185). In conclusion, our results suggest that high expression of PCAT-1 is involved in CRC progression and could be a novel biomarker of poor prognosis in patient with colorectal cancer. PMID:23640607

  6. High PD-L1 Expression Correlates with Metastasis and Poor Prognosis in Oral Squamous Cell Carcinoma.

    PubMed

    Lin, Yueh-Min; Sung, Wen-Wei; Hsieh, Ming-Ju; Tsai, Shih-Chen; Lai, Hung-Wen; Yang, Shu-Mei; Shen, Ko-Hong; Chen, Mu-Kuan; Lee, Huei; Yeh, Kun-Tu; Chen, Chih-Jung

    2015-01-01

    PD-L1 has been widely demonstrated to contribute to failed antitumor immunity. Blockade of PD-L1 with monoclonal antibody could modulate the tumor immune environment to augment immunotherapy. PD-L1 expression is also detected in several types of cancer and is associated with poor prognosis. However, the prognostic role of PD-L1 in oral squamous cell carcinoma (OSCC) is still controversial. Our aim was to determine the role of PD-L1 in the prognosis of OSCC patients to identify its potential therapeutic relevance. PD-L1 immunoreactivity was analyzed by immunohistochemistry in 305 cancer specimens from primary OSCC patients. The medium follow-up time after surgery was 3.8 years (range from 0.1 to 11.1 years). The prognostic value of PD-L1 on overall survival was determined by Kaplan-Meier analysis and Cox proportional hazard models. Higher PD-L1 expression is more likely in tumor tissues of female than male OSCC patients (P = 0.0062). Patients with distant metastasis also had high PD-L1 expression (P = 0.0103). Multivariate analysis identified high PD-L1 expression as an independent risk factor in males and smokers (males: hazard ratio = 1.556, P = 0.0077; smokers: hazard ratio = 2.058, P = 0.0004). We suggest that PD-L1 expression, determined by IHC staining, could be an independent prognostic marker for OSCC patients who are male or who have a smoking habit. PMID:26562534

  7. Loss of 11βHSD1 enhances glycolysis, facilitates intrahepatic metastasis, and indicates poor prognosis in hepatocellular carcinoma.

    PubMed

    Liu, Xu; Tan, Xiao-Long; Xia, Meng; Wu, Chao; Song, Jia; Wu, Jing-Jing; Laurence, Arian; Xie, Qing-Guo; Zhang, Ming-Zhi; Liang, Hui-Fang; Zhang, Bi-Xiang; Chen, Xiao-Ping

    2016-01-12

    11beta-hydroxysteroid dehydrogenase type 1 (11βHSD1), converting glucocorticoids from hormonally inactive cortisone to active cortisol, plays an essential role in glucose homeostasis. Accumulating evidence suggests that enhanced glycolytic activity is closely associated with postoperative recurrence and prognosis of hepatocellular carcinoma (HCC). Whether 11βHSD1 contributes to HCC metastasis and recurrence remains unclear. Here we found that expression of 11βHSD1 in human HCC (310 pairs) was frequently decreased compared to the adjacent non-neoplastic liver tissues (ANT), which correlated well with the intrahepatic-metastatic index, serum glycemia, and other malignant clinicopathological characteristics of HCC and predicted poor prognosis. Knockdown of 11βHSD1 in BEL-7402 cells drastically reduced the pH of culture medium and induced cell death. Meanwhile, overexpression of 11βHSD1 in SMMC-7721 HCC cells resulted in repression of cell migration, invasion, angiogenesis, and proliferation in vitro. When transferred into BALB/c nude mice, 11βHSD1 overexpression resulted in decreased intrahepatic metastasis, angiogenesis, and tumor size. F-18-2-fluoro-2-deoxyglucose accumulation assay measured by positron emission tomography elucidated that 11βHSD1 reduced glucose uptake and glycolysis in SMMC-7721 cells in vitro, and intrahepatic metastasis foci and subcutaneous tumor growth in vivo. We showed that 11βHSD1 repressed cell metastasis, angiogenesis and proliferation of HCC by causing disruption of glycolysis via the HIF-1α and c-MYC pathways. In conclusion, 11βHSD1 inhibits the intrahepatic metastasis of HCC via restriction of tumor glycolysis activity and may serve as a prognostic biomarker for patients. PMID:26700460

  8. Allelic loss at chromosome 13q12-q13 is associated with poor prognosis in familial and sporadic breast cancer.

    PubMed Central

    van den Berg, J.; Johannsson, O.; Håkansson, S.; Olsson, H.; Borg, A.

    1996-01-01

    Loss of heterozygosity (LOH) was analysed in 84 primary tumours from sporadic, familial and hereditary breast cancer using five microsatellite markers spanning the chromosomal region 13q12-q13 which harbours the BRCA2 breast cancer susceptibility gene, and using one other marker located within the RBI tumour-suppressor gene at 13q14. LOH at the BRCA2 region was found in 34% and at RBI in 27% of the tumours. Selective LOH at BRCA2 occurred in 7% of the tumours, whereas selective LOH at RBI was observed in another 7%. Moreover, a few tumours demonstrated a restricted deletion pattern, suggesting the presence of additional tumour-suppressor genes both proximal and distal of BRCA2. LOH at BRCA2 was significantly correlated to high S-phase values, low oestrogen and progesterone receptor content and DNA non-diploidy. LOH at BRCA2 was also associated, albeit non-significantly, with large tumour size and the ductal and medullar histological types. No correlation was found with lymph node status, patient age or a family history of breast cancer. A highly significant and independent correlation existed between LOH at BRCA2 and early recurrence and death. LOH at RBI was not associated with the above mentioned factors or prognosis. The present study does not provide conclusive evidence that BRCA2 is the sole target for deletions at 13q12-q13 in breast tumours. However, the results suggest that inactivation of one or several tumour-suppressor genes in the 13q12-q13 region confer a strong tumour growth potential and poor prognosis in both familial and sporadic breast cancer. Images Figure 1 PMID:8932343

  9. Overexpression of STAT3/pSTAT3 was associated with poor prognosis in gastric cancer: a meta-analysis

    PubMed Central

    He, Shaozhong; Liao, Guixiang; Liu, Yungen; Huang, Liling; Kang, Mafei; Chen, Longhua

    2015-01-01

    Signal transducer and activator of transcription 3 (STAT3) and phospho-STAT3 (pSTAT3) play important roles in the development of gastric cancer. STAT3 is often associated with cell survival, proliferation, and transformation. The prognostic value of STAT3/pSTAT3 in patients with gastric cancer remains controversial in numerous published studies. The aim of this study was to summarize recent findings relevant to the prognostic role of STAT3 and pSTAT3 in patients with gastric cancer. A meta-analysis was performed by searching Web of Knowledge, EMBASE, and PubMed to identify studies on the prognostic impact of STAT3/pSTAT3 in gastric cancers in August 2014. In all, 10 studies were included in the analysis. Data were collected for comparing survival rates in patients with high STAT3 levels compared to those with low levels. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. Sensitivity analysis was conducted, and publication bias was evaluated. Eventually, 1667 cases of gastric cancer were subjected to the final analysis. Among patients with gastric cancer, poor survival was predicted by higher expressions of STAT3 (HR=2.30; 95% CI=1.13-4.68; P=0.02) and pSTAT3 (HR=1.75; 95% CI=1.17-2.61; P=0.006). Moreover, overexpression of STAT3 was associated with poor tumor stage. Additionally, our analysis did not show any statistically significant effect of publication bias regarding STAT3 or pSTAT3. The results of this meta-analysis demonstrated that overexpression of STAT3 and pSTAT3 was associated with poor prognosis in gastric cancer. PMID:26884913

  10. Stromal Myofibroblasts Are Associated with Poor Prognosis in Solid Cancers: A Meta-Analysis of Published Studies

    PubMed Central

    Zhu, Zhi Qiang; Ning, Zhong Liang; Huang, Qiang

    2016-01-01

    Objective Published studies have evaluated the impact of stromal myofibroblasts on prognosis in solid cancers. However, the results of these studies remain controversial. We therefore performed a meta-analysis to address this issue. Methods The PubMed, ISI Web of Science and Embase databases were searched through November 30th, 2015 by two investigators, and a total of 17 studies that contained 2606 patients were included. Stromal myofibroblasts were quantified in solid cancers using α-smooth muscle actin staining. Pooled Odds Ratio with 95% Confidence Intervals were calculated, and publication bias was analyzed. Results The results of this study suggest that in solid cancers, a high density of stromal myofibroblasts is significantly associated with poor 3- and 5-year overall survival (pooled odds ratio (95% confidence interval): 1.33 (1.10–1.60) for 3-year overall survival and 1.68 (1.22–2.32) for 5-year overall survival). In addition, a high density of stromal myofibroblasts also predicted poor 3- and 5-year disease-free survival (1.30 (1.05–1.60) for 3-year disease-free survival and 1.36 (1.01–1.83) for 5-year disease-free survival). However, stromal myofibroblasts were not associated with 3- and 5-year cancer-specific survival. No publication bias was found for all analyses. Conclusions The results of this study suggest that a high density of stromal myofibroblasts is associated with poor survival in solid cancers. More studies were required to investigate the prognostic value of stromal myofibroblasts in different types of solid cancers. PMID:27459365

  11. SALL4 Expression in Hepatocellular Carcinomas Is Associated with EpCAM-Positivity and a Poor Prognosis

    PubMed Central

    Park, Hyunjin; Lee, Hyejung; Seo, An Na; Cho, Jai Young; Choi, Young Rok; Yoon, Yoo-Seok; Han, Ho-Seong; Park, Young Nyun; Kim, Haeryoung

    2015-01-01

    Background: There is increasing interest in hepatocellular carcinomas (HCC) expressing “stemness”-related markers, as they have been associated with aggressive behavior and poor prognosis. In this study, we investigated the usefulness of Sal-like protein 4 (SALL4), a recently proposed candidate marker of “stemness.” Methods: Immunohistochemical stains were performed for SALL4, K19, and epithelial cellular adhesion molecule (EpCAM) on tissue microarrays constructed from 190 surgically resected HCCs, and the results were correlated with the clinicopathological features and patient survival data. Results: Nuclear SALL4 expression was observed in 39/190 HCCs (20.5%), while K19 and EpCAM were expressed in 30 (15.9%) and 92 (48.7%) HCCs, respectively. The nuclear expression was generally weak, punctate or clumped. SALL4 expression was significantly associated with a poor overall survival compared to SALL4-negative HCCs (p = .014) compared to SALL4-negative HCCs. On multivariate analysis adjusted for tumor size, multiplicity, vascular invasion, and pathological tumor stage, SALL4 remained as a significant independent predictor of decreased overall survival (p= .004). SALL4 expression was positively correlated with EpCAM expression (p = .013) but not with K19 expression. HCCs that expressed both SALL4 and EpCAM were associated with significantly decreased overall survival, compared to those cases which were negative for both of these markers (p = .031). Conclusions: Although SALL4 expression was not significantly correlated with other clinicopathological parameters suggestive of tumor aggressiveness, SALL4 expression was an independent predictor of poor overall survival in human HCCs, and was also positively correlated with EpCAM expression. PMID:26265684

  12. High expression of interleukin-11 is an independent indicator of poor prognosis in clear-cell renal cell carcinoma

    PubMed Central

    Pan, Deng; Xu, Le; Liu, Haiou; Zhang, Weijuan; Liu, Weisi; Liu, Yidong; Fu, Qiang; Xu, Jiejie

    2015-01-01

    Interleukin-11 (IL-11), a member of the IL-6 family of cytokines, exerts pleiotropic oncogenic activities by stimulating angiogenesis and metastasis in many cancer types. The present study aims to evaluate the impact of IL-11 expression on recurrence and mortality of patients with clear-cell renal cell carcinoma (ccRCC). We retrospectively enrolled 193 ccRCC patients undergoing nephrectomy at a single center. Clinicopathologic features, recurrence-free survival (RFS) and overall survival (OS) were recorded. IL-11 intensity was assessed by immunohistochemistry in tumor specimens. The Kaplan–Meier method was applied to compare survival curves. Cox regression models were used to analyze the impact of prognostic factors on RFS and OS. The concordance index (C-index) was calculated to assess predictive accuracy. High IL-11 expression is associated with increased risk of recurrence and poor survival for ccRCC patients (P < 0.001 and P < 0.001, respectively), especially those with early-stage disease (TNM stage I + II). Multivariate analyses confirmed that IL-11 expression was an independent prognostic factor for RFS and OS (P = 0.006 and P = 0.008, respectively). The predictive accuracy of well-established prognostic models was improved when IL-11 expression was integrated. In conclusion, high IL-11 expression is an independent predictor of poor prognosis in ccRCC patients. It may help identify patients who could benefit from additional treatments and closer follow up. PMID:25702890

  13. Decreased expression of Beclin-1 is significantly associated with a poor prognosis in oral tongue squamous cell carcinoma

    PubMed Central

    Hu, Zedong; Zhong, Zhaoming; Huang, Shaohui; Wen, Haojie; Chen, Xue; Chu, Hongying; Li, Qiuli; Sun, Chuanzheng

    2016-01-01

    The autophagy-related gene Beclin-1 is critical in the regulation of tumourigenesis and progression, but its role in oral tongue squamous cell carcinoma (OTSCC) has not yet been reported. This study aimed to investigate Beclin-1 expression and its significance in OTSCC. Beclin-1 expression was assessed by reverse transcription-quantitative polymerase chain reaction or western blot analysis in 14 OTSCC tissues and matched adjacent noncancerous tissues as well as in 5 OTSCC cell lines and a normal tongue epithelial cell line. Beclin-1 protein expression was examined by immunohistochemistry in 133 OTSCC specimens, and the correlation between Beclin-1 expression and clinicopathological features was investigated. Furthermore, MTT and colony formation assays were performed to investigate the effect of Beclin-1 on the proliferation and clonogenicity of OTSCC cells. It was demonstrated that Beclin-1 expression was significantly decreased in the majority of the 14 OTSCC tissues and the 5 OTSCC cell lines relative to the matched non-cancerous tissues and the normal tongue epithelial cell line, respectively. Immunohistochemistry analysis revealed that decreased Beclin-1 expression was significantly correlated with poor differentiation, lymph node metastasis, advanced clinical tumour-node-metastasis stage, and a poor prognosis in patients with OTSCC. The in vitro assays indicated that the overexpression of Beclin-1 significantly inhibits the proliferation and clonogenicity of OTSCC cells. These results demonstrate that Beclin-1 acts as a tumour suppressor in the development or progression of OTSCC and that Beclin-1 may represent a novel prognostic marker for patients with OTSCC. PMID:27356955

  14. Decreased expression of Beclin‑1 is significantly associated with a poor prognosis in oral tongue squamous cell carcinoma.

    PubMed

    Hu, Zedong; Zhong, Zhaoming; Huang, Shaohui; Wen, Haojie; Chen, Xue; Chu, Hongying; Li, Qiuli; Sun, Chuanzheng

    2016-08-01

    The autophagy-related gene Beclin-1 is critical in the regulation of tumourigenesis and progression, but its role in oral tongue squamous cell carcinoma (OTSCC) has not yet been reported. This study aimed to investigate Beclin‑1 expression and its significance in OTSCC. Beclin‑1 expression was assessed by reverse transcription‑quantitative polymerase chain reaction or western blot analysis in 14 OTSCC tissues and matched adjacent noncancerous tissues as well as in 5 OTSCC cell lines and a normal tongue epithelial cell line. Beclin‑1 protein expression was examined by immunohistochemistry in 133 OTSCC specimens, and the correlation between Beclin‑1 expression and clinicopathological features was investigated. Furthermore, MTT and colony formation assays were performed to investigate the effect of Beclin‑1 on the proliferation and clonogenicity of OTSCC cells. It was demonstrated that Beclin‑1 expression was significantly decreased in the majority of the 14 OTSCC tissues and the 5 OTSCC cell lines relative to the matched non‑cancerous tissues and the normal tongue epithelial cell line, respectively. Immunohistochemistry analysis revealed that decreased Beclin‑1 expression was significantly correlated with poor differentiation, lymph node metastasis, advanced clinical tumour‑node‑metastasis stage, and a poor prognosis in patients with OTSCC. The in vitro assays indicated that the overexpression of Beclin‑1 significantly inhibits the proliferation and clonogenicity of OTSCC cells. These results demonstrate that Beclin‑1 acts as a tumour suppressor in the development or progression of OTSCC and that Beclin‑1 may represent a novel prognostic marker for patients with OTSCC. PMID:27356955

  15. M6P/IGF2R loss of heterozygosity in head and neck cancer associated with poor patient prognosis

    PubMed Central

    Jamieson, Timothy A; Brizel, David M; Killian, J Keith; Oka, Yoshihiko; Jang, Hong-Seok; Fu, Xiaolong; Clough, Robert W; Vollmer, Robin T; Anscher, Mitchell S; Jirtle, Randy L

    2003-01-01

    Background The mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) encodes for a multifunctional receptor involved in lysosomal enzyme trafficking, fetal organogenesis, cytotoxic T cell-induced apoptosis and tumor suppression. The purpose of this investigation was to determine if the M6P/IGF2R tumor suppressor gene is mutated in human head and neck cancer, and if allelic loss is associated with poor patient prognosis. Methods M6P/IGF2R loss of heterozygosity in locally advanced squamous cell carcinoma of the head and neck was assessed with six different gene-specific nucleotide polymorphisms. The patients studied were enrolled in a phase 3 trial of twice daily radiotherapy with or without concurrent chemotherapy; median follow-up for surviving patients is 76 months. Results M6P/IGF2R was polymorphic in 64% (56/87) of patients, and 54% (30/56) of the tumors in these informative patients had loss of heterozygosity. M6P/IGF2R loss of heterozygosity was associated with a significantly reduced 5 year relapse-free survival (23% vs. 69%, p = 0.02), locoregional control (34% vs. 75%, p = 0.03) and cause specific survival (29% vs. 75%, p = 0.02) in the patients treated with radiotherapy alone. Concomitant chemotherapy resulted in a better outcome when compared to radiotherapy alone only in those patients whose tumors had M6P/IGF2R loss of heterozygosity. Conclusions This study provides the first evidence that M6P/IGF2R loss of heterozygosity predicts for poor therapeutic outcome in patients treated with radiotherapy alone. Our findings also indicate that head and neck cancer patients with M6P/IGF2R allelic loss benefit most from concurrent chemotherapy. PMID:12589712

  16. CENP-F expression is associated with poor prognosis and chromosomal instability in patients with primary breast cancer

    PubMed Central

    O’Brien, Sallyann L.; Fagan, Ailís; Fox, Edward J.P.; Millikan, Robert C.; Culhane, Aedín C.; Brennan, Donal J.; McCann, Amanda H.; Hegarty, Shauna; Moyna, Siobhan; Duffy, Michael J.; Higgins, Desmond G.; Jirström, Karin; Landberg, Göran; Gallagher, William M.

    2016-01-01

    DNA microarrays have the potential to classify tumors according to their transcriptome. Tissue microarrays (TMAs) facilitate the validation of biomarkers by offering a high-throughput approach to sample analysis. We reanalyzed a high profile breast cancer DNA microarray dataset containing 96 tumor samples using a powerful statistical approach, between group analyses. Among the genes we identified was centromere protein-F (CENP-F), a gene associated with poor prognosis. In a published follow-up breast cancer DNA microarray study, comprising 295 tumour samples, we found that CENP-F upregulation was significantly associated with worse overall survival (p < 0.001) and reduced metastasis-free survival (p < 0.001). To validate and expand upon these findings, we used 2 independent breast cancer patient cohorts represented on TMAs. CENP-F protein expression was evaluated by immunohistochemistry in 91 primary breast cancer samples from cohort I and 289 samples from cohort II. CENP-F correlated with markers of aggressive tumor behavior including ER negativity and high tumor grade. In cohort I, CENP-F was significantly associated with markers of CIN including cyclin E, increased telomerase activity, c-Myc amplification and aneuploidy. In cohort II, CENP-F correlated with VEGFR2, phosphorylated Ets-2 and Ki67, and in multivariate analysis, was an independent predictor of worse breast cancer-specific survival (p = 0.036) and overall survival (p = 0.040). In conclusion, we identified CENP-F as a biomarker associated with poor outcome in breast cancer and showed several novel associations of biological significance. PMID:17205517

  17. Low expression of PKCα and high expression of KRAS predict poor prognosis in patients with colorectal cancer

    PubMed Central

    Chen, Suxian; Wang, Yadi; Zhang, Yun; Wan, Yizeng

    2016-01-01

    The current study aimed to determine the association between protein kinase Cα (PKCα) and Kirsten rat sarcoma viral oncogene homolog (KRAS) expression and the response to folinic acid, 5-fluorouracil and oxaliplatin (FOLFOX regimen) in patients with colorectal cancer (CRC). The protein levels of PKCα and KRAS were analyzed by immunohistochemistry in tissue samples from patients with CRC and in non-cancerous tissues, including 152 cases of colorectal adenocarcinoma, 30 cases of colorectal adenoma and 20 normal colonic mucosa samples. The association between PKCα and KRAS expression and clinicopathological features was analyzed. The rates of positive PKCα protein expression in patients with poorly, moderately and well-differentiated adenocarcinoma were 16.7% (6/36), 40.0% (24/60), and 57.1% (32/56), respectively (P<0.013). The rate of positive KRAS expression in CRC patients was significantly higher than in patients with colon adenoma and normal colon mucosa (P<0.001). Expression levels of KRAS were associated with the degree of differentiation of CRC (P<0.001). Expression of PKCα was negatively correlated with KRAS expression in CRC tissues. The mean progression-free survival (PFS) times in patients with high and low expression of PKCα were 43.9 and 38.8 months, respectively (P<0.001). The mean PFS times were 38.5 and 45.5 months in patients with high and low expression of KRAS, respectively (P=0.001). In conclusion, low PKCα and high KRAS expression predicted relatively poor prognosis in patients with CRC.

  18. High circulating activin A level is associated with tumor progression and predicts poor prognosis in lung adenocarcinoma

    PubMed Central

    Hoda, Mir Alireza; Rozsas, Anita; Lang, Elisabeth; Klikovits, Thomas; Lohinai, Zoltan; Torok, Szilvia; Berta, Judit; Bendek, Matyas; Berger, Walter; Hegedus, Balazs; Klepetko, Walter; Renyi-Vamos, Ferenc; Grusch, Michael; Dome, Balazs; Laszlo, Viktoria

    2016-01-01

    Activin A (ActA)/follistatin (FST) signaling has been shown to be deregulated in different tumor types including lung adenocarcinoma (LADC). Here, we report that serum ActA protein levels are significantly elevated in LADC patients (n=64) as compared to controls (n=46, p=0.015). ActA levels also correlated with more advanced disease stage (p<0.0001) and T (p=0.0035) and N (p=0.0002) factors. M1 patients had significantly higher ActA levels than M0 patients (p<0.001). High serum ActA level was associated with poor overall survival (p<0.0001) and was confirmed as an independent prognostic factor (p=0.004). Serum FST levels were increased only in female LADC patients (vs. female controls, p=0.031). Two out of five LADC cell lines secreted biologically active ActA, while FST was produced in all of them. Transcripts of both type I and II ActA receptors were detected in all five LADC cell lines. In conclusion, our study does not only suggest that measuring blood ActA levels in LADC patients might improve the prediction of prognosis, but also indicates that this parameter might be a novel non-invasive biomarker for identifying LADC patients with organ metastases. PMID:26950277

  19. GIT1 promotes lung cancer cell metastasis through modulating Rac1/Cdc42 activity and is associated with poor prognosis.

    PubMed

    Chang, Jeng-Shou; Su, Chia-Yi; Yu, Wen-Hsuan; Lee, Wei-Jiunn; Liu, Yu-Peng; Lai, Tsung-Ching; Jan, Yi-Hua; Yang, Yi-Fang; Shen, Chia-Ning; Shew, Jin-Yuh; Lu, Jean; Yang, Chih-Jen; Huang, Ming-Shyan; Lu, Pei-Jung; Lin, Yuan-Feng; Kuo, Min-Liang; Hua, Kuo-Tai; Hsiao, Michael

    2015-11-01

    G-protein-coupled receptor kinase interacting protein 1 (GIT1) is participated in cell movement activation, which is a fundamental process during tissue development and cancer progression. GIT1/PIX forming a functional protein complex that contributes to Rac1/Cdc42 activation, resulting in increasing cell mobility. Although the importance of Rac1/Cdc42 activation is well documented in cancer aggressiveness, the clinical importance of GIT1 remains largely unknown. Here, we investigated the clinical significance of GIT1 expression in non-small-cell lung cancer (NSCLC) and also verified the importance of GIT1-Rac1/Cdc42 axis in stimulating NSCLC cell mobility. The result indicated higher GIT1 expression patients had significantly poorer prognoses in disease-free survival (DFS) and overall survival (OS) compared with lower GIT1 expression patients. Higher GIT1 expression was an independent prognostic factor by multivariate analysis and associated with migration/invasion of NSCLC cells in transwell assay. In vivo studies indicated that GIT1 promotes metastasis of NSCLC cells. Finally, GIT1 was found to stimulate migration/invasion by altering the activity of Rac1/Cdc42 in NSCLC cells. Together, the GIT1 expression is associated with poor prognosis in patients with NSCLC. GIT1 is critical for the invasiveness of NSCLC cells through stimulating the activity of Rac1/Cdc42. PMID:26462147

  20. Elevated Preoperative Serum CA19-9 Levels in Patients with Hepatocellular Carcinoma Is Associated with Poor Prognosis after Resection

    PubMed Central

    Chen, Chien-Hung; Hu, Rey-Heng; Ho, Ming-Chih

    2013-01-01

    Serum levels of the tumor marker CA19-9 have been reported to be elevated in patients with hepatocellular carcinoma (HCC), but its clinicopathologic significance is still unknown. A cohort of 304 patients undergoing surgical resection for HCC and having preoperative CA19-9 data was enrolled in this study. Serum CA19-9 levels were correlated with clinicopathologic factors. Univariate and multivariate analyses were performed to determine the predictors of patient survival. On receiver operating characteristic curve analysis, the cut off value of CA19-9 was determined to be 27 U/mL. One hundred and six patients had preoperative CA19-9 values >27 U/mL. High serum CA19-9 levels did not correlate with patient age, sex, viral status, α-fetoprotein level, tumor size, tumor grade, tumor stage, multiplicity, and vascular invasion. Patients with elevated preoperative CA19-9 levels had lower 10-year survival than those without CA19-9 elevation. Multivariate analysis revealed that CA19-9 level, tumor grade, and tumor size are independent prognostic factors for long-term survival. In conclusion, a preoperative CA19-9 value >27 U/mL is associated with poor prognosis after resection for HCC. PMID:23843733

  1. Deletion and low expression of NFKBIA are associated with poor prognosis in lower-grade glioma patients.

    PubMed

    Kinker, Gabriela Sarti; Thomas, Andrew Maltez; Carvalho, Vinicius Jardim; Lima, Felipe Prata; Fujita, André

    2016-01-01

    Lower-grade gliomas (LGGs), which are uniformly fatal in young adults, are classified as grades II-III tumors according to their histological features. The NFκB transcription factor, a crucial player in cancer initiation and progression, is inactivated in the cytoplasm by inhibitory proteins (IκBs) that have been shown to exert tumor-suppressor activity. Therefore, using The Cancer Genome Atlas copy number alteration and RNA-Seq data from 398 patients, we evaluated the association between the expression and dosage of NFKBIA, which encodes IκBα, and the overall malignancy of LGGs. Deletion and low expression of NFKBIA were associated with enhanced tumor aggressiveness and poor prognosis in LGGs. Accordingly, the dosage and expression of NFKBIA were independent prognostic factors for 5-year survival (dosage: P = 0.016; expression: P = 0.002) and 5-year recurrence-free survival (dosage: P = 0.009; expression: P = 0.005). Moreover, gene set enrichment analyses and co-expression network analyses indicated a role for NFKBIA in the negative regulation of cell proliferation, possibly through the modulation of downstream NFκB activation. Overall, the present findings reveal the prognostic value of NFKBIA in LGGs, reinforcing the relevance of NFκB signaling in the development and progression of gliomas. PMID:27052952

  2. GIT1 promotes lung cancer cell metastasis through modulating Rac1/Cdc42 activity and is associated with poor prognosis

    PubMed Central

    Chang, Jeng-Shou; Su, Chia-Yi; Yu, Wen-Hsuan; Lee, Wei-Jiunn; Liu, Yu-Peng; Lai, Tsung-Ching; Jan, Yi-Hua; Yang, Yi-Fang; Shen, Chia-Ning; Shew, Jin-Yuh; Lu, Jean; Yang, Chih-Jen; Huang, Ming-Shyan; Lu, Pei-Jung; Lin, Yuan-Feng; Kuo, Min-Liang; Hua, Kuo-Tai; Hsiao, Michael

    2015-01-01

    G-protein-coupled receptor kinase interacting protein 1 (GIT1) is participated in cell movement activation, which is a fundamental process during tissue development and cancer progression. GIT1/PIX forming a functional protein complex that contributes to Rac1/Cdc42 activation, resulting in increasing cell mobility. Although the importance of Rac1/Cdc42 activation is well documented in cancer aggressiveness, the clinical importance of GIT1 remains largely unknown. Here, we investigated the clinical significance of GIT1 expression in non-small-cell lung cancer (NSCLC) and also verified the importance of GIT1-Rac1/Cdc42 axis in stimulating NSCLC cell mobility. The result indicated higher GIT1 expression patients had significantly poorer prognoses in disease-free survival (DFS) and overall survival (OS) compared with lower GIT1 expression patients. Higher GIT1 expression was an independent prognostic factor by multivariate analysis and associated with migration/invasion of NSCLC cells in transwell assay. In vivo studies indicated that GIT1 promotes metastasis of NSCLC cells. Finally, GIT1 was found to stimulate migration/invasion by altering the activity of Rac1/Cdc42 in NSCLC cells. Together, the GIT1 expression is associated with poor prognosis in patients with NSCLC. GIT1 is critical for the invasiveness of NSCLC cells through stimulating the activity of Rac1/Cdc42. PMID:26462147

  3. CCR4 frameshift mutation identifies a distinct group of adult T cell leukaemia/lymphoma with poor prognosis.

    PubMed

    Yoshida, Noriaki; Miyoshi, Hiroaki; Kato, Takeharu; Sakata-Yanagimoto, Mamiko; Niino, Daisuke; Taniguchi, Hiroaki; Moriuchi, Yukiyoshi; Miyahara, Masaharu; Kurita, Daisuke; Sasaki, Yuya; Shimono, Joji; Kawamoto, Keisuke; Utsunomiya, Atae; Imaizumi, Yoshitaka; Seto, Masao; Ohshima, Koichi

    2016-04-01

    Adult T cell leukaemia/lymphoma (ATLL) is an intractable T cell neoplasm caused by human T cell leukaemia virus type 1. Next-generation sequencing-based comprehensive mutation studies have revealed recurrent somatic CCR4 mutations in ATLL, although clinicopathological findings associated with CCR4 mutations remain to be delineated. In the current study, 184 cases of peripheral T cell lymphoma, including 113 cases of ATLL, were subjected to CCR4 mutation analysis. This sequence analysis identified mutations in 27% (30/113) of cases of ATLL and 9% (4/44) of cases of peripheral T cell lymphoma not otherwise specified. Identified mutations included nonsense (NS) and frameshift (FS) mutations. No significant differences in clinicopathological findings were observed between ATLL cases stratified by presence of CCR4 mutation. All ATLL cases with CCR4 mutations exhibited cell-surface CCR4 positivity. Semi-quantitative CCR4 protein analysis of immunohistochemical sections revealed higher CCR4 expression in cases with NS mutations of CCR4 than in cases with wild-type (WT) CCR4. Furthermore, among ATLL cases, FS mutation was significantly associated with a poor prognosis, compared with NS mutation and WT CCR4. These results suggest that CCR4 mutation is an important determinant of the clinical course in ATLL cases, and that NS and FS mutations of CCR4 behave differently with respect to ATLL pathophysiology. PMID:26847489

  4. Deletion and low expression of NFKBIA are associated with poor prognosis in lower-grade glioma patients

    PubMed Central

    Kinker, Gabriela Sarti; Thomas, Andrew Maltez; Carvalho, Vinicius Jardim; Lima, Felipe Prata; Fujita, André

    2016-01-01

    Lower-grade gliomas (LGGs), which are uniformly fatal in young adults, are classified as grades II-III tumors according to their histological features. The NFκB transcription factor, a crucial player in cancer initiation and progression, is inactivated in the cytoplasm by inhibitory proteins (IκBs) that have been shown to exert tumor-suppressor activity. Therefore, using The Cancer Genome Atlas copy number alteration and RNA-Seq data from 398 patients, we evaluated the association between the expression and dosage of NFKBIA, which encodes IκBα, and the overall malignancy of LGGs. Deletion and low expression of NFKBIA were associated with enhanced tumor aggressiveness and poor prognosis in LGGs. Accordingly, the dosage and expression of NFKBIA were independent prognostic factors for 5-year survival (dosage: P = 0.016; expression: P = 0.002) and 5-year recurrence-free survival (dosage: P = 0.009; expression: P = 0.005). Moreover, gene set enrichment analyses and co-expression network analyses indicated a role for NFKBIA in the negative regulation of cell proliferation, possibly through the modulation of downstream NFκB activation. Overall, the present findings reveal the prognostic value of NFKBIA in LGGs, reinforcing the relevance of NFκB signaling in the development and progression of gliomas. PMID:27052952

  5. Overexpression of lncRNA AFAP1-AS1 correlates with poor prognosis and promotes tumorigenesis in colorectal cancer.

    PubMed

    Wang, Feng; Ni, Hongbing; Sun, Feng; Li, Min; Chen, Lin

    2016-07-01

    Accumulating evidence has shown that long non-coding RNAs (lncRNAs) are emerging as key molecules in human malignancies. The lncRNA actin filament associated protein 1 antisense RNA1 (AFAP1-AS1) was recently found deregulated in several cancers. However, its expression pattern, clinical performance and functional roles in colorectal cancer (CRC) had not been addressed. In this study, we found that AFAP1-AS1 was aberrantly over-expressed in CRC tissues and closely correlated with tumor size, TNM stage and distant metastasis. Kaplan-Meier analysis indicated that patients with high level of AFAP1-AS1 expression had poorer overall survival (OS) and disease-free survival (DFS). Univariate and multivariable Cox regression analyses further identified that up-regulated AFAP1-AS1 might act as an independent prognostic factor for CRC patients. Moreover, AFAP1-AS1 depletion resulted in the inhibition of CRC cell proliferation and colony formation. In addition, AFAP1-AS1 knockdown induced G0/G1 cell cycle arrest in CRC cells. Taken together, our findings indicate that AFAP1-AS1 is significantly up-regulated in CRC, which may act as an oncogene and correlate with tumor malignant progression and poor prognosis of CRC. This study may shed a new light on better understanding the pathogenesis of CRC. Moreover, AFAP1-AS1 also may be a promising diagnostic and therapeutic target for this deadly disease. PMID:27261589

  6. Results of a prospective phase II trial evaluating interim positron emission tomography-guided high dose therapy for poor prognosis diffuse large B-cell lymphoma.

    PubMed

    Stewart, Douglas A; Kloiber, Reinhard; Owen, Carolyn; Bahlis, Nizar J; Duggan, Peter; Mansoor, Adnan; Bence-Bruckler, Isabelle

    2014-09-01

    Patients with diffuse large B-cell lymphoma (DLBCL) with a poor prognosis based upon advanced stage and elevated serum lactate dehydrogenase achieve a 3-4-year progression-free survival (PFS) of only 55%. The role of interim fluoro-2-deoxy-d-glucose (FDG) positron emission tomography (PET) to guide use of upfront high dose chemotherapy (HDCT) and autologous stem cell transplant (ASCT) for patients with poor prognosis DLBCL is unproven. A prospective phase II clinical trial was designed to evaluate the outcomes of HDCT/ASCT for patients with poor prognosis DLBCL aged 18-65 years who had unfavorable interim restaging PET scans. Of the 70 eligible patients, 36 had unfavorable and 34 favorable interim PET responses, with 3-year PFS rates of 65.2% and 52.7%, respectively. In conclusion, favorable interim PET response as defined in this study is not associated with improved PFS rates for patients with poor prognosis DLBCL treated with RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). A phase III trial evaluating this PET-guided approach is not warranted. PMID:24188476

  7. Upregulation of long non-coding RNA TUG1 correlates with poor prognosis and disease status in osteosarcoma.

    PubMed

    Ma, Bing; Li, Meng; Zhang, Lei; Huang, Ming; Lei, Jun-Bin; Fu, Gui-Hong; Liu, Chun-Xin; Lai, Qi-Wen; Chen, Qing-Quan; Wang, Yi-Lian

    2016-04-01

    The pathogenesis of osteosarcoma involves complex genetic and epigenetic factors. This study was to explore the impact and clinical relevance of long non-coding RNA (lncRNA), Taurine up-regulated gene 1 (TUG1) on patients with osteosarcoma. Seventy-six osteosarcoma tissues and matched adjacent normal tissues were included for analysis. The plasma samples were obtained from 29 patients with osteosarcoma at pre-operation and post-operation, 42 at newly diagnosed, 18 who experienced disease progression or relapse, 45 post-treatment, 36 patients with benign bone tumor, and 20 healthy donors. Quantitative real-time reverse transcript polymerase chain reactions were used to assess the correlation of the expression levels of TUG1 with clinical parameters of osteosarcoma patients. TUG1 was significantly overexpressed in the osteosarcoma tissues compared with matched adjacent normal tissues (P < 0.01) and was closely correlated with tumor size, post-operative chemotherapy, and Enneking surgical stage. Upregulation of TUG1 strongly correlated with poor prognosis and was an independent prognostic indicator for overall survival (HR = 2.78, 95% CI = 1.29-6.00, P = 0.009) and progression-free survival (HR = 1.81, 95% CI = 1.01-3.54, P = 0.037). Our constructed nomogram containing TUG1 had more predictive accuracy than that without TUG1 (c-index 0.807 versus 0.776, respectively). In addition, for plasma samples, TUG1 expression levels were obviously decreased in post-operative patients (mean ΔCT -4.98 ± 0.22) compared with pre-operation patients (mean ΔCT -6.09 ± 0.74), and the changes of TUG1 expression levels were significantly associated with disease status. Receiver operating characteristic (ROC) curve analysis demonstrated that TUG1 could distinguish patients with osteosarcoma from healthy individuals compared with alkaline phosphatase (ALP) (the area under curve 0.849 versus 0.544). TUG1 was overexpressed in patients with osteosarcoma

  8. Poor Prognosis with In Vitro Fertilization in Indian Women Compared to Caucasian Women Despite Similar Embryo Quality

    PubMed Central

    Shahine, Lora K.; Lamb, Julie D.; Lathi, Ruth B.; Milki, Amin A.; Langen, Elizabeth; Westphal, Lynn M.

    2009-01-01

    Background Disease prevalence and response to medical therapy may differ among patients of diverse ethnicities. Poor outcomes with in vitro fertilization (IVF) treatment have been previously shown in Indian women compared to Caucasian women, and some evidence suggests that poor embryo quality may be a cause for the discrepancy. In our center, only patients with the highest quality cleavage stage embryos are considered eligible for extending embryo culture to the blastocyst stage. We compared live birth rates (LBR) between Indian and Caucasian women after blastocyst transfer to investigate whether differences in IVF outcomes between these ethnicities would persist in patients who transferred similar quality embryos. Methodology/Principal Findings In this retrospective cohort analysis, we compared IVF outcome between 145 Caucasians and 80 Indians who had a blastocyst transfer between January 1, 2005 and June 31, 2007 in our university center. Indians were younger than Caucasians by 2.7 years (34.03 vs. 36.71, P = 0.03), were more likely to have an agonist down regulation protocol (68% vs. 43%, P<0.01), and were more likely to have polycystic ovarian syndrome (PCOS), although not significant, (24% vs. 14%, P = 0.06). Sixty eight percent of Indian patients had the highest quality embryos (4AB blastocyst or better) transferred compared to 71% of the Caucasians (P = 0.2). LBR was significantly lower in the Indians compared to the Caucasians (24% vs. 41%, P<0.01) with an odds ratio of 0.63, (95%CI 0.46–0.86). Controlling for age, stimulation protocol and PCOS showed persistently lower LBR with an adjusted odds ratio of 0.56, (95%CI 0.40–0.79) in the multivariate analysis. Conclusions/Significance Despite younger age and similar embryo quality, Indians had a significantly lower LBR than Caucasians. In this preliminary study, poor prognosis after IVF for Indian ethnicity persisted despite limiting analysis to patients with high quality embryos transferred

  9. Overexpression of SPARC correlates with poor prognosis in patients with cervical carcinoma and regulates cancer cell epithelial-mesenchymal transition

    PubMed Central

    SHI, DEHUAN; JIANG, KAN; FU, YING; FANG, RUI; LIU, XI; CHEN, JIE

    2016-01-01

    Secreted protein acidic and rich in cysteine (SPARC) is associated with the progression of numerous types of cancer. However, the role of SPARC in the progression of cervical cancer has not yet been adequately elucidated. In the current study, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry were employed to evaluate the mRNA and protein expression of SPARC in normal cervical tissue, cervical intraepithelial neoplasia (CIN) and cervical cancer. In addition, three epithelial-mesenchymal transition (EMT) markers (E-cadherin, N-cadherin and vimentin) were detected by immunohistochemistry in the same specimens, and an enzyme-linked immunosorbent assay was conducted to detect the serum levels of SPARC in patients with cervical neoplasia. In highly invasive subclones of human cervical carcinoma cells, HeLa-1 and SiHa-1, lentiviral transfections were performed and RT-qPCR and western blot were used to investigate the effects of downregulated EGF-containing fibulin-like extracellular matrix protein 1 on the expression of E-cadherin, N-cadherin and vimentin. The results revealed that, in cervical carcinoma tissue, SPARC expression was significantly upregulated in a manner that positively correlated with N-cadherin and vimentin expression, and negatively correlated with E-cadherin expression. SPARC overexpression and high serum levels were significantly associated with the progression of cervical cancer and adverse prognosis of cervical cancer patients. Downregulation of SPARC can markedly reduce the expression of N-cadherin and vimentin and increase the expression of E-cadherin. Thus, overexpression of SPARC is significantly associated with poor prognostic clinicopathological characteristics in cervical carcinoma, and may be important in EMT. The results of the current study suggest that SPARC may be a potential therapeutic option for individuals diagnosed with cervical carcinoma. PMID:27123099

  10. Expression of Sirtuin 1 and 2 Is Associated with Poor Prognosis in Non-Small Cell Lung Cancer Patients

    PubMed Central

    Martínez-Terroba, Elena; Agorreta, Jackeline; Mikecin, Ana-Matea; Larráyoz, Marta; Idoate, Miguel A.; Gall-Troselj, Koraljka; Pio, Ruben; Montuenga, Luis M.

    2015-01-01

    Background Sirtuin 1 (SIRT1) and sirtuin 2 (SIRT2) are NAD+-dependent protein deacetylases involved in the regulation of key cancer-associated genes. In this study we evaluated the relevance of these deacetylases in lung cancer biology. Material and Methods Protein levels of SIRT1 and SIRT2 were determined in non-small cell lung cancer (NSCLC) cell lines and primary tumors from 105 patients. Changes in proliferation were assessed after SIRT1 and SIRT2 downregulation in lung cancer cell lines using siRNA-mediated technology or tenovin-1, a SIRT1 and SIRT2 inhibitor. Results High SIRT1 and SIRT2 protein levels were found in NSCLC cell lines compared with non-tumor lung epithelial cells. The expression of SIRT1 and SIRT2 proteins was also significantly higher in lung primary tumors than in normal tissue (P<0.001 for both sirtuins). Stronger nuclear SIRT1 staining was observed in adenocarcinomas than in squamous cell carcinomas (P=0.033). Interestingly, in NSCLC patients, high SIRT1 and SIRT2 expression levels were associated with shorter recurrence-free survival (P=0.04 and P=0.007, respectively). Moreover, the combination of high SIRT1 and SIRT2 expression was an independent prognostic factor for shorter recurrence-free survival (P=0.002) and overall survival (P=0.022). In vitro studies showed that SIRT1 and/or SIRT2 downregulation significantly decreased proliferation of NSCLC. Conclusions Our results support the hypothesis that SIRT1 and SIRT2 have a protumorigenic role in lung cancer, promoting cell proliferation. Moreover, the expression of these proteins is associated with poor prognosis in NSCLC patients and may help to identify those NSCLC patients with high risk of recurrence that could benefit from adjuvant therapy after resection. PMID:25915617

  11. Osteopontin promoter polymorphisms at locus -443 are associated with metastasis and poor prognosis of human intrahepatic cholangiocarcinoma in Chinese population

    PubMed Central

    Zhao, Xiang-Qian; Ma, Huan-Xian; Su, Mao-Sheng; He, Lei

    2014-01-01

    Purpose: Osteopontin (OPN) is known to be a secreted adhesive glycoprotein. Role of OPN in human intrahepatic cholangiocarcinoma (ICC) has not been well understood. This study explored whether genetic variations in the osteopontin gene are associated with ICC risk, progression and metastasis. Material and methods: 260 patients with stages I to IV between 2008 and 2013 were recruited in this study and same number healthy persons were used as control. OPN-66 T/G, -156 G/GG and -443 C/T variants were genotyped using DNA from blood lymphocytes. Chi-square test and a Fisher’s exact test were used to analyze the genotype distribution between healthy subjects and patients, and further its distribution among TNM stages and incidence metastasis in patients. Results: For the variant at nt- 443 (CC), there was a significant difference between the number of patients with stage IV and those with all other stages of ICC (P < 0.01). Patients with -443 (CC) variant had significant higher incidence of lymph and distant metastasis development compared to other genotypes. For the variant at nt- 443 (CT), there was a significant difference between the number of ICC patients with stage III + IV and those with stage I + II (P < 0.01). The survival rates for ICC patients with the C/C genotype were significantly lower than for patients with the other two genotypes (C/T, T/T). Conclusion: OPN -443 C/T polymorphism is a potential predictive marker of metastasis and poor prognosis in ICC patients. PMID:25400775

  12. Association of Decreased Expression of Serum miR-9 with Poor Prognosis of Oral Squamous Cell Carcinoma Patients

    PubMed Central

    Sun, Legang; Liu, Ling; Fu, Honghai; Wang, Qiuqin; Shi, Yao

    2016-01-01

    Background Dysregulation of miR-9 is a common feature of many types of cancers, including oral squamous cell carcinoma (OSCC). However, whether the expression level of serum miR-9 is changed in patients with OSCC remains unknown. Material/Methods Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to examine the expression level of serum miR-9 in OSCC patients, oral leukoplakia (OLK) patients, and healthy volunteers, then we evaluated the association between serum miR-9 expression level and clinical outcome of OSCC patients. Results The expression level of serum miR-9 was significantly downregulated in patients with OSCC or OLK in comparison with healthy controls (P<0.01). Serum miR-9 expression level was associated with various clinicopathological parameters, including T stage (P=0.013), lymph node metastasis (P=0.002), and TNM stage (P=0.007). In addition, the OSCC patients in the low serum miR-9 expression group had poorer overall survival rate (P=0.022) and disease-free survival rate (P=0.004) compared with those in the high serum miR-9 expression group. Multivariate analysis showed that serum miR-9 was an independent prognostic factor for OSCC. Conclusions Serum miR-9 was downregulated in patients with OSCC and patients with OLK. In addition, low serum miR-9 was correlated with poor prognosis of OSCC, indicating miR-9 might play a tumor suppressive role in OSCC and can serve as a promising biomarker for this deadly disease. PMID:26813876

  13. High expression of pituitary tumor-transforming gene-1 predicts poor prognosis in clear cell renal cell carcinoma

    PubMed Central

    WEI, CAN; YANG, XIAOLIANG; XI, JUNHUA; WU, WEI; YANG, ZHENXING; WANG, WEI; TANG, ZHIGUO; YING, QUANSHENG; ZHANG, YANBIN

    2015-01-01

    Pituitary tumor-transforming gene-1 (PTTG1) is a recently identified oncogene involved in the progression of malignant tumors; however, the expression level of PTTG1 in clear cell renal cell carcinoma (ccRCC) and its potential value as a novel prognostic marker for ccRCC remains unclear. In this study, PTTG1 mRNA and protein levels were assessed in 44 paired ccRCC tissues and adjacent normal tissues by quantitative polymerase chain reaction (qPCR) and immunohistochemistry, respectively. Further immunohistochemical analysis was implemented in 192 samples of ccRCC to evaluate the associations between PTTG1 levels and the clinical characteristics in ccRCC. Reverse transcription qPCR and immunohistochemical analysis demonstrated that the PTTG1 mRNA and protein levels were significantly higher in ccRCC compared to normal tissues. In addition, the PTTG1 protein level in 192 ccRCC samples was found to be significantly correlated with T stage, N classification, metastasis, recurrence and Fuhrman grade, whereas it was not associated with age and gender. Patients with low PTTG1 levels exhibited a better survival outcome compared to those with a higher PTTG1 level. PTTG1 expression and N stage were identified as independent prognostic factors for the overall survival of ccRCC patients. The results suggested that the overexpression of PTTG1 indicates a poor prognosis in ccRCC patients and, therefore, PTTG1 may serve as a novel prognostic marker for ccRCC. PMID:25798272

  14. h-Prune is associated with poor prognosis and epithelial-mesenchymal transition in patients with colorectal liver metastases.

    PubMed

    Hashimoto, Masakazu; Kobayashi, Tsuyoshi; Tashiro, Hirotaka; Arihiro, Koji; Kikuchi, Akira; Ohdan, Hideki

    2016-08-15

    The prognosis of patients with colorectal liver metastases (CRLM) remains low despite advances in chemotherapy and surgery. The expression of h-prune (human homolog of Drosophila prune protein; HGNC13420), an exopolyphosphatase, is correlated with progression and aggressiveness in several cancers and promotes migration and invasion. We investigated the role of h-prune in CRLM. To investigate the role of h-prune, immunohistochemical analysis for h-prune was performed in 87 surgically resected specimens of CRLM obtained between 2001 and 2009 at the Hiroshima University Hospital. Immunohistochemical analysis revealed positive staining for h-prune in 24 (28%) cases. The overall survival rate was significantly lower in h-prune-positive cases than in h-prune-negative cases (p = 0.003). Multivariate analysis showed that h-prune positivity was the only independent factor related to poor overall survival of patients after curative hepatectomy of CRLM. In vitro and in vivo, h-prune-knocked-down and h-prune-overexpressing cells were analyzed. In vitro, h-prune was associated with increased cell motility and upregulation of epithelial-mesenchymal transition (EMT) markers. In a mouse model, h-prune was associated with invasion of the tumor and distant metastases. In summary, h-prune expression is a useful marker to identify high-risk patients for resectable colorectal liver metastasis. h-Prune expression is necessary for cancer cell motility and EMT and is associated with liver and lung metastasis in colorectal cancer cells. h-Prune could be a new prognostic marker and molecular target for CRLM. PMID:27037526

  15. Tumor necrosis is associated with increased alphavbeta3 integrin expression and poor prognosis in nodular cutaneous melanomas

    PubMed Central

    Bachmann, Ingeborg M; Ladstein, Rita G; Straume, Oddbjørn; Naumov, George N; Akslen, Lars A

    2008-01-01

    Background Tumor necrosis and apoptotic activity are considered important in cancer progression, but these features have not been much studied in melanomas. Our hypothesis was that rapid growth in cutaneous melanomas of the vertical growth phase might lead to tissue hypoxia, alterations in apoptotic activity and tumor necrosis. We proposed that these tumor characteristics might be associated with changes in expression of cell adhesion proteins leading to increased invasive capacity and reduced patient survival. Methods A well characterized series of nodular melanoma (originally 202 cases) and other benign and malignant melanocytic tumors (109 cases) were examined for the presence of necrosis, apoptotic activity (TUNEL assay), immunohistochemical expression of hypoxia markers (HIF-1 α, CAIX, TNF-α, Apaf-1) and cell adhesion proteins (αvβ3 integrin, CD44/HCAM and osteopontin). We hypothesized that tumor hypoxia and necrosis might be associated with increased invasiveness in melanoma through alterations of tumor cell adhesion proteins. Results Necrosis was present in 29% of nodular melanomas and was associated with increased tumor thickness, tumor ulceration, vascular invasion, higher tumor proliferation and apoptotic index, increased expression of αvβ3 integrin and poor patient outcome by multivariate analysis. Tumor cell apoptosis did also correlate with reduced patient survival. Expression of TNF-α and Apaf-1 was significantly associated with tumor thickness, and osteopontin expression correlated with increased tumor cell proliferation (Ki-67). Conclusion Tumor necrosis and apoptotic activity are important features of melanoma progression and prognosis, at least partly through alterations in cell adhesion molecules such as increased αvβ3 integrin expression, revealing potentially important targets for new therapeutic approaches to be further explored. PMID:19061491

  16. High ABCG4 Expression Is Associated with Poor Prognosis in Non-Small-Cell Lung Cancer Patients Treated with Cisplatin-Based Chemotherapy

    PubMed Central

    Zhou, Yong-An; Tian, Feng; Zhao, Jin-Bo; Chen, Peng; Liu, Bo-Ya; Wen, Miao-Miao; Li, Xiao-Fei; Zhang, Zhi-Pei

    2015-01-01

    ATP-binding cassette (ABC) transporters are associated with poor response to chemotherapy, and confer a poor prognosis in various malignancies. However, the association between the expression of the ABC sub-family G member 4 (ABCG4) and prognosis in patients with non-small-cell lung cancer (NSCLC) remains unclear. NSCLC tissue samples (n = 140) and normal lung tissue samples (n = 90) were resected from patients with stage II to IV NSCLC between May 2004 and May 2009. ABCG4 mRNA and protein expressions were detected by RT-PCR, western blot, and immunohistochemistry. Patients received four cycles of cisplatin-based post-surgery chemotherapy and were followed up until May 31st, 2014. ABCG4 positivity rate was higher in NSCLC than in normal lung tissues (48.6% vs. 0%, P<0.001) and ABCG4 expression was significantly associated with poor differentiation, higher tumor node metastasis (TNM) stage, and adenocarcinoma histological type (all P<0.001). Univariate (HR = 2.284, 95%CI: 1.570–3.324, P<0.001) and multivariate (HR = 2.236, 95%CI: 1.505–3.321, P<0.001) analyses showed that ABCG4 expression was an independent factor associated with a poor prognosis in NSCLC. Patients with ABCG4-positive NSCLC had shorter median survival than ABCG4-negative NSCLC (20.1 vs. 43.2 months, P<0.001). The prognostic significance of ABCG4 expression was apparent in stages III and IV NSCLC. In conclusion, high ABCG4 expression was associated with a poor prognosis in patients with NSCLC treated with cisplatin-based chemotherapy. PMID:26270652

  17. Reduced Expression of the Polymeric Immunoglobulin Receptor in Pancreatic and Periampullary Adenocarcinoma Signifies Tumour Progression and Poor Prognosis

    PubMed Central

    Fristedt, Richard; Elebro, Jacob; Gaber, Alexander; Jonsson, Liv; Heby, Margareta; Yudina, Yulyana; Nodin, Björn; Uhlén, Mathias; Eberhard, Jakob; Jirström, Karin

    2014-01-01

    The polymeric immunoglobulin receptor (pIgR) is a key component of the mucosal immune system that mediates epithelial transcytosis of immunoglobulins. High pIgR expression has been reported to correlate with a less aggressive tumour phenotype and an improved prognosis in several human cancer types. Here, we examined the expression and prognostic significance of pIgR in pancreatic and periampullary adenocarcinoma. The study cohort encompasses a consecutive series of 175 patients surgically treated with pancreaticoduodenectomy for pancreatic and periampullary adenocarcinoma in Malmö and Lund University Hospitals, Sweden, between 2001–2011. Tissue microarrays were constructed from primary tumours (n = 175) and paired lymph node metastases (n = 105). A multiplied score was calculated from the fraction and intensity of pIgR staining. Classification and regression tree analysis was used to select the prognostic cut-off. Unadjusted and adjusted hazard ratios (HR) for death and recurrence within 5 years were calculated. pIgR expression could be evaluated in 172/175 (98.3%) primary tumours and in 96/105 (91.4%) lymph node metastases. pIgR expression was significantly down-regulated in lymph node metastases as compared with primary tumours (p = 0.018). Low pIgR expression was significantly associated with poor differentiation grade (p<0.001), perineural growth (p = 0.027), lymphatic invasion (p = 0.016), vascular invasion (p = 0.033) and infiltration of the peripancreatic fat (p = 0.039). In the entire cohort, low pIgR expression was significantly associated with an impaired 5-year survival (HR = 2.99, 95% confidence interval (CI) 1.71–5.25) and early recurrence (HR = 2.89, 95% CI 1.67–4.98). This association remained significant for survival after adjustment for conventional clinicopathological factors, tumour origin and adjuvant treatment (HR = 1.98, 95% CI 1.10–3.57). These results demonstrate, for the first time, that high

  18. CSF2 Overexpression Is Associated with STAT5 Phosphorylation and Poor Prognosis in Patients with Urothelial Carcinoma

    PubMed Central

    Lee, Yi-Ying; Wu, Wen-Jeng; Huang, Chun-Nung; Li, Ching-Chia; Li, Wei-Ming; Yeh, Bi-Wen; Liang, Peir-In; Wu, Ting-Feng; Li, Chien-Feng

    2016-01-01

    prognosis for both DSS (UTUC, p=0.0001; UBUC, p<0.0001) and MeFS (UTUC, p=0.0001; UBUC, p=0.0002). High expression of CSF2 still remained prognostically for DSS (UTUC, p=0.015; UBUC, p=0.004) and MeFS (UTUC, p=0.008; UBUC, p=0.027) in multivariate comparison. Conclusion: Our data showed that overexpression of CSF2 was inferred in advanced disease status and poor clinical outcomes for both UTUC and UBUC patients, suggesting that CSF2 may serve as an important prognosticator and a potential therapeutic target of UC. PMID:27076853

  19. Decreased maspin combined with elevated vascular endothelial growth factor C is associated with poor prognosis in non-small cell lung cancer

    PubMed Central

    Wang, Xing; Wang, Yang; Li, Shaolei; Dong, Bin; Zheng, Qingfeng; Yan, Shi; Ma, Yuanyuan; Zhang, Jianzhi; Fang, Jian; Wu, Nan; Wu, Huijuan; Yang, Yue

    2014-01-01

    Background This study aimed to investigate the clinical significance of the combination of maspin and vascular endothelial growth factor (VEGF)-C expression in the prognosis of non-small cell lung cancer (NSCLC). Methods Immunohistochemistry was performed to assay the expression of maspin and VEGF-C in primary tumor tissues, metastatic, and non-metastatic lymph nodes in 98 NSCLC patients. Survival analysis was determined by Kaplan-Meier curves. Results The positive expression rate of maspin was 26.5% (26/98) in NSCLC primary tumor tissues, significantly associated with histological type (P = 0.005) and the absence of nodal metastasis (P < 0.001). The expression of maspin in primary tumor tissues was stronger than metastatic lymph nodes of the N1 group (P = 0.048), while the metastatic lymph nodes of the N1 group had a stronger maspin expression than the N2 group (P = 0.008). In survival analysis, a positive expression of maspin of the N1 lymph node was also found to be an independent positive prognostic factor in overall survival (P = 0.003). We also found that decreased maspin combined with elevated VEGF-C is associated with a poor prognosis for disease-free survival (P = 0.019). Conclusion Our results suggest that positive expression of maspin might significantly inhibit nodal metastasis in NSCLC. Decreased maspin combined with elevated VEGF-C might be associated with a poor prognosis in NSCLC. PMID:26767029

  20. Elevated serum CA72-4 levels predict poor prognosis in pancreatic adenocarcinoma after intensity-modulated radiation therapy.

    PubMed

    Liu, Peng; Zhu, Yuan; Liu, Luying

    2015-04-20

    Carbohydrate antigen 72-4 (CA72-4) is a human tumor-associated glycoprotein, commonly used as a tumor marker for diagnosing and predicting outcome in gastric and ovarian cancers. However, the relationship between serum CA72-4 levels and prognosis of pancreatic adenocarcinoma has not been fully elucidated. A total of 113 consecutive locally advanced pancreatic adenocarcinoma patients who underwent intensity-modulated radiation therapy (IMRT) with or without chemotherapy were enrolled in this study. Serum CA72-4 levels were analyzed using immunoenzymometric assays. The association between serum CA72-4 levels and prognosis was evaluated. Serum CA72-4 levels was related with lymph node metastasis (P<0.001). The median overall survival time was 14.0 months for patients with serum CA72-4 normal levels and 10.0 months for the elevated levels (P<0.001). Multivariate analysis identified that Serum CA72-4 concentration was a significant prognostic factor (P<0.001). The hazard ratio (HR) of elevated serum CA72-4 levels compared with normal serum CA72-4 levels was 2.34 (95% confidence interval [CI]: 1.46-3.73), after adjusted for gender and age. Based on this finding, Serum CA72-4 is a potential marker to predict lymph node metastasis and prognosis in pancreatic adenocarcinoma. PMID:25860937

  1. Loss of ataxia-telangiectasia-mutated protein expression correlates with poor prognosis but benefits from anthracycline-containing adjuvant chemotherapy in breast cancer.

    PubMed

    Suh, Koung Jin; Ryu, Han Suk; Lee, Kyung-Hun; Kim, Hyojin; Min, Ahrum; Kim, Tae-Yong; Yang, Yaewon; Moon, Hyeong-Gon; Han, Sae-Won; Oh, Do-Youn; Han, Wonshik; Park, In Ae; Noh, Dong-Young; Im, Seock-Ah

    2016-07-01

    We investigated the correlation of ataxia-telangiectasia-mutated (ATM) protein expression with clinicopathological features and prognosis in patients with breast cancer. ATM expression was determined by immunohistochemistry in 420 surgically resected breast tumors. ATM loss was observed in 126/407 evaluable cases (31.0 %), and was significantly associated with larger tumor size, lymph node metastasis, higher tumor grade, and ER- and/or PR-negative status. ATM loss was also associated with significantly lower disease-free survival rates than those in patients with intact ATM (5-year disease-free survival rate 81.2 vs. 90.7 %, p = 0.015). In multivariate analysis, ATM loss combined with abnormal p53 expression was an independent predictor of shorter disease-free survival [hazard ratio (HR) 3.48; 95 % confidence interval (CI), 1.48-8.17, p = 0.004]. A tendency towards a poorer prognosis was observed for tumoral ATM loss alone, although statistical significance was not reached (HR 1.74; 95 % CI 0.95-3.20; p = 0.075). In subgroup analysis, ATM loss was associated with shorter disease-free survival in patients who did not receive adjuvant anthracycline chemotherapy (5-year disease-free survival rate 92.7 % in intact ATM group vs. 68.1 % in ATM loss group, p = 0.002), but this poor prognosis was overcome in patients who did (5-year disease-free survival rate 89.8 vs. 84.4 %, p = 0.243), suggesting more benefit from anthracycline-based chemotherapy. Tumors with loss of ATM expression have a poor prognosis and their prognoses are dependent on the use of adjuvant anthracycline. ATM loss might be a practical tool for predicting benefits from anthracycline-based adjuvant therapy. PMID:27329169

  2. Elevated RNA expression of long non‑coding HOTAIR promotes cell proliferation and predicts a poor prognosis in patients with diffuse large B cell lymphoma.

    PubMed

    Yan, Yuling; Han, Jingyin; Li, Zhenqing; Yang, Honglan; Sui, Yanmin; Wang, Minglin

    2016-06-01

    Diffuse large B cell lymphoma (DLBCL) is one of the most common types of malignancy worldwide. The lack of clear symptoms and early detection make it difficult to diagnose at an early stage, leading to poor prognosis of the patients. Long non‑coding RNAs (lncRNAs) have come into focus for their important regulatory roles in fundamental biological processes, particularly in cancer initiation, development and progression. The aim of the present study was to investigate the expression of lncRNA Hox transcript antisense intergenic RNA (HOTAIR) in a cohort of patients with DLBCL to assess its clinical value and biological function in DLBCL. The reverse transcription‑polymerase chain reaction was used to detect HOTAIR expression levels and cells were transfected with small interfering RNA to compare cell proliferation, cell cycle progression and apoptosis. Western blotting was also conducted to detect possible signaling pathways. It was first found that the expression levels of HOTAIR were upregulated in DLBCL tumor tissues and cell lines, compared with normal tissues and cells. In addition, HOTAIR was significantly correlated with tumor size, clinical stage, B symptoms and International Prognostic Index scores; and higher expression levels of HOTAIR were correlated with improved prognosis. Univariate and multivariate analyses verified that HOTAIR was a key independent predictive factor for DLBCL prognosis. Furthermore, it was revealed that the knockdown of the expression of HOTAIR led to growth inhibition, cell cycle arrest and apoptosis in vitro, possibly through the phosphoinositide 3‑kinase/AKT/nuclear factor‑κB pathway. These results suggested that HOTAIR may be regarded as a novel indicator of poor prognosis, and may serve as a potential target for gene therapy in the treatment of DLBCL. PMID:27122348

  3. Elevated RNA expression of long non-coding HOTAIR promotes cell proliferation and predicts a poor prognosis in patients with diffuse large B cell lymphoma

    PubMed Central

    YAN, YULING; HAN, JINGYIN; LI, ZHENQING; YANG, HONGLAN; SUI, YANMIN; WANG, MINGLIN

    2016-01-01

    Diffuse large B cell lymphoma (DLBCL) is one of the most common types of malignancy worldwide. The lack of clear symptoms and early detection make it difficult to diagnose at an early stage, leading to poor prognosis of the patients. Long non-coding RNAs (lncRNAs) have come into focus for their important regulatory roles in fundamental biological processes, particularly in cancer initiation, development and progression. The aim of the present study was to investigate the expression of lncRNA Hox transcript antisense intergenic RNA (HOTAIR) in a cohort of patients with DLBCL to assess its clinical value and biological function in DLBCL. The reverse transcription-polymerase chain reaction was used to detect HOTAIR expression levels and cells were transfected with small interfering RNA to compare cell proliferation, cell cycle progression and apoptosis. Western blotting was also conducted to detect possible signaling pathways. It was first found that the expression levels of HOTAIR were upregulated in DLBCL tumor tissues and cell lines, compared with normal tissues and cells. In addition, HOTAIR was significantly correlated with tumor size, clinical stage, B symptoms and International Prognostic Index scores; and higher expression levels of HOTAIR were correlated with improved prognosis. Univariate and multivariate analyses verified that HOTAIR was a key independent predictive factor for DLBCL prognosis. Furthermore, it was revealed that the knockdown of the expression of HOTAIR led to growth inhibition, cell cycle arrest and apoptosis in vitro, possibly through the phosphoinositide 3-kinase/AKT/nuclear factor-κB pathway. These results suggested that HOTAIR may be regarded as a novel indicator of poor prognosis, and may serve as a potential target for gene therapy in the treatment of DLBCL. PMID:27122348

  4. Single high-dose etoposide and melphalan with non-cryopreserved autologous marrow rescue as primary therapy for relapsed, refractory and poor-prognosis Hodgkin's disease.

    PubMed Central

    Seymour, L. K.; Dansey, R. D.; Bezwoda, W. R.

    1994-01-01

    A simplified schedule of high-dose chemotherapy (HDC) consisting of melphalan (140 mg m-2) plus VP16 (2.5 g m-2) given over 12-18 h together with autologous non-cryopreserved autologous bone marrow transplant (ABMT) was used for treatment of relapsed (37 patients) and refractory (seven patients) patients and as first-line treatment (four patients) for poor-prognosis Hodgkin's disease. Two patients had a second HDC-ABMT after relapse following prior HDC-ABMT, giving a total of 50 procedures among 48 patients. The haematological recovery rate was 98% with a complete response rate of the Hodgkin's disease of > 90%. Factors significantly influencing response rate were performance status and the presence of liver involvement. Thirty-nine patients are alive, with 37 in continuous complete remission. The median duration of survival and median duration of remission have not been reached at a median follow-up time of 45 months. Adverse prognostic factors for survival were disease status at the time of HDC-ABMT (refractory versus relapse, with primarily refractory patients showing significantly poor survival) and the presence of liver involvement. High-dose chemotherapy with short-duration chemotherapy and non-cryopreserved bone marrow is an effective and safe treatment modality for patients with relapsed and poor-prognosis Hodgkin's disease. PMID:8080741

  5. Allelic loss of chromosome 16q in endometrial cancer: correlation with poor prognosis of patients and less differentiated histology.

    PubMed

    Kihana, T; Yano, N; Murao, S; Iketani, H; Hamada, K; Yano, J; Murao, S; Iketani, H; Hamada, K; Yano, J; Matsuura, S

    1996-11-01

    Deletion of certain chromosomal regions can be demonstrated in malignant cells. Chromosome 16q is one of the regions where allelic loss is frequently detected in carcinoma of the breast and many other tumors, suggesting that gene(s) which retard tumor growth may exist here. To elucidate the clinicopathological significance of chromosome 16q, loss of heterozygosity (LOH) was investigated using microsatellite polymorphism analysis in 58 patients with endometrial lesions (50 with endometrial carcinoma and 8 who had hyperplasia with or without atypia). When 11 regions of chromosome 16q were examined, LOH was found in 20 patients with carcinoma (40%) and none of the patients with hyperplasia. The tumors of 9 of the 20 patients (45%) showed total loss of 16q, while the others (55%) showed partial deletion. Tumors with LOH were histologically less differentiated than those without LOH (P = 0.038, chi2 test). Patients with tumors showing LOH of 16q had a worse prognosis than those without LOH according to Kaplan-Meier survival analysis (P=0.0158, log-rank test). In addition, LOH of 16q showed a significant relationship to prognosis by Cox regression analysis. Deletion mapping of 16q demonstrated that two regions (16q22.1 and 16q22.2-23.1) were frequently involved. Patients with 16q22.1 LOH had a poorer prognosis than those with intact 16q22.1 (P=0.0003, log-rank test). These findings suggest that gene(s) of which defect is possibly related to the aggressiveness of endometrial cancer are localized on a limited region of 16q that includes 16q22.1. PMID:9045949

  6. Overexpression Of Hepatocyte Nuclear Factor-1beta Predicting Poor Prognosis Is Associated With Biliary Phenotype In Patients With Hepatocellular Carcinoma

    PubMed Central

    Yu, Dan-Dan; Jing, Ying-Ying; Guo, Shi-Wei; Ye, Fei; Lu, Wen; Li, Quan; Dong, Yu-Long; Gao, Lu; Yang, Yu-Ting; Yang, Yang; Wu, Meng-Chao; Wei, Li-Xin

    2015-01-01

    Hepatocyte nuclear factor-1beta (HNF-1B) is involved in the hepatobiliary specification of hepatoblasts to cholangiocytes during liver development, and is strongly expressed throughout adult biliary epithelium. The aim of this study was to examine the expression of HNF-1B in different pathologic subtypes of primary liver cancer, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (ICC), and the relationship between HNF-1B expression, clinicopathological features and prognosis. We retrospectively investigated 2 cohorts of patients, including 183 HCCs and 69 ICCs. The expression of HNF-1B was examined by immunohistochemistry. We found that HNF-1B expression was associated with pathological subtype of primary tumor, and HNF-1B expression in HCC tissue may be associated with the change of phenotype on recurrence. The HNF-1B expression was positively correlated with biliary/HPC (hepatic progenitor cell) markers expression. Further, multivariable analysis showed that HNF-1B expression was an independent prognostic factor for both overall survival and disease-free survival of HCC patients. However, no correlation between HNF-1B expression and survival was found in ICC patients. In summary, HCC with high HNF-1B expression displayed biliary phenotype and tended to show poorer prognosis. HNF-1B-positive malignant cells could be bipotential cells and give rise to both hepatocytic and cholangiocytic lineages during tumorigenesis. PMID:26311117

  7. FoxM1 Is Associated with Poor Prognosis of Non-Small Cell Lung Cancer Patients through Promoting Tumor Metastasis

    PubMed Central

    Xu, Nuo; Jia, Deshui; Chen, Wenfeng; Wang, Hao; Liu, Fanglei; Ge, Haiyan; Zhu, Xiaodan; Song, Yuanlin; Zhang, Xin; Zhang, David

    2013-01-01

    Background FoxM1 has been reported to be important in initiation and progression of various tumors. However, whether FoxM1 has any indication for prognosis in non-small cell lung cancer patients remains unclear. Methodology/Principal Findings In this study, FoxM1 expression in tumor cells was examined first by immunohistochemistry in 175 NSCLC specimens, the result of which showed that FoxM1 overexpression was significantly associated with positive smoking status (P = 0.001), poorer tissue differentiation (P = 0.0052), higher TNM stage (P<0.0001), lymph node metastasis (P<0.0001), advanced tumor stage (P<0.0001), and poorer prognosis (P<0.0001). Multivariable analysis showed that FoxM1 expression increased the hazard of death (hazard ratio, 1.899; 95% CI, 1.016–3.551). Furthermore, by various in vitro and in vivo experiments, we showed that targeted knockdown of FoxM1 expression could inhibit the migratory and invasive abilities of NSCLC cells, whereas enforced expression of FoxM1 could increased the invasion and migration of NSCLC cells. Finally, we found that one of the cellular mechanisms by which FoxM1 promotes tumor metastasis is through inducing epithelial-mesenchymal transition (EMT) program. Conclusions These results suggested that FoxM1 overexpression in tumor tissues is significantly associated with the poor prognosis of NSCLC patients through promoting tumor metastasis. PMID:23536876

  8. The correlation of microRNA-181a and target genes with poor prognosis of glioblastoma patients.

    PubMed

    Huang, Shi-Xiong; Zhao, Zhong-Yan; Weng, Guo-Hu; He, Xiang-Ying; Wu, Chan-Ji; Fu, Chuan-Yi; Sui, Zhi-Yan; Zhong, Xiao-Ming; Liu, Tao

    2016-07-01

    To investigate the expression and clinical significance of miR-181a and its target genes in glioblastoma multiforme (GBM), the expression levels of miR-181a and three target genes in human normal brain tissues and GBM were analyzed in silico using gene microarray, gene ontology, KEGG pathway and hierarchical clustering analysis followed by validation with quantitative RT-PCR. Our results show that miR-181a is down-regulated in GBM patients. The three target genes, ANGPT2, ARHGAP18 and LAMC1, are negatively correlated with the expression of miR-181a. Moreover, high expression of ANGPT2 or LAMC1 together with large size of GBM is correlated with a shorter median overall survival. In conclusion, our results showed that miR-181a and it targets ANGPT2 and LAMC1 might be predictors of prognosis in GBM patients. PMID:27176932

  9. Exosomal levels of miRNA-21 from cerebrospinal fluids associated with poor prognosis and tumor recurrence of glioma patients.

    PubMed

    Shi, Rui; Wang, Pei-Yin; Li, Xin-Yi; Chen, Jian-Xin; Li, Yan; Zhang, Xin-Zhong; Zhang, Chen-Guang; Jiang, Tao; Li, Wen-Bin; Ding, Wei; Cheng, Shu-Jun

    2015-09-29

    Glioma is a most common type of primary brain tumors. Extracellular vesicles, in the form of exosomes, are known to mediate cell-cell communication by transporting cell-derived proteins and nucleic acids, including various microRNAs (miRNAs). Here we examined the cerebrospinal fluid (CSF) from patients with recurrent glioma for the levels of cancer-related miRNAs, and evaluated the values for prognosis by comparing the measures of CSF-, serum-, and exosome-contained miR-21 levels. Samples from seventy glioma patients following surgery were compared with those from brain trauma patients as a non-tumor control group. Exosomal miR-21 levels in the CSF of glioma patients were found significantly higher than in the controls; whereas no difference was detected in serum-derived exosomal miR-21 expression. The CSF-derived exosomal miR-21 levels correlated with tumor spinal/ventricle metastasis and the recurrence with anatomical site preference. From additional 198 glioma tissue samples, we verified that miR-21 levels associated with tumor grade of diagnosis and negatively correlated with the median values of patient overall survival time. We further used a lentiviral inhibitor to suppress miR-21 expression in U251 cells. The results showed that the levels of miR-21 target genes of PTEN, RECK and PDCD4 were up-regulated at protein levels. Therefore, we concluded that the exosomal miR-21 levels could be demonstrated as a promising indicator for glioma diagnosis and prognosis, particularly with values to predict tumor recurrence or metastasis. PMID:26284486

  10. Low claudin-6 expression correlates with poor prognosis in patients with non-small cell lung cancer

    PubMed Central

    Wang, Qiang; Zhang, Yan; Zhang, Tao; Han, Zhi-Gang; Shan, Li

    2015-01-01

    Objective Claudins are found in junctional complexes mediating cell adhesion and are involved in the attachment of tight junctions to the underlying cytoskeleton. Abnormal claudin-6 expression has been observed for a variety of malignant solid tumors, but the expression of claudin-6 in non-small cell lung cancer (NSCLC) has not yet been characterized. Methods Immunohistochemistry, reverse transcription-polymerase chain reaction (RT-PCR), and western blot analysis were used to quantify claudin-6 expression in 123 cases of NSCLC and non-cancerous adjacent tissue. We analyzed the relationship between claudin-6 expression and clinicopathological features of NSCLC. The Kaplan–Meier method was used to analyze postoperative survival rates, and the log-rank test was used to assess differences in survival rates. The Cox regression model was used to perform multivariate analysis. Results Claudin-6 expression was low for 61 of 123 (49.6%) NSCLC tissue samples and for 33 of 123 (26.8%) normal adjacent tissue samples. RT-PCR and western blot analyses confirmed the immunohistochemistry results. Claudin-6 expression was associated with lymph node metastasis (P<0.001) and TNM stage (P=0.007). Kaplan–Meier analysis indicated that patients with low claudin-6 expression had significantly lower survival rates than those with high claudin-6 expression. Multivariate analysis suggested that low claudin-6 expression was an independent indicator of prognosis in NSCLC patients. Conclusion Low claudin-6 expression is an independent prognostic biomarker that indicates a worse prognosis in patients with NSCLC. PMID:26261421

  11. High leukocyte mtDNA content contributes to poor prognosis through ROS-mediated immunosuppression in hepatocellular carcinoma patients

    PubMed Central

    Zhou, Feng; Zhou, Xingchun; Chen, Yibing; Guo, Xu; Li, Jibin; Huang, Qichao; Yang, Yefa; Lyu, Zhuomin; Zhang, Hongxin; Xing, Jinliang

    2016-01-01

    Compelling epidemiological evidences indicate a significant association between leukocyte mitochondrial DNA (mtDNA) content and incidence risk of several malignancies, including hepatocellular carcinoma (HCC). However, whether leukocyte mtDNA content affect prognosis of HCC patients and underlying mechanism has never been explored. In our study, leukocyte mtDNA content was measured in 618 HCC patients and its prognostic value was analyzed. Moreover, we detected the immunophenotypes of peripheral blood mononuclear cells (PBMCs) and plasma concentrations of several cytokines in 40 HCC patients and assessed the modulating effects of mtDNA content on immunosuppression in cell models. Our results showed that HCC patients with high leukocyte mtDNA content exhibited a significantly worse recurrence-free survival (RFS) and overall survival (OS) than those with low leukocyte mtDNA content. Leukocyte mtDNA content and TNM stage exhibited a notable joint effect in prognosis prediction. Furthermore, we found that patients with high leukocyte mtDNA content exhibited a higher frequency of CD4+CD25+FOXP3+ regulatory T (Treg) cells and lower frequency of NK cells in PBMCs and had higher TGF-β1 and lower TNF-α and IFN-γ plasma concentration when compared with those with low leukocyte mtDNA content, which suggests an immunosuppressive status. High leukocyte mtDNA content significantly enhanced the ROS-mediated secretion of TGF-β1, which accounted for higher Treg and lower NK frequency in PBMCs. In a conclusion, our study for the first time demonstrates that leukocyte mtDNA content is an independent prognostic marker complementing TNM stage and associated with an ROS-mediated immunosuppressive phenotype in HCC patients. PMID:26985767

  12. Ultra-early microsurgical treatment within 24 h of SAH improves prognosis of poor-grade aneurysm combined with intracerebral hematoma

    PubMed Central

    CHEN, JUNHUI; ZHU, JUN; HE, JIANQING; WANG, YUHAI; CHEN, LEI; ZHANG, CHUNLEI; ZHOU, JINGXU; YANG, LIKUN

    2016-01-01

    Spontaneous subarachnoid hemorrhage (SAH) is the most common cerebrovascular disease. The conventional treatment for SAH is usually associated with high mortality. The present study aims to assess the prognosis of microsurgical treatment for patients with poor-grade aneurysm (Hunt and Hess grades IV–V) associated with intracerebral hematoma. A total of 18 consecutive patients who were diagnosed with poor-grade aneurysm accompanied with intracerebral hematoma were retrospectively recruited. All patients underwent microsurgical treatment between April 2010 and June 2013 at The 101st Hospital of Chinese People's Liberation Army (Wuxi, China). Among them, 15 cases underwent microsurgery within 24 h of SAH, and 3 cases underwent microsurgery 24 h following SAH. All 18 cases were examined by computed tomography angiography (CTA). The outcome was assessed during a follow-up time of 6–36 months. According to the Glasgow Outcome Scale, 4 patients experienced a good recovery, 6 were dissatisfied with the outcome, 4 were in vegetative state and 4 succumbed to disease. Poor outcome occurred in patients with an aneurysm diameter >10 mm, exhibited >50 ml volume of intracerebral hematoma or presented cerebral hernia prior to the surgical operation. The outcome of ultra-early surgery (within 24 h of SAH) was improved, compared with that of surgery following 24 h of SAH (P=0.005). Among 7 patients who accepted extraventricular drainage, good outcomes were achieved in 4 of them, whereas dissatisfaction and mortality occurred in 2 and 1 patients, respectively. Therefore, ultra-early microsurgery (within 24 h of SAH) combined with extraventricular drainage may improve the prognosis of patients with poor-grade aneurysm. PMID:27123084

  13. High expression of lncRNA MALAT1 suggests a biomarker of poor prognosis in colorectal cancer

    PubMed Central

    Zheng, Hong-Tu; Shi, De-Bing; Wang, Yu-Wei; Li, Xin-Xiang; Xu, Ye; Tripathi, Pratik; Gu, Wei-Lie; Cai, Guo-Xiang; Cai, San-Jun

    2014-01-01

    Objective: This study sought to investigate the role of the long noncoding RNA MALAT1 in the prognosis of stage II/III colorectal cancer (CRC) patients. Methods: The expression of MALAT1 was evaluated in cancer tissues from 146 stage II/III CRC patients undergoing radical resection and 23 paired normal colonic mucosa samples using quantitative real-time reverse transcriptase PCR. Differences in the expression of MALAT1 between 23 CRC and paired normal colonic mucosa samples were analysed with the Wilcoxon test. Relationships between the expression level of MALAT1, patient clinicopathological parameters and disease-free survival (DFS) and overall survival (OS) were analysed using the univariate Kaplan-Meier method and the multivariate COX regression model. Results: The MALAT1 levels in cancerous tissues were 2.26 times higher than those measured in noncancerous tissues, and this difference was statistically significant (P = 0.0004). Based on their expression level of MALAT1, the patients were divided into a high MALAT1 expression group (n = 73) and a low expression group (n = 73). Patients with tumours harbouring higher expression of MALAT1 showed a significantly worse prognosis with a hazard ratio (HR) of 2.863 (95% CI, 1.659 to 4.943; P < 0.001) for DFS and 3.968 (95% CI, 1.665 to 9.456; P = 0.002) for OS. Furthermore, patients with perineural invasion demonstrated significantly worse DFS (HR = 3.459, 95% CI 2.008 to 5.957; P < 0.001) and OS (HR = 3.750, 95% CI 1.743 to 8.069; P = 0.001) than those without perineural invasion. Multivariate analyses indicated that MALAT1 expression and perineural invasion were two independent prognostic risk factors for patients with CRC. Conclusion: The expression of MALAT1 is upregulated in CRC tissues, and a higher expression level of MALAT1 might serve as a negative prognostic marker in stage II/III CRC patients. PMID:25031737

  14. DNMT3A R882 Mutations Predict a Poor Prognosis in AML: A Meta-Analysis From 4474 Patients.

    PubMed

    Yuan, Xiao-Qing; Peng, Li; Zeng, Wen-Jing; Jiang, Bin-Yuan; Li, Guan-Cheng; Chen, Xiao-Ping

    2016-05-01

    DNA (cytosine-5)-methyltransferase 3 alpha (DNMT3A) mutations were widely believed to be independently associated with inferior prognosis in acute myeloid leukemia (AML) patients. As dominant missense alterations in DNMT3A mutations, R882 mutations cause the focal hypomethylation phenotype. However, there remains debate on the influence of R882 mutations on AML prognosis. Thus, this meta-analysis aimed at further illustrating the prognostic power of DNMT3A R882 mutations in AML patients.Eligible studies were identified from 5 databases containing PubMed, Embase, Web of Science, Clinical Trials, and the Cochrane Library (up to October 25, 2015). Effects (hazard ratios [HRs] with 95% confidence interval [CI]) of relapse-free survival (RFS) and overall survival (OS) were pooled to estimate the prognostic power of mutant DNMT3A R882 in overall patients and subgroups of AML patients.Eight competent studies with 4474 AML patients including 694 with DNMT3A R882 mutations were included. AML patients with DNMT3A R882 mutations showed significant shorter RFS (HR = 1.40, 95% CI = 1.24-1.59, P < 0.001) and OS (HR = 1.47, 95% CI = 1.17-1.86, P = 0.001) in the overall population. DNMT3A R882 mutations predicted worse RFS and OS among the subgroups of patients under age 60 (RFS: HR = 1.44, 95% CI = 1.25-1.66, P < 0.001; OS: HR = 1.48, 95% CI = 1.15-1.90, P = 0.002), over age 60 (RFS: HR = 2.03, 95% CI = 1.40-2.93, P < 0.001; OS: HR = 1.85, 95% CI = 1.36-2.53, P < 0.001), cytogenetically normal (CN)-AML (RFS: HR = 1.52, 95% CI = 1.26-1.83, P < 0.001; OS: HR = 1.67, 95% CI = 1.16-2.41, P = 0.006), and non-CN-AML (RFS: HR = 1.96, 95% CI = 1.20-3.21, P = 0.006; OS: HR = 2.51, 95% CI = 1.52-4.15, P = 0.0038).DNMT3A R882 mutations possessed significant unfavorable prognostic influence on RFS and OS in AML patients. PMID:27149454

  15. Ring finger protein 43 expression is associated with genetic alteration status and poor prognosis among patients with intrahepatic cholangiocarcinoma.

    PubMed

    Talabnin, Chutima; Janthavon, Patcharee; Thongsom, Sunisa; Suginta, Wipa; Talabnin, Krajang; Wongkham, Sopit

    2016-06-01

    Ring finger E3 ligases have roles in processes central to maintenance of genomic integrity and cellular homeostasis. Many ring finger E3 ligases are implicated in malignancy. Ring finger protein 43 (RNF43) is a ring finger E3 ligase that negatively regulates the Wnt/β-catenin signaling pathway. RNF43 is frequently mutated in several types of malignancy, including intrahepatic cholangiocarcinoma (ICC). The significance of its expression in ICC has not, however, been reported. We determined RNF43 expression and identified RNF43 polymorphisms in ICC tissues. We also investigated the correlation between RNF43 expression and RNF43 mutation status, RNF43 polymorphisms, clinicopathological features, and prognosis of ICC patients. RNF43 reduced expression in ICC, and the reduction of RNF43 messenger RNA expression was significantly correlated with the presence of rs2257205 and RNF43 somatic mutations, confirming that all RNF43 somatic mutations in ICC are inactivating. Overall survival was worst in patients with down-regulation of RNF43. Univariate and multivariate analyses revealed that RNF43 expression was an independent prognostic factor. There was no statistically significant association between RNF43 messenger RNA and protein expression nor any clinicopathological features or RNF43 polymorphisms. The results imply that RNF43 is down-regulated in ICC and may play a crucial role during development of ICC. PMID:26980022

  16. Decreased expression of Siglec-8 associates with poor prognosis in patients with gastric cancer after surgical resection.

    PubMed

    Cao, Yifan; Liu, Hao; Zhang, Heng; Lin, Chao; Li, Ruochen; Zhang, Weijuan; Shen, Zhenbin; Xu, Jiejie

    2016-08-01

    The expression of sialic acid-binding Ig-like lectin (Siglec) family has been detected in many malignant tumors and correlated with patient outcomes. The present study aims to investigate the prognostic value of Siglec-8 expression and refine current risk stratification system in patients with gastric cancer. Two independent sets of patients (n = 78; n = 356, respectively) with gastric cancer from Zhongshan Hospital were enrolled into this study. The expression of Siglec-8 was detected by immunohistochemistry. Cox regression analysis was used to assess the prognostic value of Siglec-8 expression and clinical outcomes. A novel molecular prognostic stratification system combining intratumoral Siglec-8 expression with TNM stage was determined by means of receiver operating characteristic analysis. Multivariate Cox regression analysis identified that intratumoral Siglec-8 low expression was an independent prognostic factor for dismal overall survival of patients with gastric cancer. Incorporating intratumoral Siglec-8 expression into the current TNM staging system showed more accuracy for predicting prognosis of patients with gastric cancer. Our study suggested that intratumoral Siglec-8 expression was an independent prognostic factor for overall survival of patients with gastric cancer. Incorporating Siglec-8 expression level into current TNM staging system might add more comprehensive prognostic information for patients with gastric cancer and lead to a more precise risk stratification system for predicting clinical outcomes. PMID:26883254

  17. Increased Expression of Eps15 Homology Domain 1 is Associated with Poor Prognosis in Resected Small Cell Lung Cancer

    PubMed Central

    Meng, Qingwei; Sun, Weiling; Li, Man; Zhao, Yanbin; Chen, Xuesong; Sun, Lichun; Cai, Li

    2015-01-01

    One of the great challenges of small cell lung cancer (SCLC) treatment is identifying patients at high risk for recurrence after surgical resection and chemotherapy. We examined Eps15 homology domain 1 (EHD1) protein expression in paraffin sections of 85 resected SCLC tissues, metastatic lymph nodes and normal bronchial epithelial tissues using immunohistochemistry to study the correlation between EHD1 expression and patient clinicopathological features. Within these variables, disease free survival (DFS) analyzed by the log-rank test was constructed using the multivariate Cox proportional hazards regression model and Kaplan-Meier analysis. Immunohistochemistry results showed that EHD1 protein was significantly increased in SCLC tissues compared with normal tissues (P < 0.001). Moreover, EHD1 expression was positively correlated with tumor size (P = 0.019). Multivariate Cox proportional hazards model analysis showed that EHD1 expression (P = 0.047; HR, 1.869; 95% CI, 1.008-3.466) and American Joint Committee on Cancer (AJCC) status (P < 0.001; HR, 1.412; 95% CI, 1.165-1.711) were independent prognostic indicators of DFS. In conclusion, these data demonstrated a remarkable correlation between the cytoplasmic expression of EHD1 protein and adverse prognosis in patients receiving early-stage cisplatin treatment for resected SCLC. PMID:26366212

  18. High expression of CTHRC1 promotes EMT of epithelial ovarian cancer (EOC) and is associated with poor prognosis

    PubMed Central

    He, Shanyang; Li, Yang; Pan, Yunping; Feng, Chongjin; Chen, Xinlin; Zhang, Yang; Lin, Millicent; Wang, Liantang; Ke, Zunfu

    2015-01-01

    Collagen triple helix repeat-containing 1 (CTHRC1) is aberrantly overexpressed in multiple malignant tumors. However, the expression characteristics and function of CTHRC1 in epithelial ovarian cancer (EOC) remain unclear. We found that CTHRC1 expression was up-regulated in the paraffin-embedded EOC tissues compared to borderline or benign tumor tissues. CTHRC1 expression was positively correlated with tumor size (p = 0.008), menopause (p = 0.037), clinical stage (p = 0.002) and lymph node metastasis (p < 0.001) and was also an important prognostic factor for the overall survival of EOC patients, as revealed by Kaplan-Meier analysis. CTHRC1 increased the invasive capabilities of EOC cells in vitro by activating the Wnt/β-catenin signaling pathway. We showed that ectopic transfection of CTHRC1 in EOC cells up-regulated the expression of EMT markers such as N-cadherin and vimentin, and EMT-associated transcriptional factor Snail. Knockdown of CTHRC1 expression in EOC cells resulted in down-regulation of N-cadherin, vimentin, Snail and translocation of β-catenin. Collectively, CTHRC1 may promote EOC metastasis through the induction of EMT process and serve as a potential biomarker for prognosis as well as a target for therapy. PMID:26452130

  19. Overexpression of Notch3 and pS6 Is Associated with Poor Prognosis in Human Ovarian Epithelial Cancer

    PubMed Central

    Yun, Rongna; Yu, Xiaolin; Huang, Genhua; Tan, Buzhen

    2016-01-01

    Notch3 and pS6 play important roles in tumor angiogenesis. To assess the expression of Notch3 and pS6 in Chinese ovarian epithelial cancer patients, a ten-year follow-up study was performed in ovarian epithelial cancer tissues from 120 specimens of human ovarian epithelial cancer, 30 specimens from benign ovarian tumors, and 30 samples from healthy ovaries by immunohistochemistry. The results indicate that the expression of Notch3 and pS6 was higher in ovarian epithelial cancer than in normal ovary tissues and in benign ovarian tumor tissues (p < 0.01). In tumor tissues, Notch3 expression and pS6 expression were negatively associated with age (p > 0.05) but positively associated with clinical stage, pathological grading, histologic type, lymph node metastasis, and ascites (p < 0.05 or p < 0.01). A follow-up survey of 64 patients with ovarian epithelial cancer showed that patients with high Notch3 and pS6 expression had a shorter survival time (p < 0.01), in which the clinical stage (p < 0.05) and Notch3 expression (p < 0.01) played important roles. In conclusion, Notch3 and pS6 are significantly related to ovarian epithelial cancer development and prognosis, and their combination represents a potential biomarker and therapeutic target in ovarian tumor angiogenesis. PMID:27445438

  20. Upregulation of MAGEA4 correlates with poor prognosis in patients with early stage of esophageal squamous cell carcinoma

    PubMed Central

    Tang, Wei-Wei; Liu, Zi-Hao; Yang, Tong-Xin; Wang, Han-Jin; Cao, Xiu-Feng

    2016-01-01

    Esophageal cancer is a common type of cancer in the People’s Republic of China. Many genes have been reported to be linked with it. Melanoma antigen gene family A (MAGEA) genes are frequently highly expressed in various types of carcinoma. However, the specific role of MAGEA gene expression in esophageal squamous cell carcinoma (ESCC) still remains unclear. MAGEA4 is a member of MAGEA genes. We aimed to investigate the expression and prognosis of MAGEA4 expression in ESCC. MAGEA4 messenger RNA expression levels of 120 pairs of tumor and nontumor tissues of patients with ESCC were measured by quantitative real-time polymerase chain reaction. The results showed that MAGEA4 messenger RNA was significantly elevated in tumor tissues of patients with ESCC compared to nontumor ones. In addition, overexpression of MAGEA4 messenger RNA was significantly correlated with poorer overall survival (P=0.018) in early stage of patients with ESCC (I–IIA). In conclusion, MAGEA4 played an important role in the early stage of ESCC and overexpression of MAGEA4 was expected to become a potential prognostic marker for patients with early stage of ESCC. PMID:27478386

  1. Galectin-1 is associated with poor prognosis in patients with cutaneous head and neck cancer with perineural spread.

    PubMed

    Chawla, Sharad; Warren, Timothy A; Wockner, Leesa F; Lambie, Duncan L J; Brown, Ian S; Martin, Thomas P C; Khanna, Rajiv; Leggatt, Graham R; Panizza, Benedict J

    2016-02-01

    Spread of head and neck cancer along the cranial nerves is often a lethal complication of this tumour. Current treatment options include surgical resection and/or radiotherapy, but recurrence is a frequent event suggesting that our understanding of this tumour and its microenvironment is incomplete. In this study, we have analysed the nature of the perineural tumour microenvironment by immunohistochemistry with particular focus on immune cells and molecules, which might impair anti-tumour immunity. Moderate to marked lymphocyte infiltrates were present in 58.8% of the patient cohort including T cells, B cells and FoxP3-expressing T cells. While human leukocyte antigen (HLA) class I and more variably HLA class II were expressed on the tumour cells, this did not associate with patient survival or recurrence. In contrast, galectin-1 staining within lymphocyte areas of the tumour was significantly associated with a poorer patient outcome. Given the known role of galectin-1 in immune suppression, the data suggest that galectin inhibitors might improve the prognosis of patients with perineural spread of cancer. PMID:26759008

  2. Decreased expression of miR-378 correlates with tumor invasiveness and poor prognosis of patients with glioma

    PubMed Central

    Li, Bing; Wang, Yilin; Li, Shiting; He, Hua; Sun, Fengbin; Wang, Chunlin; Lu, Yicheng; Wang, Xiaoqiang; Tao, Bangbao

    2015-01-01

    microRNAs (miRNAs) are a class of small non-coding RNAs that play important roles in a variety of biological process. It has been reported that dysregulation of miRNA is always associated with cancer progression and development, and miR-378 aberrant expression has been found in some types of cancers. However, the association of miR-378 and glioma has not been evaluated. In this work, we measured the expression of miR-378 in glioma tissues and non-neoplastic brain tissues was measured using real-time PCR, and found that miRNA-378 expression level was significantly lower in glioma tissues compared with non-neoplastic brain tissues. Patients with lower miR-378 expression level had significantly poorer overall survival. Multivariate Cox regression analysis showed that miR-378 expression was an independent prognostic factor for 5-year overall survival. Over-expression of miR-378 inhibits glioma cell migration and invasion. In conclusion, our results indicated that miR-378 may serve as a tumor suppressor and play an important role in inhibiting tumor migration and invasion. Our work implicates the potential effect of miR-378 on the prognosis of glioma. PMID:26261592

  3. ARID1A Alterations Are Associated with FGFR3-Wild Type, Poor-Prognosis, Urothelial Bladder Tumors

    PubMed Central

    Balbás-Martínez, Cristina; Rodríguez-Pinilla, María; Casanova, Ariel; Domínguez, Orlando; Pisano, David G.; Gómez, Gonzalo; Lloreta, Josep; Lorente, José A.; Malats, Núria; Real, Francisco X.

    2013-01-01

    Urothelial bladder cancer (UBC) is heterogeneous at the clinical, pathological, genetic, and epigenetic levels. Exome sequencing has identified ARID1A as a novel tumor suppressor gene coding for a chromatin remodeling protein that is mutated in UBC. Here, we assess ARID1A alterations in two series of patients with UBC. In the first tumor series, we analyze exons 2–20 in 52 primary UBC and find that all mutant tumors belong to the aggressive UBC phenotype (high grade non-muscle invasive and muscle invasive tumors) (P = 0.05). In a second series (n = 84), we assess ARID1A expression using immunohistochemistry, a surrogate for mutation analysis, and find that loss of expression increases with higher stage/grade, it is inversely associated with FGFR3 overexpression (P = 0.03) but it is not correlated with p53 overexpression (P = 0.30). We also analyzed the expression of cytokeratins in the same set of tumor and find, using unsupervised clustering, that tumors with ARID1A loss of expression are generally KRT5/6-low. In this patient series, loss of ARID1A expression is also associated with worse prognosis, likely reflecting the higher prevalence of losses found in tumors of higher stage and grade. The independent findings in these two sets of patients strongly support the notion that ARID1A inactivation is a key player in bladder carcinogenesis occurring predominantly in FGFR3 wild type tumors. PMID:23650517

  4. Down-regulation of miR-503 expression predicate advanced mythological features and poor prognosis in patients with NSCLC

    PubMed Central

    Liu, Lei; Qu, Weiqing; Zhong, Zhaokun

    2015-01-01

    Objective: We aimed to explore what impact miR-503 has on the prognosis of patients with non-small cell lung cancer (NSCLC). Methods: Cancer and matched non-malignant lung tissue specimens were collected from 109 patients who underwent surgery in Tanisha Hospital from Jun 2006 to July 2013. Overall survival (OS) curves were analyzed using the Lapland-Meier method, and the differences were examined using log-rank tests. Cox proportional- hazards regression analysis was applied in order to estimate univariate and multivariate hazard ratios for OS. Results: The relative expression of miR-503 in NSCLC tissues (0.366 ± 0.130) was significantly lower than that in matched noncancerous lung tissues (1.667 ± 1.047, P < 0.01). Statistically significant association was observed between miR-503 expression and lymphatic invasion (P = 0.005), distant metastasis (P = 0.002), TNM stage (P = 0.008), and tumor grade (P = 0.043). Lapland Meier analysis clearly illustrated that the patients with the lower expression of miR-503 had a worse outcome compared to patients with higher miR-503 expression (P = 0.004). Furthermore, multivariate analysis revealed that miR-503 expression level was an independent prognostic factor for overall survival (HR = 3.992, 95% CI: 2.276-9.872; P = 0.018) in NSCLC. Conclusion: In patients with NSCLC, low miR-503 expression is an independent prognostic factor. PMID:26191272

  5. Micropapillary morphology is an indicator of poor prognosis in patients with urothelial carcinoma treated with transurethral resection and radiochemotherapy.

    PubMed

    Bertz, Simone; Wach, S; Taubert, H; Merten, R; Krause, F S; Schick, S; Ott, O J; Weigert, E; Dworak, O; Rödel, C; Fietkau, R; Wullich, B; Keck, B; Hartmann, A

    2016-09-01

    Purpose of this study was to evaluate prognostic impact of rare variants of urothelial bladder cancer (BC) after treatment with combined radiochemotherapy (RCT). To this end tumour tissue of 238 patients with urothelial carcinoma (UC) treated with transurethral resection of the bladder (TUR-B) and RCT with curative intent was collected. Histomorphological analysis included re-evaluation and semi-quantitative assessment of rare UC subtypes. Additionally, human epidermal growth factor receptor 2 (HER2) chromogenic in situ hybridisation (CISH) was performed in tumours with a micropapillary component exceeding 30 %. Long-term follow-up was available for 200 patients (range 3-282 months). Variant UC histology was found in 45 of 238 tumours, most frequently micropapillary UC (N = 17) including cases with a small fraction of tumour with micropapillary morphology. The mere presence of micropapillary morphology did not affect prognosis. In tumours with extensive (≥30 %) micropapillary morphology (N = 8) Kaplan-Meier analysis revealed significantly worse cancer specific survival (CSS) (P = 0.002) compared to conventional UC (mean survival times 97 months and 229 months, respectively). Univariate Cox regression analysis of cases with ≥30 % micropapillary morphology revealed a hazard ratio of 4.726 (95 % CI 1.629-13.714) for CSS (P = 0.004). CISH revealed HER2 gene amplification in 3/10 tumours with ≥30 % micropapillary component. In conclusion, for BC treated with TUR-B and RCT, the presence of micropapillary morphology in more than 30 % of the tumour is an adverse prognostic factor. Further studies are needed to evaluate a potential benefit of different, especially multimodal treatment strategies for micropapillary UC and also other subtypes of UC. Her2 represents a promising therapeutic target in a subset of micropapillary UC. PMID:27392930

  6. Overexpression of HOXB7 homeobox gene in oral cancer induces cellular proliferation and is associated with poor prognosis.

    PubMed

    De Souza Setubal Destro, Maria Fernanda; Bitu, Carolina Cavalcanti; Zecchin, Karina G; Graner, Edgard; Lopes, Marcio A; Kowalski, Luis Paulo; Coletta, Ricardo D

    2010-01-01

    A growing body of evidence has confirmed the involvement of dysregulated expression of HOX genes in cancer. HOX genes are a family of 39 transcription factors, divided in 4 clusters (HOXA to HOXD), that during normal development regulate cell proliferation and specific cell fate. In the present study it was investigated whether genes of the HOXB cluster play a role in oral cancer. We showed that most of the genes in the HOXB network are inactive in oral tissues, with exception of HOXB2, HOXB7 and HOXB13. Expression of HOXB7 was significantly higher in oral squamous cell carcinomas (OSCC) compared to normal oral mucosas. We further demonstrated that HOXB7 overexpression in HaCAT human epithelial cell line promoted proliferation, whereas downregulation of HOXB7 endogenous levels in human oral carcinoma cells (SCC9 cells) decreased proliferation. In OSCCs, expression of HOXB7 and Ki67, a marker of proliferation, correlate strongly with each other (rs=0.79, p<0.006). High immunohistochemical expression of HOXB7 was correlated with T stage (p=0.06), N stage (p=0.07), disease stage (p=0.09) and Ki67 expression (p=0.01), and patients with tumors showing high number of HOXB7-positive cells had shorter overall survival (p=0.08) and shorter disease-free survival after treatment (p=0.10) compared with patients with tumors exhibiting low amount of HOXB7-positive cells. Our data suggest that HOXB7 may contribute to oral carcinogenesis by increasing tumor cell proliferation, and imply that HOXB7 may be an important determinant of OSCC patient prognosis. PMID:19956843

  7. Up-Regulation of Long Non-Coding RNA AB073614 Predicts a Poor Prognosis in Patients with Glioma.

    PubMed

    Hu, Lei; Lv, Qiao-Li; Chen, Shu-Hui; Sun, Bao; Qu, Qiang; Cheng, Lin; Guo, Ying; Zhou, Hong-Hao; Fan, Lan

    2016-01-01

    Dysregulated long noncoding RNAs (lncRNAs) have been found in human diseases, especially in cancer. Emerging evidence indicates that dysregulated lncRNAs are implicated in tumorigenesis and cancer progression. LncRNA AB073614 characterized as a new candidate lncRNA promotes the development of ovarian cancer. However, the role of lncRNA AB073614 in human gliomas remains unknown. The expression of AB073614 was detected in 65 glioma tissues and 13 normal brain tissues by qRT-PCR, showing that lncRNA AB073614 expression was significantly up-regulated in cancerous tissues compared with normal brain tissues (p < 0.001), and it was positively correlated with tumor grade (I-II grades vs. III-IV grades, p = 0.013) in glioma patients. Kaplan-Meier analysis demonstrated that increased AB073614 expression contributed to poor overall survival (HR (hazard ratio) = 1.952, 95%CI: 1.202-3.940, p = 0.0129). Further, univariate Cox regression analysis indicated that lncRNA AB073614 overexpression was an unfavorable prognostic factor in gliomas (HR = 1.997, 95%CI: 1.135-3.514, p = 0.016), regardless of the tumor grade (I-II grades vs. III-IV grades, HR = 1.902, 95%CI: 1.066-3.391, p = 0.029). Finally, after adjustment with age, sex, tumor grade and tumor location, multivariate Cox regression analysis suggested that both highly expressed lncRNA AB073614 (HR = 2.606, 95%CI: 1.408-4.824, p = 0.002) and high tumor grade (III-IV grades, HR = 2.720, 95%CI: 1.401-5.282, p = 0.003) could be considered independent poor prognostic indicators for glioma patients. In conclusion, our study suggested that increased lncRNA AB073614 expression may be identified as a poor prognostic biomarker in gliomas. PMID:27104549

  8. Elevated preoperative neutrophil-to-lymphocyte ratio is associated with poor prognosis in gastrointestinal stromal tumor patients

    PubMed Central

    Jiang, Chang; Hu, Wan-Ming; Liao, Fang-Xin; Yang, Qiong; Chen, Ping; Rong, Yu-Ming; Guo, Gui-Fang; Yin, Chen-Xi; Zhang, Bei; He, Wen-Zhuo; Xia, Liang-Ping

    2016-01-01

    Purpose To investigate the prognostic relevance of preoperative peripheral neutrophil- to-lymphocyte ratio (NLR) in gastrointestinal stromal tumor (GIST) patients. Materials and methods We enrolled 129 consecutive GIST patients who underwent initial curative surgical resection with or without adjuvant/palliative imatinib treatment in our study. Blood NLR was calculated as neutrophil count (number of neutrophils ×109/L) divided by lymphocyte count (number of lymphocytes ×109/L). Survival curves were constructed by using the Kaplan–Meier method. Univariate and multivariate Cox proportional hazard regression models were performed to identify associations with outcome variable. All tests were two-sided, and P<0.05 was considered statistically significant. Results The optimal cut-off value of NLR was 2.07 in the receiver operating characteristic curve analysis. The median overall survival (OS) of high NLR group was 113.0 months, whereas that of the low NLR group had not reached the median OS both in the general (P<0.001) and subgroup analyses. The elevated NLR suggested shorter OS in the high malignant potential groups (P=0.01) and the combined low and moderate groups (P=0.02). Increased NLR indicated poor OS in patients regardless of whether if received imatinib treatment or not (P=0.005, and P=0.032, respectively). High NLR indicated poor OS of patients in stage I and II disease (P=0.005) and a clear tendency that increased level of NLR is inimical to OS. Conclusion Elevated NLR was detected as an independent adverse prognostic factor. Elevated preoperative NLR predicts poor clinical outcome in GIST patients and may serve as a cost-effective and broadly available independent prognostic biomarker. PMID:26966375

  9. Wntless (GPR177) expression correlates with poor prognosis in B-cell precursor acute lymphoblastic leukemia via Wnt signaling.

    PubMed

    Chiou, Shyh-Shin; Wang, Li-Ting; Huang, Shih-Bo; Chai, Chee-Yin; Wang, Shen-Nien; Liao, Yu-Mei; Lin, Pei-Chin; Liu, Kwei-Yan; Hsu, Shih-Hsien

    2014-10-01

    B-cell precursor acute lymphoblastic leukemia (BCP ALL) is the most common childhood leukemia, with a cure rate of 80%. Nevertheless, disease relapse is the most important prognostic factor for the disease outcome. We aimed to elucidate the role of Wnt secretion-regulating protein, Wntless (Wls)/GPR177, on disease outcome in pediatric patients with BCP ALL, and assess its pathogenetic role in the regulation of the disease. Wls expression was characterized and correlated with Wnt pathway signaling in the bone marrow leukemia cells isolated from 44 pediatric patients with BCP ALL. The overexpression of Wls was detected in leukemia cells and was significantly correlated with the disease relapse and poor survival in the patients. The high expression of Wls also correlated with the Wnt expression and consequent downstream signaling activation, which was shown to provide essential proliferation, transformation and anti-apoptotic activity during leukemogenesis. These results indicated that Wls played an essential role in disease relapse and poor survival in patients with BCP ALL. Therefore, Wls may provide a potential future therapeutic target, particularly for patients who do not respond to existing therapies and suffer relapse. PMID:25115440

  10. Migration-inducing gene 7 promotes tumorigenesis and angiogenesis and independently predicts poor prognosis of epithelial ovarian cancer.

    PubMed

    Huang, Bihui; Yin, Mingzhu; Li, Xia; Cao, Guosheng; Qi, Jin; Lou, Ge; Sheng, Shijie; Kou, Junping; Chen, Kang; Yu, Boyang

    2016-05-10

    Epithelial ovarian carcinomas (EOC) cause more mortality than any other cancer of the female reproductive system. New therapeutic approaches to reduce EOC mortality have been largely unsuccessful due to the poor understanding of the mechanisms underlying EOC proliferation and metastasis. Progress in EOC treatment is further hampered by a lack of reliable prognostic biomarkers for early risk assessment. In this study, we identify that Migration-Inducting Gene 7 (MIG-7) is specifically induced in human EOC tissues but not normal ovaries or ovarian cyst. Ovarian MIG-7 expression strongly correlated with EOC progression. Elevated MIG-7 level at the time of primary cytoreductive surgery was a strong and independent predictor of poor survival of EOC patients. Cell and murine xenograft models showed that MIG-7 was required for EOC proliferation and invasion, and MIG-7 enhanced EOC-associated angiogenesis by promoting the expression of vascular endothelial growth factor. Inhibiting MIG-7 by RNA interference in grafted EOC cells retarded tumor growth, angiogenesis and improved host survival, and suppressing MIG-7 expression with a small molecule inhibitor D-39 identified from the medicinal plant Liriope muscari mitigated EOC growth and invasion and specifically abrogated the expression of vascular endothelial growth factor. Our data not only reveal a critical function of MIG-7 in EOC growth and metastasis and support MIG-7 as an independent prognostic biomarker for EOC, but also demonstrate that therapeutic targeting of MIG-7 is likely beneficial in the treatment of EOC. PMID:27050277

  11. Overexpression of ST3Gal-I promotes migration and invasion of HCCLM3 in vitro and poor prognosis in human hepatocellular carcinoma

    PubMed Central

    Wu, Han; Shi, Xue-Liang; Zhang, Hai-Jian; Song, Qing-Jie; Yang, Xiao-Bing; Hu, Wei-Dong; Mei, Guang-Lin; Chen, Xi; Mao, Qin-Sheng; Chen, Zhong

    2016-01-01

    Purpose Excessive ST3Gal-I levels predict a poor outcome for patients with several types of tumors. This study aims to investigate the role of ST3Gal-I in determining the invasive and metastatic potential of human hepatocellular carcinoma (HCC) and clinical prognosis for patients with HCC. Methods We compared the expression of ST3Gal-I in various HCC cell lines and in 20 pairs of tumor and peritumor tissue samples using Western blot analysis. Changes in the degree of invasiveness and migration were determined before and after small interfering RNA-induced knockdown of ST3Gal-I using a Transwell matrigel invasion assay and scratch wound assay. The correlation between ST3Gal-I expression and prognosis was determined in a large HCC patient cohort (n=273). Results ST3Gal-I expression was higher in metastatic HCCLM3 cells and tumor tissue compared with normal adjacent tissue. Following the ST3Gal-I knockdown, the invasiveness and migration of HCCLM3 cells were markedly reduced. ST3Gal-I expression in HCC correlated closely with tumor thrombus (P<0.001), tumor size (>5.0 cm, P=0.032), tumor node metastasis stages II–III (P=0.002), and Barcelona Clinic Liver Cancer stages B–C (P<0.001). Cox regression analysis demonstrated that ST3Gal-I is an independent predictor of prognosis in patients with HCC, and related to disease-free survival (hazard ratio =1.464, P=0.037) and overall survival (hazard ratio =1.662, P=0.012). Conclusion ST3Gal-I might contribute to the invasiveness and metastatic nature of HCC and, thus, could be an independent predictor of recurrence and a suitable pharmaceutical target in patients with HCC. PMID:27143918

  12. Up-Regulation of Long Non-Coding RNA AB073614 Predicts a Poor Prognosis in Patients with Glioma

    PubMed Central

    Hu, Lei; Lv, Qiao-Li; Chen, Shu-Hui; Sun, Bao; Qu, Qiang; Cheng, Lin; Guo, Ying; Zhou, Hong-Hao; Fan, Lan

    2016-01-01

    Dysregulated long noncoding RNAs (lncRNAs) have been found in human diseases, especially in cancer. Emerging evidence indicates that dysregulated lncRNAs are implicated in tumorigenesis and cancer progression. LncRNA AB073614 characterized as a new candidate lncRNA promotes the development of ovarian cancer. However, the role of lncRNA AB073614 in human gliomas remains unknown. The expression of AB073614 was detected in 65 glioma tissues and 13 normal brain tissues by qRT-PCR, showing that lncRNA AB073614 expression was significantly up-regulated in cancerous tissues compared with normal brain tissues (p < 0.001), and it was positively correlated with tumor grade (I–II grades vs. III–IV grades, p = 0.013) in glioma patients. Kaplan-Meier analysis demonstrated that increased AB073614 expression contributed to poor overall survival (HR (hazard ratio) = 1.952, 95%CI: 1.202–3.940, p = 0.0129). Further, univariate Cox regression analysis indicated that lncRNA AB073614 overexpression was an unfavorable prognostic factor in gliomas (HR = 1.997, 95%CI: 1.135–3.514, p = 0.016), regardless of the tumor grade (I–II grades vs. III–IV grades, HR = 1.902, 95%CI: 1.066–3.391, p = 0.029). Finally, after adjustment with age, sex, tumor grade and tumor location, multivariate Cox regression analysis suggested that both highly expressed lncRNA AB073614 (HR = 2.606, 95%CI: 1.408–4.824, p = 0.002) and high tumor grade (III–IV grades, HR = 2.720, 95%CI: 1.401–5.282, p = 0.003) could be considered independent poor prognostic indicators for glioma patients. In conclusion, our study suggested that increased lncRNA AB073614 expression may be identified as a poor prognostic biomarker in gliomas. PMID:27104549

  13. Phylogenetic analysis of multiple FISH markers in oral tongue squamous cell carcinoma suggests that a diverse distribution of copy number changes is associated with poor prognosis.

    PubMed

    Wangsa, Darawalee; Chowdhury, Salim Akhter; Ryott, Michael; Gertz, E Michael; Elmberger, Göran; Auer, Gert; Åvall Lundqvist, Elisabeth; Küffer, Stefan; Ströbel, Philipp; Schäffer, Alejandro A; Schwartz, Russell; Munck-Wikland, Eva; Ried, Thomas; Heselmeyer-Haddad, Kerstin

    2016-01-01

    Oral tongue squamous cell carcinoma (OTSCC) is associated with poor prognosis. To improve prognostication, we analyzed four gene probes (TERC, CCND1, EGFR and TP53) and the centromere probe CEP4 as a marker of chromosomal instability, using fluorescence in situ hybridization (FISH) in single cells from the tumors of sixty-five OTSCC patients (Stage I, n = 15; Stage II, n = 30; Stage III, n = 7; Stage IV, n = 13). Unsupervised hierarchical clustering of the FISH data distinguished three clusters related to smoking status. Copy number increases of all five markers were found to be correlated to non-smoking habits, while smokers in this cohort had low-level copy number gains. Using the phylogenetic modeling software FISHtrees, we constructed models of tumor progression for each patient based on the four gene probes. Then, we derived test statistics on the models that are significant predictors of disease-free and overall survival, independent of tumor stage and smoking status in multivariate analysis. The patients whose tumors were modeled as progressing by a more diverse distribution of copy number changes across the four genes have poorer prognosis. This is consistent with the view that multiple genetic pathways need to become deregulated in order for cancer to progress. PMID:26175310

  14. Presence of a putative tumor-initiating progenitor cell population predicts poor prognosis in smokers with non-small cell lung cancer

    PubMed Central

    Ooi, Aik T.; Mah, Vei; Nickerson, Derek W.; Gilbert, Jennifer L.; Ha, Vi Luan; Hegab, Ahmed E.; Horvath, Steve; Alavi, Mohammad; Maresh, Erin L.; Chia, David; Gower, Adam C.; Lenburg, Marc E.; Spira, Avrum; Solis, Luisa M.; Wistuba, Ignacio I.; Walser, Tonya C.; Wallace, William D.; Dubinett, Steven M.; Goodglick, Lee; Gomperts, Brigitte N.

    2010-01-01

    Smoking is the most important known risk factor for the development of lung cancer. Tobacco exposure results in chronic inflammation, tissue injury and repair. A recent hypothesis argues for a stem/progenitor cell involved in airway epithelial repair that may be a tumor-initiating cell in lung cancer, and which may be associated with recurrence and metastasis. We used immunostaining, quantitative real-time PCR, Western blots and lung cancer tissue microarrays to identify subpopulations of airway epithelial stem/progenitor cells under steady state conditions, normal repair, aberrant repair with premalignant lesions and lung cancer and their correlation with injury and prognosis. We identified a population of keratin 14 (K14)-expressing progenitor epithelial cells that was involved in repair after injury. Dysregulated repair resulted in persistence of K14+ cells in the airway epithelium in premalignant lesions. The presence of K14+ cells in non-small cell lung cancer (NSCLC) samples predicted poorer outcomes. This was especially true in smokers where the presence of K14+ cells in NSCLC was predictive of metastasis. The presence of K14+ progenitor airway epithelial cells in NSCLC predicted a poor prognosis and this predictive value was strongest in smokers, where it also correlated with metastasis. This suggests that reparative K14+ progenitor cells may be tumor-initiating cells in this subgroup of smokers with NSCLC. PMID:20710044

  15. The A Allele at rs13419896 of EPAS1 Is Associated with Enhanced Expression and Poor Prognosis for Non-Small Cell Lung Cancer

    PubMed Central

    Lee, Kian Leong; Yamane, Yuko; Gustine, Ewita; Isobe, Takeshi; Nishiyama, Masahiko; Hiyama, Keiko; Poellinger, Lorenz; Tanimoto, Keiji

    2015-01-01

    Hypoxia-inducible factor-2α (HIF-2α, or EPAS1) is important for cancer progression, and is a putative biomarker for poor prognosis for non-small cell lung cancer (NSCLC). However, molecular mechanisms underlying the EPAS1 overexpression are not still fully understood. We explored a role of a single nucleotide polymorphism (SNP), rs13419896 located within intron 1 of the EPAS1 gene in regulation of its expression. Bioinformatic analyses suggested that a region including the rs13419896 SNP plays a role in regulation of the EPAS1 gene expression and the SNP alters the binding activity of transcription factors. In vitro analyses demonstrated that a fragment containing the SNP locus function as a regulatory region and that a fragment with A allele showed higher transactivation activity than one with G, especially in the presence of overexpressed c-Fos or c-Jun. Moreover, NSCLC patients with the A allele showed poorer prognosis than those with G at the SNP even after adjustment with various variables. In conclusion, the genetic polymorphism of the EPAS1 gene may lead to variation of its gene expression levels to drive progression of the cancer and serve as a prognostic marker for NSCLC. PMID:26263511

  16. Upregulated long non-coding RNA AFAP1-AS1 expression is associated with progression and poor prognosis of nasopharyngeal carcinoma

    PubMed Central

    Bo, Hao; Gong, Zhaojian; Zhang, Wenling; Li, Xiayu; Zeng, Yong; Liao, Qianjin; Chen, Pan; Shi, Lei; Lian, Yu; Jing, Yizhou; Tang, Ke; Li, Zheng; Zhou, Yanhong; Zhou, Ming; Xiang, Bo; Li, Xiaoling; Yang, Jianbo; Xiong, Wei; Li, Guiyuan; Zeng, Zhaoyang

    2015-01-01

    Altered expression of long noncoding RNAs (lncRNAs) associated with human carcinogenesis. We performed a cDNA microarray analysis of lncRNA expression in 12 cases of nasopharyngeal carcinoma (NPC) and 4 non-tumor nasopharyngeal epitheliums. One lncRNA, actin filament associated protein 1 antisense RNA1 (AFAP1-AS1), was identified and selected for further study. AFAP1-AS1 expression was upregulated in NPC and associated with NPC metastasis and poor prognosis. In vitro experiments demonstrated that AFAP1-AS1 knockdown significantly inhibited the NPC cell migration and invasive capability. AFAP1-AS1 knockdown also increased AFAP1 protein expression. Proteomic and bioinformatics analyses suggested that AFAP1-AS1 affected the expression of several small GTPase family members and molecules in the actin cytokeratin signaling pathway. AFAP1-AS1 promoted cancer cell metastasis via regulation of actin filament integrity. AFAP1-AS1 might be a potential novel marker that can predict cancer patient prognosis and as a potential therapeutic target for NPC. PMID:26246469

  17. Activating Transcription Factor 4 Promotes Esophageal Squamous Cell Carcinoma Invasion and Metastasis in Mice and Is Associated with Poor Prognosis in Human Patients

    PubMed Central

    Chen, Bin; Chen, Bei; Song, Weibing; Sun, Dayong; Zhao, Yagang

    2014-01-01

    Background Activating transcription factor 4 (ATF4) is a stress response gene that is involved in homeostasis and cellular protection. However, its expression and function in esophageal squamous cell carcinoma (ESCC) remains unknown. In this study, we aimed to determine the clinicopathologic significance of ATF4 in ESCC and its potential role in ESCC invasion and metastasis. Methodology/Principal Findings We demonstrated that ATF4 overexpression is correlated with multiple malignant characteristics and indicates poor prognosis in ESCC patients. ATF4 expression was an independent factor that affected the overall survival of patients with ESCC after surgical resection. ATF4 promoted cell invasion and metastasis by promoting matrix metalloproteinase (MMP)-2 and MMP-7 expression, while its silencing significantly attenuated these activities both in vitro and in vivo. Conclusions/Significance We report that ATF4 is a potential biomarker for ESCC prognosis and that its dysregulation may play a key role in the regulation of invasion and metastasis in ESCC cells. The targeting of ATF4 may provide a new strategy for blocking ESCC metastasis. PMID:25078779

  18. Phylogenetic Analysis of Multiple FISH Markers in Oral Tongue Squamous Cell Carcinoma Suggests that a Diverse Distribution of Copy Number Changes Is Associated with Poor Prognosis

    PubMed Central

    Wangsa, Darawalee; Chowdhury, Salim Akhter; Ryott, Michael; Gertz, E. Michael; Elmberger, Göran; Auer, Gert; Lundqvist, Elisabeth Åvall; Küffer, Stefan; Ströbel, Philipp; Schäffer, Alejandro A.; Schwartz, Russell; Munck-Wikland, Eva; Ried, Thomas; Heselmeyer-Haddad, Kerstin

    2016-01-01

    Oral tongue squamous cell carcinoma (OTSCC) is associated with poor prognosis. To improve prognostication, we analyzed four gene probes (TERC, CCND1, EGFR, and TP53) and the centromere probe CEP4 as a marker of chromosomal instability, using fluorescence in situ hybridization (FISH) in single cells from the tumors of sixty-five OTSCC patients (Stage I, n=15; Stage II, n=30; Stage III, n=7; Stage IV, n=13). Unsupervised hierarchical clustering of the FISH data distinguished three clusters related to smoking status. Copy number increases of all five markers were found to be correlated to non-smoking habits, while smokers in this cohort had low-level copy number gains. Using the phylogenetic modeling software FISHtrees, we constructed models of tumor progression for each patient based on the four gene probes. Then, we derived test statistics on the models that are significant predictors of disease-free and overall survival, independent of tumor stage and smoking status in multivariate analysis. The patients whose tumors were modeled as progressing by a more diverse distribution of copy number changes across the four genes have poorer prognosis. This is consistent with the view that multiple genetic pathways need to become deregulated in order for cancer to progress. PMID:26175310

  19. High expression of hexokinase domain containing 1 is associated with poor prognosis and aggressive phenotype in hepatocarcinoma.

    PubMed

    Zhang, Zijian; Huang, Shanzhou; Wang, Huanyu; Wu, Jian; Chen, Dong; Peng, Baogang; Zhou, Qi

    2016-06-10

    Rapid progress and metastasis remain the major treatment failure modes of hepatocarcinoma (HCC). Unfortunately, the underlying molecular mechanisms of hepatoma cell proliferation and migration are poorly understood. Metabolic abnormalities play critical roles in tumorigenesis and progression. Hexokinase domain containing 1 (HKDC1) catalyzes the phosphorylation of glucose. However, the functions and mechanisms of HKDC1 in cancer remain unknown. In this study, real-time RT-PCR and Western blotting assays were used to detect the HKDC1 expression levels in HCC tissues and cell lines. The Oncomine™ Cancer Microarray Database was applied to analysis the correlations between HKDC1 expression and HCC clinical characteristics. MTT and Transwell migration assays were performed to determine the functions of HKDC1 in HCC cells. The effect of HKDC1 on Wnt/β-catenin signaling pathway was assessed using Western blotting assay. In this study, we found that HKDC1 expression levels were elevated in HCC tissues compared with the adjacent tissues. HCC patients with high expression levels of HKDC1 had poor overall survival (OS). Furthermore, higher HKDC1 levels also predicted a worse OS of patients within solitary, elevated pre-operated serum alpha fetoprotein (AFP) level and higher tumor diameter. Moreover, silencing HKDC1 suppressed HCC cells proliferation and migration in vitro. Downregulated HKDC1 expression repressed β-Catenin and c-Myc expression, which indicates that silencing HKDC1 may reduce proliferation and migration via inhibiting the Wnt/β-catenin signaling pathway in HCC. In summary, HKDC1 provides further insight into HCC tumor progression and may provide a novel prognostic biomarker and therapeutic target for HCC treatment. PMID:27155152

  20. High Infiltration of Tumor-Associated Macrophages Influences Poor Prognosis in Human Gastric Cancer Patients, Associates With the Phenomenon of EMT

    PubMed Central

    Zhang, Jia; Yan, Yan; Yang, Ya; Wang, Li; Li, Min; Wang, Jizhao; Liu, Xu; Duan, Xiaoyi; Wang, Jiansheng

    2016-01-01

    Abstract Tumor-associated macrophages (TAMs) are associated with poor prognosis in numerous human cancers and play important roles in tumor progression. Epithelial-mesenchymal transition (EMT) contributes to invasion and metastasis in cancer. However, the associations between TAMs and EMT are not clear in gastric cancer (GC). The present study was designed to investigate the effects of TAMs on EMT in human GC. TAMs marker CD68 and EMT-related proteins were detected by immunohistochemistry (IHC) in human GC tissues and their clinical significance were evaluated. A high level of infiltration of TAMs was associated with aggressive characteristics of tumor and an independent poor prognostic factor in human GC tissues. Infiltration of TAMs was also associated with EMT-related proteins in human GC tissues. Our findings suggest that the high level of infiltration TAMs was associated with aggressive features of GC and is an independent poor prognostic factor in GC patients. TAMs are associated with EMT induction in human GC tissues. The level of TAMs infiltration may be used as a prognostic factor and even a therapeutic target in GC. PMID:26871785

  1. High Infiltration of Tumor-Associated Macrophages Influences Poor Prognosis in Human Gastric Cancer Patients, Associates With the Phenomenon of EMT.

    PubMed

    Zhang, Jia; Yan, Yan; Yang, Ya; Wang, Li; Li, Min; Wang, Jizhao; Liu, Xu; Duan, Xiaoyi; Wang, Jiansheng

    2016-02-01

    Tumor-associated macrophages (TAMs) are associated with poor prognosis in numerous human cancers and play important roles in tumor progression. Epithelial-mesenchymal transition (EMT) contributes to invasion and metastasis in cancer. However, the associations between TAMs and EMT are not clear in gastric cancer (GC). The present study was designed to investigate the effects of TAMs on EMT in human GC.TAMs marker CD68 and EMT-related proteins were detected by immunohistochemistry (IHC) in human GC tissues and their clinical significance were evaluated.A high level of infiltration of TAMs was associated with aggressive characteristics of tumor and an independent poor prognostic factor in human GC tissues. Infiltration of TAMs was also associated with EMT-related proteins in human GC tissues.Our findings suggest that the high level of infiltration TAMs was associated with aggressive features of GC and is an independent poor prognostic factor in GC patients. TAMs are associated with EMT induction in human GC tissues. The level of TAMs infiltration may be used as a prognostic factor and even a therapeutic target in GC. PMID:26871785

  2. Down-regulated expression of the protein-tyrosine phosphatase 1B (PTP1B) is associated with aggressive clinicopathologic features and poor prognosis in hepatocellular carcinoma

    SciTech Connect

    Zheng, Long-Yi; Zhou, Dong-Xun; Lu, Jin; Zhang, Wen-Jun; Zou, Da-Jin

    2012-04-13

    Highlights: Black-Right-Pointing-Pointer PTP1B protein showed decreased expression in 67.79% of the HCC patients. Black-Right-Pointing-Pointer Low PTP1B expression predicts poor prognosis of HCC. Black-Right-Pointing-Pointer Low PTP1B expression is correlated with expansion of OV6{sup +} tumor-initiating cells. Black-Right-Pointing-Pointer Down-regulation of PTP1B is associated with activation of Wnt/{beta}-Catenin signaling. -- Abstract: The protein-tyrosine phosphatase 1B (PTP1B) is a classical non-transmembrane protein tyrosine phosphatase that plays a key role in metabolic signaling and can exert both tumor suppressing and tumor promoting effects in different cancers depending on the substrate involved and the cellular context. However, the expression level and function of PTP1B in hepatocellular carcinoma (HCC) remain unclear. In this study, PTP1B expression was detected by immunohistochemistry in normal liver tissue (n = 16) and hepatocellular carcinoma (n = 169). The correlations between PTP1B expression level and clinicopathologic features and patient survival were also analyzed. One hundred and eleven of 169 HCC patients (65.7%) had negative or low PTP1B expression in tumorous tissues, whereas normal tissues always expressed strong PTP1B. Decreased PTP1B expression was significantly associated with aggressive clinicopathologic features and poor prognosis. Immunohistochemistry also showed that low PTP1B expression level was correlated with high percentage of OV6{sup +} tumor-initiating cells (T-ICs) and high frequency of nuclear {beta}-Catenin expression in HCC specimens. Our findings demonstrate for the first time that the loss of inhibitory effect of PTP1B may contribute to progression and invasion of HCC through activation of Wnt/{beta}-Catenin signaling and expansion of liver T-ICs. PTP1B may serve as a valuable prognostic biomarker and potential therapeutic target in HCC.

  3. Maintenance of remission following 2 years of standard treatment then dose reduction with abatacept in patients with early rheumatoid arthritis and poor prognosis

    PubMed Central

    Westhovens, Rene; Robles, Manuel; Ximenes, Antonio Carlos; Wollenhaupt, Jurgen; Durez, Patrick; Gomez-Reino, Juan; Grassi, Walter; Haraoui, Boulos; Shergy, William; Park, Sung-Hwan; Genant, Harry; Peterfy, Charles; Becker, Jean-Claude; Murthy, Bindu

    2015-01-01

    Objectives To evaluate maintenance of response while reducing intravenous abatacept dose from ∼10 mg/kg to ∼5 mg/kg in patients with early rheumatoid arthritis (RA) who achieved disease activity score (DAS)28 (erythrocyte sedimentation rate, ESR) <2.6. Methods This 1-year, multinational, randomised, double-blind substudy evaluated the efficacy and safety of ∼10 mg/kg and ∼5 mg/kg abatacept in patients with early RA with poor prognosis who had reached DAS28 (ESR) <2.6 at year 2 of the AGREE study. The primary outcome was time to disease relapse (defined as additional disease-modifying antirheumatic drugs, ≥2 courses high-dose steroids, return to open-label abatacept ∼10 mg/kg, or DAS28 (C reactive protein) ≥3.2 at two consecutive visits). Results 108 patients were randomised (∼10 mg/kg, n=58; ∼5 mg/kg, n=50). Three and five patients, respectively, discontinued, and four per group returned to open-label abatacept. Relapse over time and the proportion of patients relapsing were similar in both groups (31% (∼10 mg/kg) vs 34% (∼5 mg/kg); HR: 0.87 (95% CI 0.45 to 1.69)). Mean steady-state trough serum concentration for the ∼10 mg/kg group was 20.3–24.1 µg/mL, compared with 8.8–12.0 µg/mL for the ∼5 mg/kg group. Conclusions This exploratory study suggests that abatacept dose reduction may be an option in patients with poor prognosis early RA who achieve DAS28 (ESR) <2.6 after ≥1 year on abatacept (∼10 mg/kg). Trial registration number NCT00989235. PMID:25550337

  4. Copy number gain of PIK3CA and MET is associated with poor prognosis in head and neck squamous cell carcinoma.

    PubMed

    Brauswetter, Diána; Dános, Kornél; Gurbi, Bianka; Félegyházi, Éva Fruzsina; Birtalan, Ede; Meggyesházi, Nóra; Krenács, Tibor; Tamás, László; Peták, István

    2016-05-01

    The incidence of head and neck squamous cell carcinomas is still growing, and the long-term prognosis of advanced disease remains poor. Only a fraction of head and neck cancers are sensitive to the EGFR-inhibitor cetuximab, which is the only registered targeted therapy available today. In several cancers, gene copy number alterations of MET and PIK3CA have been found to be prognostic and predictive for therapy response. The aim of this study was to systematically analyze in head and neck cancers the pathological characteristics and prognostic significance of copy number changes of MET and PIK3CA genes. MET and PIK3CA copy numbers were analyzed by fluorescence in situ hybridization in tumor samples of 152 patients. Expression of EGFR, p16, and Ki67 was studied by immunohistochemistry. High polysomy of PIK3CA (chromosome 3) was found in 20 % of cases and amplification in 4.5 %. Regarding MET, 35 % of cases showed low or high polysomy of the gene (chromosome 7), while no intra-chromosomal amplification of MET was detected. PIK3CA copy number gain (high polysomy or amplification) was significantly associated with shorter disease-specific survival, larger tumor volume, and lower p16 expression. MET copy number gain (low or high polysomy) in tumors was significantly associated with shorter disease-specific survival and lower level of EGFR. PIK3CA and MET may play an important role in oncogenesis of certain specific subtypes of head and neck cancer. There is an urgent need for the development of novel targeted therapies against these tumors associated with poor prognosis. PMID:26832731

  5. Decreased expression of 14-3-3σ is predictive of poor prognosis for patients with human uterine papillary serous carcinoma.

    PubMed

    Suzuki, Fumihiko; Nagase, Satoru; Suzuki, Kichiya; Oba, Etsuko; Hiroki, Eri; Matsuda, Yukika; Akahira, Jun-Ichi; Nishigori, Hidekazu; Sugiyama, Takashi; Otsuki, Takeo; Yoshinaga, Kousuke; Takano, Tadao; Niikura, Hitoshi; Ito, Kiyoshi; Sasano, Hironobu; Yaegashi, Nobuo

    2013-01-01

    Uterine papillary serous carcinoma (UPSC) morphologically resembles ovarian serous carcinoma and is categorized as a type II endometrial cancer. UPSC comprises about 10% of all types of endometrial cancer and has an aggressive clinical course and a poor prognosis. The 14-3-3σ gene was originally discovered as a p53-inducible gene; its expression is induced by DNA damage in a p53-dependent manner, which leads to G2 arrest and repair of damaged DNA. Moreover, it has been reported that expression of 14-3-3σ is frequently lost in various types of human cancer, including ovarian cancer. We therefore examined the association between 14-3-3σ expression determined by immunohistochemistry and clinical outcomes of 51 patients with UPSC. UPSC was considered positive for 14-3-3σ when > 30% of tumor cells were stained with a specific antibody. Of these patients, 29 (58.7%) showed positive immunoreactivity for 14-3-3σ and 22 (41.3%) had decreased 14-3-3σ staining. Decreased immunoreactivity for 14-3-3σ was associated with stage (P = 0.001) and lymphovascular space involvement (P = 0.005). Moreover, decreased 14-3-3σ expression was an independent risk factor for reduced overall survival (P = 0.0416) in multivariate analysis. Direct bisulfite sequencing was performed to evaluate the methylation status of the 27 CpG islands in the promoter region and first exon of the 14-3-3σ gene. These CpG islands were hypermethylated in 30% of 14-3-3σ-positive UPSC and 80% of 14-3-3σ-negative UPSC, although the difference was not statistically significant. These findings suggest that decreased expression of immunoreactive 14-3-3σ may be a predictor of poor prognosis in patients with UPSC. PMID:24201220

  6. Neuropilin-1 Promotes Epithelial-to-Mesenchymal Transition by Stimulating Nuclear Factor-Kappa B and Is Associated with Poor Prognosis in Human Oral Squamous Cell Carcinoma

    PubMed Central

    Chu, Weiming; Song, Xiaomeng; Yang, Xueming; Ma, Lu; Zhu, Jiang; He, Mengying; Wang, Zilu; Wu, Yunong

    2014-01-01

    Background The epithelial-to-mesenchymal transition (EMT) is a key process in carcinogenesis, invasion, and metastasis of oral squamous cell carcinoma (OSCC). In our previous studies, we found that neuropilin-1 (NRP1) is overexpressed in tongue squamous cell carcinoma and that this overexpression is associated with cell migration and invasion. Nuclear factor-kappa B (NF-κB) plays an essential role both in the induction and the maintenance of EMT and tumor metastasis. Therefore, we hypothesized that NRP1 induces EMT, and that NRP1-induced migration and invasion may be an important mechanism for promoting invasion and metastasis of OSCC through NF-κB activation. Methods/Results The variations in gene and protein expression and the changes in the biological behavior of OSCC cell lines transfected with a vector encoding NRP1, or the corresponding vector control, were evaluated. NRP1 overexpression promoted EMT and was associated with enhanced invasive and metastatic properties. Furthermore, the induction of EMT promoted the acquisition of some cancer stem cell (CSC)-like characteristics in OSCC cells. We addressed whether selective inhibition of NF-κB suppresses the NRP1-mediated EMT by treating cells with pyrrolidinedithiocarbamate ammonium (PDTC), an inhibitor of NF-κB. Immunohistochemical analysis of NRP1 in OSCC tissue samples further supported a key mediator role for NRP1 in tumor progression, lymph node metastasis, and indicated that NRP1 is a predictor for poor prognosis in OSCC patients. Conclusion Our results indicate that NRP1 may regulate the EMT process in OSCC cell lines through NF-κB activation, and that higher NRP1 expression levels are associated with lymph node metastasis and poor prognosis in OSCC patients. Further investigation of the role of NRP1 in tumorigenesis may help identify novel targets for the prevention and therapy of oral cancers. PMID:24999732

  7. High expression of Y-box-binding protein 1 correlates with poor prognosis and early recurrence in patients with small invasive lung adenocarcinoma

    PubMed Central

    Zhao, Shilei; Guo, Wei; Li, Jinxiu; Yu, Wendan; Guo, Tao; Deng, Wuguo; Gu, Chundong

    2016-01-01

    Background Prognosis of small (≤2 cm) invasive lung adenocarcinoma remains poor, and identification of high-risk individuals from the patients after complete surgical resection of lung adenocarcinoma has become an urgent problem. YBX1 has been reported to be able to predict prognosis in many cancers (except lung adenocarcinoma) that are independent of TNM (tumor, nodes, metastases) staging, especially small invasive lung adenocarcinoma. Therefore, we examined the significance of YBX1 expression on prognosis and recurrence in patients with small invasive lung adenocarcinoma. Material and methods A total of 75 patients with small invasive lung adenocarcinoma after complete resection were enrolled from January 2008 to December 2010. Immunohistochemical staining was used to detect the expression of YBX1, and receiver operating characteristic curve analysis was performed to precisely assess the overall expression of YBX1. Meanwhile, primary lesions were identified based on the International Association for the Study of Lung Cancer, the American Thoracic Society, and the European Respiratory Society’s classification of lung adenocarcinoma. The effect of different clinicopathological factors on patients’ survival was examined. Furthermore, Western blot analysis was used to show the expression of YBX1 in vitro. Results Sensitivity and specificity of YBX1 for detecting small invasive lung adenocarcinoma from normal surrounding tissue were 66.7% and 74.7% (area under the receiver operating characteristic curve =0.731; P<0.001), respectively. High YBX1 expression was detected in 31 (41.3%) patients, and in A549, H322, Hcc827, and H1299 lung adenocarcinoma cells but not in HLF cells. In addition to sex, age, tumor size, TNM staging, pleural invasion, and lymph node metastasis, the expression of YBX1 was associated with the International Association for the Study of Lung Cancer, the American Thoracic Society, and the European Respiratory Society pathological grade risk (P

  8. High expression of Rab3D predicts poor prognosis and associates with tumor progression in colorectal cancer.

    PubMed

    Luo, Yang; Ye, Guang-Yao; Qin, Shao-Lan; Mu, Yi-Fei; Zhang, Lei; Qi, Yang; Qiu, Yi-Er; Yu, Min-Hao; Zhong, Ming

    2016-06-01

    Rab3D belongs to Rab protein family. Previous reports showed that the expression of Rab3D was dysregulated in various types of cancer. Rab3D belongsRab3D belongs. However, little is known about the role of Rab3D in carcinogenesis and progression of colorectal cancer (CRC). Here, we first evaluated the expression of Rab3D in 32 fresh CRC and matched normal tissues and found Rab3D was dramatically increased in CRC tissues compared to normal tissues (p<0.001). Furthermore, immunochemistry was used to investigate Rab3D expression in 300CRC tissue specimens. The expression of Rab3D significantly positively correlated with the tumor size (p=0.041), CEA level (p=0.007), tumor classification (p=0.030), lymphatic metastasis (p<0.001), distant metastasis (p=0.013) and clinical stage (p=0.003). We also demonstrated that overall survival is poor in CRC patients with high expression of Rab3D (p<0.001). Finally, we showed that Rab3D activated Akt/GSK3β/Snail pathway and induced EMT process in colorectal cancer cells. In conclusion, this study establishes increased Rab3D expression is associated with invasiveness of CRC cells, and Rab3D expression status may serve as a reliable prognostic biomarker in CRC patients. PMID:27046094

  9. Absent and abundant MET immunoreactivity is associated with poor prognosis of patients with oral and oropharyngeal squamous cell carcinoma

    PubMed Central

    De Herdt, Maria J.; Willems, Stefan M.; van der Steen, Berdine; Noorlag, Rob; Verhoef, Esther I.; van Leenders, Geert J.L.H.; van Es, Robert J.J.; Koljenović, Senada; de Jong, Robert J. Baatenburg; Looijenga, Leendert H.J.

    2016-01-01

    Although the receptor tyrosine kinase (RTK) MET is widely expressed in head and neck squamous cell carcinoma (HNSCC), its prognostic value remains unclear. This might be due to the use of a variety of antibodies and scoring systems. Here, the reliability of five commercial C-terminal MET antibodies (D1C2, CVD13, SP44, C-12 and C-28) was evaluated before examining the prognostic value of MET immunoreactivity in HNSCC. Using cancer cell lines, it was shown that D1C2 and CVD13 specifically detect MET under reducing, native and formalin-fixed paraffin-embedded (FFPE) conditions. Immunohistochemical staining of routinely FFPE oral SCC with D1C2 and CVD13 demonstrated that D1C2 is most sensitive in the detection of membranous MET. Examination of membranous D1C2 immunoreactivity with 179 FFPE oral and oropharyngeal SCC – represented in a tissue microarray – illustrated that staining is either uniform (negative or positive) across tumors or differs between a tumor's center and periphery. Ultimately, statistical analysis revealed that D1C2 uniform staining is significantly associated with poor 5-year overall and disease free survival of patients lacking vasoinvasive growth (HR = 3.019, p < 0.001; HR = 2.559, p < 0.001). These findings might contribute to reliable stratification of patients eligible for treatment with biologicals directed against MET. PMID:26909606

  10. High CD4+ T cell density is associated with poor prognosis in patients with non-muscle-invasive bladder cancer

    PubMed Central

    Zhang, Qinglei; Hao, Chongli; Cheng, Guangzhou; Wang, Lei; Wang, Xiang; Li, Chang; Qiu, Juhui; Ding, Kejia

    2015-01-01

    Purpose: The aim of this study was to investigate the clinical significance of CD4+ T cells in non-muscle-invasive bladder cancer (NMIBC) tissues in situ. Methods: Immunohistochemistry was used to examine the distribution of CD4+ T cells in 131 NMIBC tissues. Kaplan-Meier analysis and Cox proportional hazards regression models were applied to estimate overall survival (OS) and recurrence-free survival (RFS). Results: NMIBC patients were divided into two groups based on the median frequency of CD4+ T cells (median, 1/×400 high resolution). On univariate analysis, CD4+ T cell density was inversely associated with overall survival (P = 0.01). In those patients with high CD4+ T density, 5-year OS rates was only 77%, compared with 86% in those with low density, respectively. Although CD4+ T cell density showed no prognostic significance for RFS (P = 0.36), 5-year RFS rates of patients with high CD4+ T density (58%) was lower than those of patients with low CD4+ T density (65%, respectively). By multivariate analysis, tumor infiltrating CD4+ T cell density emerged as an independent prognostic factor for OS (HR, 2.75; P = 0.004). In addition, no association was found between CD4+ T cell density and any clinicopathological variables (P > 0.05). Conclusion: Our findings suggest that CD4+ T cells could potentially serve as a poor prognostic marker for patients with NMIBC. PMID:26617883

  11. Intra-tumour IgA1 is common in cancer and is correlated with poor prognosis in bladder cancer.

    PubMed

    Welinder, Charlotte; Jirström, Karin; Lehn, Sophie; Nodin, Björn; Marko-Varga, György; Blixt, Ola; Danielsson, Lena; Jansson, Bo

    2016-08-01

    A high frequency of IgA1-positive tumour cells was found in tissue micro-arrays of oesophagus, colon, testis, lung, breast, bladder and ovarian cancer. IgA1 was observed in the cytoplasm and the plasma membrane. A correlation was found between intra-tumour IgA1 and poor overall survival in a large cohort of bladder cancer patients (n = 99, p = 0.011, log-rank test). The number of IgA1-positive tumour cells was also found to be higher in female than male bladder cancer patients. The presence of IgA1 was confirmed in formalin-fixed paraffin-embedded ovarian carcinoma samples using LC-MS/MS analysis. Uptake of IgA1 was also observed in breast cancer and melanoma cell lines when cultivated in the presence of serum from healthy individuals, indicating a possible origin of the IgA1 antibodies in cancer cells. PMID:27579449

  12. Enhanced expression of early mitotic inhibitor-1 predicts a poor prognosis in esophageal squamous cell carcinoma patients

    PubMed Central

    GUAN, CHENGQI; ZHANG, JIANFENG; ZHANG, JIANGUO; SHI, HUI; NI, RUNZHOU

    2016-01-01

    Early mitotic inhibitor-1 (Emi1), as a key cell cycle regulatory gene, induces S phase and mitotic entry by controlling anaphase-promoting complex substrates. Emi1 overexpression may be a prognostic factor for patients with invasive breast cancer. However, its expression and clinical significance in esophageal squamous cell carcinoma (ESCC) remain unknown. In the present study, Emi1 was overexpressed in ESCC samples, contrarily to their neighboring normal tissues. The expression of Emi1 was correlated with histological differentiation (P=0.032), lymphatic metastasis (P=0.006) and Ki-67 expression (P=0.028). Multivariate analysis indicated that the presence of lymphatic metastasis and the protein expression levels of Emi1 and Ki-67 were all independent prognostic factors for ESCC patients (P=0.042, 0.018 and 0.001, respectively). In vitro, however, the expression of Emi1 was upregulated in the ECA109 cell line following release from serum starvation. In addition, depletion of endogenous Emi1 by small interfering RNA could effectively reduce cell proliferation. Thus, the present data indicated that Emi1 expression was upregulated in ESCC tissues and correlated with poor survival in ESCC patients, and suggested that Emi1 may be an independent prognostic factor for ESCC patients. PMID:27347110

  13. p63 is an alternative p53 repressor in melanoma that confers chemoresistance and a poor prognosis

    PubMed Central

    Matin, Rubeta N.; Chikh, Anissa; Law Pak Chong, Stephanie; Mesher, David; Graf, Manuela; Sanza’, Paolo; Senatore, Valentina; Scatolini, Maria; Moretti, Francesca; Leigh, Irene M.; Proby, Charlotte M.; Costanzo, Antonio; Chiorino, Giovanna; Cerio, Rino; Harwood, Catherine A.

    2013-01-01

    The role of apoptosis in melanoma pathogenesis and chemoresistance is poorly characterized. Mutations in TP53 occur infrequently, yet the TP53 apoptotic pathway is often abrogated. This may result from alterations in TP53 family members, including the TP53 homologue TP63. Here we demonstrate that TP63 has an antiapoptotic role in melanoma and is responsible for mediating chemoresistance. Although p63 was not expressed in primary melanocytes, up-regulation of p63 mRNA and protein was observed in melanoma cell lines and clinical samples, providing the first evidence of significant p63 expression in this lineage. Upon genotoxic stress, endogenous p63 isoforms were stabilized in both nuclear and mitochondrial subcellular compartments. Our data provide evidence of a physiological interaction between p63 with p53 whereby translocation of p63 to the mitochondria occurred through a codependent process with p53, whereas accumulation of p53 in the nucleus was prevented by p63. Using RNA interference technology, both isoforms of p63 (TA and ΔNp63) were demonstrated to confer chemoresistance, revealing a novel oncogenic role for p63 in melanoma cells. Furthermore, expression of p63 in both primary and metastatic melanoma clinical samples significantly correlated with melanoma-specific deaths in these patients. Ultimately, these observations provide a possible explanation for abrogation of the p53-mediated apoptotic pathway in melanoma, implicating novel approaches aimed at sensitizing melanoma to therapeutic agents. PMID:23420876

  14. CD10-Equipped Melanoma Cells Acquire Highly Potent Tumorigenic Activity: A Plausible Explanation of Their Significance for a Poor Prognosis

    PubMed Central

    Hashimoto-Hachiya, Akiko; Liu, Min; Abe, Takeru; Hagihara, Akihito; Yokomizo, Takehiko; Furue, Masutaka

    2016-01-01

    CD10 has been widely used in cancer diagnosis. We previously demonstrated that its expression in melanoma increased with tumor progression and predicted poor patient survival. However, the mechanism by which CD10 promotes melanoma progression remains unclear. In order to elucidate the role of CD10 in melanoma, we established CD10-overexpressing A375 melanoma cells and performed DNA microarray and qRT–PCR analyses to identify changes in the gene expression profile. The microarray analysis revealed that up-regulated genes in CD10-A375 were mostly involved in cell proliferation, angiogenesis, and resistance to apoptosis; down-regulated genes mostly belonged to the categories associated with cell adhesion and migration. Accordingly, in functional experiments, CD10-A375 showed significantly greater cell proliferation in vitro and higher tumorigenicity in vivo; CD10 enzymatic inhibitors, thiorphan and phosphoramidon, significantly blocked the tumor growth of CD10-A375 in mice. In migration and invasion assays, CD10-A375 displayed lower migratory and invasive capacity than mock-A375. CD10 augmented melanoma cell resistance to apoptosis mediated by etoposide and gemcitabine. These findings indicate that CD10 may promote tumor progression by regulating the expression profiles of genes related to cell proliferation, angiogenesis, and resistance to apoptosis. PMID:26881775

  15. PDK-1 regulates lactate production in hypoxia and is associated with poor prognosis in head and neck squamous cancer

    PubMed Central

    Wigfield, S M; Winter, S C; Giatromanolaki, A; Taylor, J; Koukourakis, M L; Harris, A L

    2008-01-01

    Here we describe the expression and function of a HIF-1-regulated protein pyruvate dehydrogenase kinase-1 (PDK-1) in head and neck squamous cancer (HNSCC). Using RNAi to downregulate hypoxia-inducible PDK-1, we found that lactate and pyruvate excretion after 16–48 h of hypoxia was suppressed to normoxic levels. This indicates that PDK-1 plays an important role in maintaining glycolysis. Knockdown had no effect on proliferation or survival under hypoxia. The immunohistochemical expression of PDK-1 was assessed in 140 cases of HNSCC. PDK-1 expression was not expressed in normal tissues but was upregulated in HNSCC and found to be predominantly cytoplasmic with occasional strong focal nuclear expression. It was strongly related to poor outcome (P=0.005 split by median). These results indicate that HIF regulation of PDK-1 has a key role in maintaining lactate production in human cancer and that the investigation of PDK-1 inhibitors should be investigated for antitumour effects. PMID:18542064

  16. High proliferation index, as determined by immunohistochemical expression of Aurora kinase B and geminin, indicates poor prognosis in neuroblastomas.

    PubMed

    Ramani, Pramila; Sowa-Avugrah, Emile; May, Margaret T

    2015-09-01

    Expression profile analysis of cell cycle biomarkers provides a powerful index of the proliferative state of tumors, which is linked to disease aggressiveness. We investigated the impact of the biomarkers of S-G2-M phases of cell cycle, Aurora kinase B (AURKB) and geminin (GMNN), on disease progression in neuroblastomas. The expression of AURKB and GMNN was studied by immunostaining 84 neuroblastomas. A proliferation index (PI) was obtained on scanned immunostained slides using image analysis software. The median PI was 8.5 % for AURKB- and 16.8 % for GMNN-stained slides with a high correlation between the two (r s = 0.72, P < 0.001). The PI for both markers was significantly higher in neuroblastomas from patients with unfavorable clinical (high-risk group, advanced stage, age ≥18 months at presentation, primary abdominal compared to extra-abdominal sites), biological (MYCN amplification, 1p deletion, 17q gain), and pathological (undifferentiated or poorly differentiated status, high mitosis-karyorrhexis index, [MKI], unfavorable histology) factors. Using Cox regression models, a higher-than-median AURKB and GMNN PI was associated with a significantly shorter overall survival (OS) and event-free survival (EFS) in univariable analysis. In multivariable analysis, a high AURKB PI was associated with significantly shorter OS and EFS, independent of MYCN amplification, and significantly shorter EFS, independent of MKI. High GMNN PI was also associated with significantly shorter OS and EFS after adjusting for MYCN amplification but failed to reach statistical significance after adjusting for MKI. Our study shows that in neuroblastomas, AURKB- or GMNN-based PI provides valuable prognostic information and high PI indicates aggressive disease. PMID:26199132

  17. Elevated expression of flotillin-1 is associated with lymph node metastasis and poor prognosis in early-stage cervical cancer

    PubMed Central

    Li, Zheng; Yang, Yang; Gao, Yang; Wu, Xiaoliu; Yang, Xielan; Zhu, Yingjie; Yang, Hongying; Wu, Lin; Yang, Chengang; Song, Libing

    2016-01-01

    Accumulating evidence has revealed that the expression of the lipid raft protein flotillin-1 is elevated in various human cancers, but the role flotillin-1 plays in the carcinogenesis of cervical cancer remains unclear. The expression profile of flotillin-1 was assayed using real-time PCR, western blotting, and immunohistochemical (IHC) staining in cervical cancer cell lines and cancer tissues with paired adjacent noncancerous cervical tissues. The expression of flotillin-1 protein was detected by IHC staining in a large cohort of 308 paraffin-embedded cervical cancer tissues. Ectopic expression and the short hairpin RNA interference approach were employed to determine the role of flotillin-1 in cervical cancer cell metastasis and the possible mechanism involved. Flotillin-1 expression protein and mRNA were significantly upregulated in cervical cancer cell lines and cancer tissues; elevated expression of flotillin-1 protein in early-stage cervical cancer was significantly associated with pelvic lymph node metastasis (P < 0.001), and was an independent predictive factor of poor overall survival. Moreover, flotillin-1 up- and downregulation remarkably affected cervical cancer cell motility and invasion, respectively, through epithelial-mesenchymal transition (EMT) regulated by the Wnt/β-catenin and nuclear factor-κB (NF-κB) pathways. Our results suggest that flotillin-1 facilitates cervical cancer cell metastasis through Wnt/β-catenin and NF-κB pathway-regulated EMT and that the flotillin-1 expression profile serves not only as novel predictor of pelvic lymph node metastasis, but also as neoteric risk factor for patients with early-stage cervical cancer. PMID:27073721

  18. Actin‐like 6A predicts poor prognosis of hepatocellular carcinoma and promotes metastasis and epithelial‐mesenchymal transition

    PubMed Central

    Xiao, Shuai; Chang, Rui‐Min; Yang, Ming‐Yang; Lei, Xiong; Liu, Xiao; Gao, Wen‐Bin; Xiao, Jing‐Lei

    2016-01-01

    Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide because of metastasis. Epithelial‐mesenchymal transition (EMT) is widely considered to be crucial to the invasion‐metastasis cascade during cancer progression. Actin‐like 6A (ACTL6A) is initially verified important for cell proliferation, differentiation, and migration. In this study, we find that ACTL6A plays an essential role in metastasis and EMT of HCC. ACTL6A expression is up‐regulated in HCC cells and tissues. A high level of ACTL6A in HCCs is correlated with aggressive clinicopathological features and is an independent poor prognostic factor for overall and disease‐free survival of HCC patients. Ectopic expression of ACTL6A markedly promotes HCC cells migration, invasion, as well as EMT in vitro and promotes tumor growth and metastasis in the mouse xenograft model. Opposite results are observed when ACTL6A is knocked down. Mechanistically, ACTL6A promotes metastasis and EMT through activating Notch signaling. ACTL6A knockdown has the equal blockage effect as the Notch signaling inhibitor, N‐[N‐(3,5‐difluorophenacetyl)‐L‐alanyl]‐S‐phenylglycine t‐butylester, in HCC cells. Further studies indicate that ACTL6A might manipulate SRY (sex determining region Y)‐box 2 (SOX2) expression and then activate Notch1 signaling. Conclusions: ACTL6A promotes metastasis and EMT by SOX2/Notch1 signaling, indicating a prognostic biomarker candidate and a potential therapeutic target for HCC. (Hepatology 2016;63:1256–1271) PMID:26698646

  19. Comparison of The Effectiveness of Clomiphene Citrate versus Letrozole in Mild IVF in Poor Prognosis Subfertile Women with Failed IVF Cycles

    PubMed Central

    Oktem, Mesut; Guler, Ismail; Erdem, Mehmet; Erdem, Ahmet; Bozkurt, Nuray; Karabacak, Onur

    2015-01-01

    Background Our objective was to evaluate the effectiveness of clomiphene citrate (CC) vs. letrozole (L) plus human menopausal gonadotropin (hMG) in gonadotropin releasing hormone (GnRH) antagonist protocol in poor prognosis women with previous failed ovarian stimulation undergoing intracytoplasmic sperm injection (ICSI). Materials and Methods This retrospective cohort study included cycles with CC and L plus hMG/GnRH antagonist protocols of 32 poor responders who had failed to have ideal follicles to be retrieved during oocyte pick-up (OPU) or embryo transfer (ET) at least for 2 previous in vitro fertilization (IVF) cycles with microdose flare protocol or GnRH antagonist protocol from January 2006 to December 2009. Main outcome measures were implantation, clinical pregnancy and live birth rates per cycle. Duration of stimulation, mean gonadotropin dose used, endometrial thickness, number of mature follicles, serum estradiol (E2) and progesterone (P) levels on the day of human chorionic gonadotropin (hCG) administration, number of retrieved oocytes and fertilization rates were also evaluated. Results A total number of 42 cycles of 32 severe poor responders were evaluated. Total gonadotropin consumption was significantly lower (1491 ± 873 vs. 2808 ± 1581 IU, P=0.005) and mean E2 level on the day of hCG injection were significantly higher in CC group than L group (443.3 ± 255.2 vs. 255.4 ± 285.2 pg/mL, P=0.03). ET, overall pregnancy and live birth rates per cycle were significantly higher in CC than L protocol (27.2 vs. 15%, 13.6 vs. 0% and 4.5 vs. 0%, respectively, P<0.05). Conclusion Severe poor responders who had previously failed to respond to microdose or GnRH antagonist protocols may benefit from CC plus hMG/GnRH antagonist protocol despite high cancellation rate. PMID:26644850

  20. Selective participation of c-Jun with Fra-2/c-Fos promotes aggressive tumor phenotypes and poor prognosis in tongue cancer

    PubMed Central

    Gupta, Shilpi; Kumar, Prabhat; Kaur, Harsimrut; Sharma, Nishi; Saluja, Daman; Bharti, Alok C.; Das, Bhudev C.

    2015-01-01

    Tongue squamous cell carcinoma (TSCC) is most aggressive head and neck cancer often associated with HR-HPV infection. The role of AP-1 which is an essential regulator of HPV oncogene expression and tumorigenesis is not reported in tongue cancer. One hundred tongue tissue biopsies comprising precancer, cancer and adjacent controls including two tongue cancer cell lines were employed to study the role of HPV infection and AP-1 family proteins. An exclusive prevalence (28%) of HR-HPV type 16 was observed mainly in well differentiated tongue carcinomas (78.5%). A higher expression and DNA binding activity of AP-1 was observed in tongue tumors and cancer cell lines with c-Fos and Fra-2 as the major binding partners forming the functional AP-1 complex but c-Jun participated only in HPV negative and poorly differentiated carcinoma. Knocking down of Fra-2 responsible for aggressive tongue tumorigenesis led to significant reduction in c-Fos, c-Jun, MMP-9 and HPVE6/E7 expression but Fra-1 and p53 were upregulated. The binding and expression of c-Fos/Fra-2 increased as a function of severity of tongue lesions, yet selective participation of c-Jun appears to promote poor differentiation and aggressive tumorigenesis only in HPV negative cases while HPV infection leads to well differentiation and better prognosis preferably in nonsmokers. PMID:26581505

  1. PRAME expression in head and neck cancer correlates with markers of poor prognosis and might help in selecting candidates for retinoid chemoprevention in pre-malignant lesions

    PubMed Central

    Szczepanski, Miroslaw J.; DeLeo, Albert B.; Łuczak, Michał; Molinska-Glura, Marta; Misiak, Jan; Szarzynska, Bronislawa; Dworacki, Grzegorz; Zagor, Mariola; Rozwadowska, Natalia; Kurpisz, Maciej; Krzeski, Antoni; Kruk-Zagajewska, Aleksandra; Kopec, Tomasz; Banaszewski, Jacek; Whiteside, Theresa L.

    2012-01-01

    Objectives PRAME (Preferentially Expressed Antigen in Melanoma) is a tumor-associated antigen recognized by immunocytes, and it induces cytotoxic T cell-mediated responses in melanoma. PRAME expression in tumors interferes with retinoic acid receptor (RAR) signaling thus promoting tumor progression. Here, we study PRAME expression in head and neck squamous cell carcinoma (HNSCC) to determine its potential clinical significance. Materials and Methods PRAME expression in HNSCC was evaluated by immunohistochemistry in tissue microarrays of primary tumors (n=53), metastatic lymph nodes (n=8) and normal oral mucosa (n=11). Biopsies of dysplastic oral lesions (n=12) were also examined. PRAME expression levels in tissues were correlated with markers of poor prognosis in HNSCC. PRAME mRNA in HNSCC cell lines and in normal immortalized human keratinocytes (HaCaT cell line) was measured by qRT-PCR, and the protein expression by flow cytometry and western blots. Results PRAME was expressed in HNSCC cell lines and HNSCC lesions. PRAME expression in dysplastic mucosa was variable. No or only weak expression was found in normal cells or tissues. PRAME expression levels significantly correlated with the tumor grade, size, nodal involvement and the clinical status of HNSCC patients. Conclusions Elevated PRAME expression associates with clinicopathologic markers of poor outcome in HNSCC and might identify potential candidates with pre-cancerous lesions for chemoprevention with retinoids. PMID:22944049

  2. Borealin/Dasra B is a cell cycle-regulated chromosomal passenger protein and its nuclear accumulation is linked to poor prognosis for human gastric cancer

    SciTech Connect

    Chang, J.-L.; Chen, T.-H.; Wang, C.-F.; Chiang, Y.-H.; Huang, Y.-L.; Wong, F.-H.; Chou, C.-K. . E-mail: ckchou@mail.pmf.org.tw; Chen, C.-M. . E-mail: cmchen@ym.edu.tw

    2006-04-15

    Chromosomal passenger proteins including Aurora B, Survivin, and Borealin/Dasra B, also called CDCA8/FLJ10468, are known to play crucial roles during mitosis and cell division. Inappropriate chromosomal segregation and cell division may cause auneuploidy leading to cancer. However, it is still unclear how the expression of chromosomal passenger proteins may be linked to cancer. In this study, we demonstrated that Borealin is a cell cycle-regulated gene and is upregulated at G2-M phases of the cell cycle. We showed that Borealin interacts with Survivin but not with Aurora B. The interaction domain of Survivin in Borealin was mapped to the N-terminal 92 amino-acid residues of Borealin. To examine the linkage between expression of Borealin and cancer, we performed immunohistochemistry analysis using anti-Borealin specific antibody on the paraffin-embedded gastric cancer tissues. Our results showed that Borealin expression is significantly correlated with Survivin (P = 0.003) and Ki67 (P = 0.007) in gastric cancer. Interestingly, an increased nuclear Borealin level reveals borderline association with a poor survival rate (P = 0.047). Taken together, our results demonstrated that Borealin is a cell cycle-regulated chromosomal passenger protein and its aberrant expression is linked to a poor prognosis for gastric cancer.

  3. Decreased expression of autophagy protein LC3 and stemness (CD44+/CD24-/low) indicate poor prognosis in triple-negative breast cancer.

    PubMed

    Chang, Shu-Jyuan; Ou-Yang, Fu; Tu, Hung-Pin; Lin, Chih-Hung; Huang, Shu-Hung; Kostoro, Joanna; Hou, Ming-Feng; Chai, Chee-Yin; Kwan, Aij-Lie

    2016-02-01

    This study evaluated the prognostic value of expression of autophagy protein light chain 3 (LC3) and the prognostic value of coexpression of LC3 and stemness markers CD44+/CD24-/low in triple-negative breast cancer (TNBC). LC3 and LC3/CD44+/CD24-/low immunophenotypes in tumor tissues were evaluated by immunohistochemistry in 67 TNBC patients. LC3- was expressed in 30 (44.78%) cases. The LC3- phenotype revealed a significant negative association with overall survival in both univariate (P = .0006) and multivariate (P = .0153) analyses. LC3-/CD44+/CD24-/low phenotype was observed in 24 (35.82%) of 67 TNBC patients. According to Kaplan-Meier analysis, prognosis was significantly worse in tumors with LC3-/CD44+/CD24-/low phenotype (P = .0280). Multivariate analysis indicated that LC3-/CD44+/CD24-/low phenotype was a significant independent prognostic indicator of overall survival. These results suggest that LC3 suppresses TNBC in mature tumor cells and cancer stem cells (CSCs). In conclusion, this study suggests that CSCs are linked to progression of autophagy in TNBC. During the progression and development of TNBC, autophagy of CSCs/progenitor cells is low. LC3-/CD44+/CD24-/low immunophenotype indicates a highly aggressive TNBC subgroup associated with a poor prognosis. This study investigated that LC3 deficiency may restrain TNBC in mature tumor cells and CSCs. Therefore, a reasonable inference is that inducing autophagy may be an effective therapeutic strategy in TNBC. PMID:26772398

  4. A Functional Polymorphism (rs937283) in the MDM2 Promoter Region is Associated with Poor Prognosis of Retinoblastoma in Chinese Han Population

    PubMed Central

    Jiao, Yongfa; Jiang, Zhongming; Wu, Yuxia; Chen, Xiaochong; Xiao, Xing; Yu, Haiying

    2016-01-01

    The effect of single nucleotide polymorphisms (SNPs) at MDM2 has been investigated in several cancer types. Three MDM2 SNPs(rs937283, rs2270744 and rs769412) have previously been suggested to be positively correlated with cancer. In this study, we aimed to explore the association of rs937283, rs2270744 and rs769412 polymorphisms with retinoblastoma (RB) risk, clinicopathological characteristics, and prognosis. Compared with wild-type genotype AA at rs937283, individuals carrying AG and GG genotype had a significantly increased risk for developing RB (OR = 1.86, 95% CI 1.13–3.08; OR = 2.48, 95% CI 1.10–5.62, respectively). RB patients with allele G at rs937283 were more susceptible to invasion and high tumor aggression (OR = 2.42, 95% CI 1.43–4.11; OR = 2.15, 95% CI 1.27–3.64, respectively). Kaplan-Meier curves and log-rank results revealed that RB patients harboring genotype GG and G allele at rs937283 had worse survival (P < 0.02 and P < 0.01, respectively). In addition, the A to G substitution at rs937283 significantly enhanced the transcription activity of the MDM2 gene in vitro. In vivo, we found that MDM2 mRNA and protein were overexpressed in individuals who carried the G allele at rs937283. This study suggested that the MDM2 rs937283 polymorphism is a novel functional SNP both in vitro and in vivo as well as a biomarker for poor prognosis in RB. PMID:27506496

  5. Only high disease activity and positive rheumatoid factor indicate poor prognosis in patients with early rheumatoid arthritis treated with "sawtooth" strategy

    PubMed Central

    Mottonen, T; Paimela, L; Leirisalo-Repo, M; Kautiainen, H; Ilonen, J; Hannonen, P

    1998-01-01

    OBJECTIVES—To investigate the prognostic significance of clinical and genetic markers on the outcome of patients with recent-onset rheumatoid arthritis (RA) treated actively with slow acting antirheumatic drugs (SAARDs).
METHODS—A total of 142 consecutive patients with early RA (median disease duration of 7 months) were treated according to the "sawtooth" strategy and prospectively followed up for an average of 6.2 years. Several clinical parameters at start as well as genetic markers were related to the functional outcome (ARA Functional class and HAQ disability score) and radiographic joint damage (Larsen's score) at the latest visit.
RESULTS—In logistic regression analysis only Mallya score (including morning stiffness, pain scale, grip strength, Ritchie's articular index, haemoglobin, and erythrocyte sedimentation rate) at baseline, and Mallya score and rheumatoid factor (RF) positivity at one year were found to be of significance with respect to the radiographic outcome of the patients. Furthermore, at the latest visit HAQ score was related to radiographic score. At baseline the mean ages of the DR4 positive patients and the patients with RA associated DR alleles were statistically significantly lower than those without the above mentioned risk factors (44 v 49, p=0.03 and 41 v 53, p=0.04, respectively). However, these genetic markers had no prognostic significance on the functional or radiographic outcome of the patients.
CONCLUSION—High clinical disease activity at baseline and RF positivity especially at one year after the institution of SAARD treatment are the best predictors of poor prognosis in early RA. However, from the clinical point of view, the disease outcome of an individual patient with early RA, cannot be predicted accurately enough by present means.

 Keywords: rheumatoid arthritis; prognosis; outcome; prediction PMID:9849312

  6. Overexpression of homeobox B-13 correlates with angiogenesis, aberrant expression of EMT markers, aggressive characteristics and poor prognosis in pancreatic carcinoma

    PubMed Central

    Zhai, Lu-Lu; Wu, Yang; Cai, Chong-Yang; Tang, Zhi-Gang

    2015-01-01

    To investigate the expression of homeobox B (Hoxb)-13 and analyze its relationship with tumor angiogenesis, epithelial-mesenchymal transition (EMT)-associated markers (E-cadherin and vimentin), clinicopathologic data and prognosis in pancreatic carcinoma. Immunohistochemistry was applied to determine the level of Hoxb-13 expression in tumor tissues and surrounding non-tumor tissues from 85 subjects with pancreatic carcinoma. Besides, vascular endothelial growth factor (VEGF), CD31, E-cadherin and vimentin were also detected in tumor tissues by immunostaining. We found that the level of Hoxb-13 expression was significantly higher in pancreatic carcinoma tissues than in paracarcinomatous tissues (P < 0.05). Hoxb-13 staining was positively correlated with VEGF (r = 0.429, P < 0.001) and microvessel density (MVD) (r = 0.454, P < 0.001). Likewise, Hoxb-13 staining was positively correlated with vimentin (r = 0.448, P < 0.001); while it was negatively correlated with E-cadherin (r = -0.405, P < 0.001). High Hoxb-13 expression was associated with aggressive clinicopathological characteristics, worse disease-free survival (DFS) (P < 0.001) and worse overall survival (OS) (P < 0.001). Multivariate analysis showed that Hoxb-13 was an independent predictor for poor DFS (P < 0.001) and OS (P = 0.002). In conclusion, our data show that overexpressed Hoxb-13 is correlated with tumor angiogenesis, aberrant expression of EMT-associated markers and aggressive clinicopathological characteristics, and serves as a promising marker for unfavourable prognosis in pancreatic carcinoma. PMID:26261579

  7. A Functional Polymorphism (rs937283) in the MDM2 Promoter Region is Associated with Poor Prognosis of Retinoblastoma in Chinese Han Population.

    PubMed

    Jiao, Yongfa; Jiang, Zhongming; Wu, Yuxia; Chen, Xiaochong; Xiao, Xing; Yu, Haiying

    2016-01-01

    The effect of single nucleotide polymorphisms (SNPs) at MDM2 has been investigated in several cancer types. Three MDM2 SNPs(rs937283, rs2270744 and rs769412) have previously been suggested to be positively correlated with cancer. In this study, we aimed to explore the association of rs937283, rs2270744 and rs769412 polymorphisms with retinoblastoma (RB) risk, clinicopathological characteristics, and prognosis. Compared with wild-type genotype AA at rs937283, individuals carrying AG and GG genotype had a significantly increased risk for developing RB (OR = 1.86, 95% CI 1.13-3.08; OR = 2.48, 95% CI 1.10-5.62, respectively). RB patients with allele G at rs937283 were more susceptible to invasion and high tumor aggression (OR = 2.42, 95% CI 1.43-4.11; OR = 2.15, 95% CI 1.27-3.64, respectively). Kaplan-Meier curves and log-rank results revealed that RB patients harboring genotype GG and G allele at rs937283 had worse survival (P < 0.02 and P < 0.01, respectively). In addition, the A to G substitution at rs937283 significantly enhanced the transcription activity of the MDM2 gene in vitro. In vivo, we found that MDM2 mRNA and protein were overexpressed in individuals who carried the G allele at rs937283. This study suggested that the MDM2 rs937283 polymorphism is a novel functional SNP both in vitro and in vivo as well as a biomarker for poor prognosis in RB. PMID:27506496

  8. Coexpression of IQ-Domain GTPase-Activating Protein 1 (IQGAP1) and Dishevelled (Dvl) Is Correlated with Poor Prognosis in Non-Small Cell Lung Cancer

    PubMed Central

    Zhao, Huanyu; Xie, Chengyao; Lin, Xuyong; Zhao, Yue; Han, Yang; Fan, Chuifeng; Zhang, Xiupeng; Du, Jiang; Han, Yong; Han, Qiang; Wu, Guangping; Wang, Enhua

    2014-01-01

    Background IQ-domain GTPase-activating protein 1 (IQGAP1) binds to Dishevelled (Dvl) and functions as a modulator of Dvl nuclear localization in Xenopus embryos. However, the relationship between IQGAP1 and Dvl in tumor tissues is unclear. Materials and Methods We used immunohistochemistry to assess the expressions of IQGAP1 and Dvl in a cohort of 111 non-small cell lung cancer (NSCLC) patients. Association of their localization expressions with clinicopathological factors was also analyzed. Results The positive rate of IQGAP1 in primary tumors was 48.6% (54/111) for its cytoplamic expression, 9.0% (10/111) for nuclear expression and 31.5% (35/111) for membranous expression; the positive rate of Dvl was 65.8% (73/111) for cytoplamic expression, 9.9% (11/111) for nuclear expression and 10.8% (12/111) for membranous expression. Coexpression rate of IQGAP1 and Dvl was 77.8% (42/54) in the cytoplasm, 80.0% (8/10) in the nucleus and 8.6% (3/35) in the membrane. Coexpression of IQGAP1 and Dvl in the cytoplasm and nucleus were significantly correlated (P<0.05), but not in the membrane (P>0.05). The positive expression rates of cyclin D1 and c-myc were significantly higher in the group of IQGAP1 and Dvl coexpression in the nucleus than that in the cytoplasm. Coexpression rate of IQGAP1 and Dvl in the cytoplasm and nucleus was significantly higher in lymph nodal metastases (63.3%, 19/30) than in primary growths (38.3%, 31/81), correlating with poor prognosis. Five-year survival time after resection in the group with their coexpression in the cytoplasm and nucleus was significantly lower than that with no coexpression (44.705±3.355 vs 58.403±2.543 months, p<0.05). Conclusions Coexpression of IQGAP1 and Dvl in the cytoplasm and nucleus was correlated with the lymph nodal metastase and poor prognosis of NSCLC, and coexpression in nucleus might play a critical role in the activation of canonical Wnt pathway. PMID:25436461

  9. Cytoplasmic and/or Nuclear Expression of β-Catenin Correlate with Poor Prognosis and Unfavorable Clinicopathological Factors in Hepatocellular Carcinoma: A Meta-Analysis

    PubMed Central

    Chen, Jiang; Liu, Jinghua; Jin, Renan; Shen, Jiliang; Liang, Yuelong; Ma, Rui; Lin, Hui; Liang, Xiao; Yu, Hong; Cai, Xiujun

    2014-01-01

    . Conclusions Cytoplasmic and/or nuclear accumulation of β-catenin, as an independent prognostic factor, significantly associated with poor prognosis and deeper invasion of HCC, and could serve as a valuable prognostic predictor for HCC. PMID:25401330

  10. High expression of dual-specificity phosphatase 5 pseudogene 1 (DUSP5P1) is associated with poor prognosis in acute myeloid leukemia

    PubMed Central

    Zhou, Ling-Yu; Yin, Jia-Yu; Tang, Qin; Zhai, Ling-Ling; Zhang, Tin-Juan; Wang, Yu-Xin; Yang, Dong-Qin; Qian, Jun; Lin, Jiang; Deng, Zhao-Qun

    2015-01-01

    The purpose of this study was to investigate the expression status of Dual-Specificity Phosphatase 5 Pseudogene 1 (DUSP5P1) and its clinical relevance in patients with acute myeloid leukemia (AML). Real-time quantitative PCR (RQ-PCR) was performed to detect the status of DUSP5P1 expression in 89 patients with de novo AML and 24 normal controls. The level of DUSP5P1 expression was significantly up-regulated in AML compared to controls (P=0.031). The patients with high expression of DUSP5P1 had higher percentage of blasts in bone marrow (BM) than those without high expression (P=0.027). The occurrence rate of DUSP5P1 high expression was significantly higher in M1 (2/8, 25%) and M2 subtypes (9/33, 27%) than in M3 subtype (0/17, 0%) (P=0.034). At the same time, the frequency of DUSP5P1 high expression in patients with intermediate (13/53, 24%) and poor karyotypes (5/11, 45%) was significantly higher than that in patients with favorable karyotype (0/21, 0%) (P=0.003). Meanwhile, DUSP5P1 high-expressed patients had significantly shorter overall survival (OS) than those with low expression (median 4.5 vs. 10.5 months, respectively, P=0.038). Our findings indicated that high expression of DUSP5P1 may identify high-risk AML patients and is associated with poor prognosis in AML. PMID:26884884

  11. Illness Progression as a Function of Independent and Accumulating Poor Prognosis Factors in Outpatients With Bipolar Disorder in the United States

    PubMed Central

    Altshuler, Lori L.; Leverich, Gabriele S.; Nolen, Willem A.; Kupka, Ralph; Grunze, Heinz; Frye, Mark A.; Suppes, Trisha; McElroy, Susan L.; Keck, Paul E.; Rowe, Mike

    2014-01-01

    Objective: Many patients with bipolar disorder in the United States experience a deteriorating course of illness despite naturalistic treatment in the community. We examined a variety of factors associated with this pattern of illness progression. Method: From 1995 to 2002, we studied 634 adult outpatients with bipolar disorder (mean age of 40 years) emanating from 4 sites in the United States. Patients gave informed consent and completed a detailed questionnaire about demographic, vulnerability, and course-of-illness factors and indicated whether their illness had shown a pattern of increasing frequency or severity of manic or depressive episodes. Fifteen factors previously linked in the literature to a poor outcome were examined for their relationship to illness progression using Kruskal-Wallis test, followed by a 2-sample Wilcoxon rank sum (Mann-Whitney) test, χ2, and logistical regression. Results: All of the putative poor prognosis factors occurred with a high incidence, and, with the exception of obesity, were significantly (P < .05) associated with illness progression. These factors included indicators of genetic and psychosocial risk and loss of social support, early onset, long delay to first treatment, anxiety and substance abuse comorbidity, rapid cycling in any year, and the occurrence of more than 20 prior episodes prior to entering the network. A greater number of factors were linearly associated with the likelihood of a progressively worsening course. Conclusions: Multiple genetic, psychosocial, and illness factors were associated with a deteriorating course of bipolar disorder from onset to study entry in adulthood. The identification of these factors provides important targets for earlier and more effective therapeutic intervention in the hope of achieving a more benign course of bipolar disorder. PMID:25834764

  12. CDKN2 Gene Deletion as Poor Prognosis Predictor Involved in the Progression of Adult B-Lineage Acute Lymphoblastic Leukemia Patients

    PubMed Central

    Xu, Na; Li, Yu-ling; Zhou, Xuan; Cao, Rui; Li, Huan; Lu, Qi-si; Li, Lin; Lu, Zi-yuan; Huang, Ji-xian; Sun, Jing; Liu, Qi-fa; Du, Qing-feng; Liu, Xiao-li

    2015-01-01

    Deletion of cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) is well known in many hematologic malignancies, but only few reports have investigated this deletion effect on clinical prognosis. This study performed analysis of the CDKN2 deletion in 215 adult B- lineage acute lymphoblastic leukemia (B-ALL) patients, and related cytogenetic prognostic factors (BCR/ABL; E2A/PBXl; TEL/AML1; Mixed Lineage Leukemia (MLL) rearrangement; MYC, Immunoglobulin heavy locus (IGH) translocation). The prevalence of CDKN2 deletions in all study populations was 28.4%. There is no difference between patients with CDKN2 deletion and wild-type patients in sex, age, white blood cells (WBC) count, BM blast percentage, extra infiltration and induction complete remission (CR) rate. Analysis in relapse patients revealed that the distribution of CDKN2 deletion is higher in relapse patients (44.6%) than all patients (28.4%, P=0.006). Deletion of CDKN2 was significantly associated with poor outcomes including decreased overall survival (OS) (P<0.001), lower disease free-survival (DFS) (P<0.001), and increased cumulative incidence of relapse (P=0.002); Also, CDKN2 deletion was strongly associated with IGH translocation (P=0.021); and had an adverse effect on patients with BCR-ABL fusion gene or with MLL rearrangement. Patients with CDKN2 gene deletion benefited from allogenic hematopoietic stem cell transplantation (Allo-HSCT). Deletion of CDKN2 gene was commonly observed through leukemia progression and was poor prognostic marker in long-term outcomes. PMID:26516359

  13. Loss of ATRX and DAXX expression identifies poor prognosis for smooth muscle tumours of uncertain malignant potential and early stage uterine leiomyosarcoma.

    PubMed

    Slatter, Tania L; Hsia, Howard; Samaranayaka, Ari; Sykes, Peter; Clow, William Bill; Devenish, Celia J; Sutton, Tim; Royds, Janice A; Pc, Philip; Cheung, Annie N; Hung, Noelyn Anne

    2015-04-01

    Uterine smooth muscle tumours of uncertain malignant potential (STUMP) are diagnostically and clinically challenging. The alternative lengthening of telomeres (ALT) telomere maintenance mechanism is associated with poor survival in soft tissue leiomyosarcoma. Time to first recurrence and survival were known for 18 STUMP and 43 leiomyosarcomata (LMS). These were screened for ALT telomere maintenance by the presence of ALT-associated PML bodies (APBs) and for changes associated with the ALT phenotype, namely aberrant p53 expression, isocitrate dehydrogenase 1 mutation (R132H substitution) expression, mutant ATRX (αthalassemia/mental retardation syndrome X-linked) expression and mutant DAXX (death-domain-associated protein) expression by immunohistochemistry (IHC). Overexpression of p16(INK4A) was examined immunohistologically in a subset of cases. Many of the tumours associated with death or recurrence demonstrated APBs commensurate with ALT telomere maintenance. However, all uterine STUMP (4/4), and vaginal STUMP (2/2) patients, and almost all LMS patients (88.4%, 23/26, including 90% (9/10) of stage 1 LMS cases), who had died of disease or who had recurrent disease, displayed loss of ATRX or DAXX expression. Loss of ATRX or DAXX expression identified poor prognosis (95% CI 2.1 to 40.8, p < 0.003), in the LMS group. Thus, loss of ATRX or DAXX expression in uterine smooth muscle tumours identifies a clinically aggressive molecular subtype of early stage LMS and when histopathological features are problematic such as in STUMP. As ATRX and DAXX IHC is readily performed in diagnostic laboratories these are potentially useful for routine histopathological classification and management. PMID:27499896

  14. Expression of Ribonucleotide Reductase Subunit-2 and Thymidylate Synthase Correlates with Poor Prognosis in Patients with Resected Stages I–III Non-Small Cell Lung Cancer

    PubMed Central

    Grossi, Francesco; Dal Bello, Maria Giovanna; Salvi, Sandra; Puzone, Roberto; Pfeffer, Ulrich; Fontana, Vincenzo; Alama, Angela; Rijavec, Erika; Barletta, Giulia; Genova, Carlo; Sini, Claudio; Ratto, Giovanni Battista; Taviani, Mario; Truini, Mauro; Merlo, Domenico Franco

    2015-01-01

    Biomarkers can help to identify patients with early-stages or locally advanced non-small cell lung cancer (NSCLC) who have high risk of relapse and poor prognosis. To correlate the expression of seven biomarkers involved in DNA synthesis and repair and in cell division with clinical outcome, we consecutively collected 82 tumour tissues from radically resected NSCLC patients. The following biomarkers were investigated using IHC and qRT-PCR: excision repair cross-complementation group 1 (ERCC1), breast cancer 1 (BRCA1), ribonucleotide reductase subunits M1 and M2 (RRM1 and RRM2), subunit p53R2, thymidylate synthase (TS), and class III beta-tubulin (TUBB3). Gene expression levels were also validated in an available NSCLC microarray dataset. Multivariate analysis identified the protein overexpression of RRM2 and TS as independent prognostic factors of shorter overall survival (OS). Kaplan-Meier analysis showed a trend in shorter OS for patients with RRM2, TS, and ERCC1, BRCA1 overexpressed tumours. For all of the biomarkers except TUBB3, the OS trends relative to the gene expression levels were in agreement with those relative to the protein expression levels. The NSCLC microarray dataset showed RRM2 and TS as biomarkers significantly associated with OS. This study suggests that high expression levels of RRM2 and TS might be negative prognostic factors for resected NSCLC patients. PMID:26663950

  15. Insulin-like growth factor binding protein-1 inhibits cancer cell invasion and is associated with poor prognosis in hepatocellular carcinoma

    PubMed Central

    Dai, Bin; Ruan, Bai; Wu, Juan; Wang, Jianlin; Shang, Runze; Sun, Wei; Li, Xia; Dou, Kefeng; Wang, Desheng; Li, Yu

    2014-01-01

    Insulin-like growth factor binding protein-1 (IGFBP-1) plays an important role in the development and progression of cancer. However, the expression of IGFBP-1 remains equivocal, and little is known about its clinicopathological significance and prognostic value in hepatocellular carcinoma (HCC). In this study, we evaluated the expression of IGFBP-1 in 90 paired HCC tissues and adjacent non-cancerous liver tissues and analyzed its clinical and prognostic significance. The results showed that IGFBP-1 was detected in cytoplasm as well as cell nucleus, and down-regulated in HCC tissues compared to the adjacent non-cancerous liver tissues. The decreased expression of IGFBP-1 was correlated with tumor differentiation, liver cirrhosis, microvascular invasion or metastasis, TNM stage and poor survival. Moreover, low levels of IGFBP-1 may be an independent prognostic indicator for the survival of patients with HCC. We also evaluated its function by adding recombinant IGFBP-1 to the cultured HCC cell lines HepG2 and MHCC97-H. The result of the invasion chamber assay showed that IGFBP-1 could inhibit the invasion of HepG2 and MHCC97-H. MMP-9 secretion by these cells was significantly decreased when the cells were treated with IGFBP-1. Our results suggest that IGFBP-1 inhibits the invasion and metastasis of HCC cells and that IGFBP-1 may be useful as a valuable marker for the prognosis of patients with HCC. PMID:25337205

  16. Acquisition of Cytogenetic Abnormalities in Patients with IPSS defined Lower-Risk Myelodysplastic Syndrome Is Associated with Poor Prognosis and Transformation to Acute Myelogenous Leukemia

    PubMed Central

    Jabbour, Elias; Takahashi, Koichi; Wang, Xuemei; Cornelison, A Megan; Abruzzo, Lynne; Kadia, Tapan; Borthakur, Gautam; Estrov, Zeev; O’Brien, Susan; Mallo, Mar; Wierda, William; Pierce, Sherry; Wei, Yue; Sole, Francisco; Chen, Rui; Kantarjian, Hagop; Garcia-Manero, Guillermo

    2014-01-01

    We hypothesized that the dynamic acquisition of cytogenetic abnormalities (ACA) during the follow up of myelodysplastic syndromes (MDS) could be associated with poor prognosis. We conducted a retrospective analysis of 365 patients with IPSS low or intermediate-1 risk MDS who had at least two consecutive cytogenetic analyses during the follow up. Acquisition of cytogenetic abnormalities was detected in 107 patients (29%). The most frequent alteration involved chromosome 7 in 21% of ACA cases. Median transformation-free and overall survival for patients with and without ACA were 13 vs. 52 months (P =0.01) and 17 vs. 62 months (P =0.01), respectively. By fitting ACA as a time-dependent covariate, multivariate Cox regression analysis showed that patients with ACA had increased risk of transformation (HR=1.40; P = 0.03) or death (HR=1.45; P = 0.02). Notably, female patients with therapy-related MDS (t-MDS) had an increased risk of developing ACA (OR= 5.26; P<0.0001), although subgroup analysis showed that prognostic impact of ACA was not evident in t-MDS. In conclusion, ACA occurs in close to one third of patients with IPSS defined lower risk MDS, more common among patients with t-MDS, but has a significant prognostic impact on de novo MDS. PMID:23760779

  17. Acquisition of cytogenetic abnormalities in patients with IPSS defined lower-risk myelodysplastic syndrome is associated with poor prognosis and transformation to acute myelogenous leukemia.

    PubMed

    Jabbour, Elias; Takahashi, Koichi; Wang, Xuemei; Cornelison, A Megan; Abruzzo, Lynne; Kadia, Tapan; Borthakur, Gautam; Estrov, Zeev; O'Brien, Susan; Mallo, Mar; Wierda, William; Pierce, Sherry; Wei, Yue; Sole, Francisco; Chen, Rui; Kantarjian, Hagop; Garcia-Manero, Guillermo

    2013-10-01

    We hypothesized that the dynamic acquisition of cytogenetic abnormalities (ACA) during the follow up of myelodysplastic syndromes (MDS) could be associated with poor prognosis. We conducted a retrospective analysis of 365 patients with IPSS low or intermediate-1 risk MDS who had at least two consecutive cytogenetic analyses during the follow up. Acquisition of cytogenetic abnormalities was detected in 107 patients (29%). The most frequent alteration involved chromosome 7 in 21% of ACA cases. Median transformation-free and overall survival for patients with and without ACA were 13 vs. 52 months (P = 0.01) and 17 vs. 62 months (P = 0.01), respectively. By fitting ACA as a time-dependent covariate, multivariate Cox regression analysis showed that patients with ACA had increased risk of transformation (HR = 1.40; P = 0.03) or death (HR = 1.45; P = 0.02). Notably, female patients with therapy-related MDS (t-MDS) had an increased risk of developing ACA (OR = 5.26; P < 0.0001), although subgroup analysis showed that prognostic impact of ACA was not evident in t-MDS. In conclusion, ACA occurs in close to one third of patients with IPSS defined lower risk MDS, more common among patients with t-MDS, but has a significant prognostic impact on de novo MDS. PMID:23760779

  18. Elevated expression of IFN-inducible CXCR3 ligands predicts poor prognosis in patients with non-metastatic clear-cell renal cell carcinoma

    PubMed Central

    Liu, Weisi; Liu, Yidong; Fu, Qiang; Zhou, Lin; Chang, Yuan; Xu, Le; Zhang, Weijuan; Xu, Jiejie

    2016-01-01

    IFN-inducible CXCR3 ligands (ICL), namely CXCL9, CXCL10 and CXCL11, exhibit pleiotropic roles in orchestrating immunity and angiogenesis. However, the prognosis value of them in renal cell carcinoma (RCC) was still obscure. Thus, we retrospectively used immunohistochemistry approach to evaluate the impact of these ligands on recurrence and survival of non-metastatic clear cell RCC (ccRCC) patients after nephrectomy. We systemically built a prespecified ICL score based on these ligands, and found specimens with high ICL score were prone to possess high Fuhrman grade, necrosis, and high-risk level of SSIGN. Moreover, ICL score stratified patients into different risk subgroups, and remained an independent adverse prognosticator for overall survival (OS) and recurrence-free survival (RFS). Meanwhile, in TCGA database, the increasing ICL mRNA predicted poor survival and early recurrence. Furthermore, after adding ICL score into SSIGN, the C-index for OS and RFS increased from 0.705 to 0.746 and 0.712 to 0.765, respectively. In conclusion, the ICL score based on expression of CXCL9, CXCL10 and CXCL11 stratified non-metastatic ccRCC patients into different risk subgroups of recurrence and death, which might benefit preoperative risk stratification and guide immune therapy in the future. PMID:26910919

  19. Up-regulated expression of scavenger receptor class B type 1 (SR-B1) is associated with malignant behaviors and poor prognosis of breast cancer.

    PubMed

    Li, Juan; Wang, Jing; Li, Ming; Yin, Linlin; Li, Xiang-An; Zhang, Ting-Guo

    2016-06-01

    Scavenger receptor class B type 1 (SR-B1) is an integral membrane protein that is expressed in numerous cells and tissue types. The primary role of SR-B1 is to facilitate uptake of cholesteryl esters from high-density lipoproteins (HDL) in the liver. Altered SR-B1 expression contributes to human diseases. This study assessed association of SR-B1 expression in breast tissue specimens with breast cancer development and prognosis. Tissue specimens from 30 cases of adjacent normal breast tissues, ductal carcinoma in situ (DCIS) and invasive ductal breast cancer (IDCA) were subjected to Western blot analysis, and 135 cases of DCIS and IDCA were used for quantitative immunohistochemical analysis of SR-B1 expression. The data showed that SR-B1 was significantly overexpressed in IDCA tissues compared to normal breast and DCIS tissues. SR-B1 expression was associated with pre-menopausal status, tumor size, and worse overall survival of patients. The data from this ex vivo study suggests that up-regulated SR-B1 protein expression is associated with malignant behaviors of breast cancer and that SR-B1 is an independent predictor for poor survival in breast cancer patients. PMID:27067809

  20. High tumor-associated macrophages infiltration is associated with poor prognosis and may contribute to the phenomenon of epithelial–mesenchymal transition in gastric cancer

    PubMed Central

    Yan, Yan; Zhang, Jia; Li, Jun-Hai; Liu, Xu; Wang, Ji-Zhao; Qu, Hang-Ying; Wang, Jian-Sheng; Duan, Xiao-Yi

    2016-01-01

    Background Recent studies show that epithelial–mesenchymal transition (EMT) and tumor-associated macrophages (TAMs) contribute to the progression and poor prognosis of carcinoma through multiple mechanisms. Both inflammation and changing of epithelium have a close relationship with tumorigenesis of gastric cancer. However, the relevance between EMT and TAMs is still unclear in gastric cancer and needs more scientific research. This study is designed to explore the relationship between EMT and TAMs in gastric cancer. Materials and methods Immunohistochemistry was used to detect the expression of EMT-related proteins and TAM markers in cancer tissues and normal gastric tissues. Results High levels of EMT and TAMs infiltration are related to aggressive features and independent prognostic factors in gastric cancer, respectively. In addition, expression of the two indicators is associated with expression of transforming growth factor-β1 (TGF-β1). Infiltration of TAMs is also associated with EMT-related marker in gastric cancer. Conclusion Our results suggest that high levels of EMT and TAMs infiltration are related to aggressive features and independent prognostic factors in gastric cancer, respectively. A correlation was found between EMT- and TAM-related indicators, which may be associated with TGF-β signaling pathway. The level of TAMs infiltration plays an important role in gastric cancer, the markers of which can be used as prognostic indicators. PMID:27418840

  1. Ofatumumab in poor-prognosis chronic lymphocytic leukemia: a Phase IV, non-interventional, observational study from the European Research Initiative on Chronic Lymphocytic Leukemia

    PubMed Central

    Moreno, Carol; Montillo, Marco; Panayiotidis, Panayiotis; Dimou, Maria; Bloor, Adrian; Dupuis, Jehan; Schuh, Anna; Norin, Stefan; Geisler, Christian; Hillmen, Peter; Doubek, Michael; Trněný, Marek; Obrtlikova, Petra; Laurenti, Luca; Stilgenbauer, Stephan; Smolej, Lukas; Ghia, Paolo; Cymbalista, Florence; Jaeger, Ulrich; Stamatopoulos, Kostas; Stavroyianni, Niki; Carrington, Patrick; Zouabi, Hamadi; Leblond, Veronique; Gomez-Garcia, Juan C.; Rubio, Martin; Marasca, Roberto; Musuraca, Gerardo; Rigacci, Luigi; Farina, Lucia; Paolini, Rossella; Pospisilova, Sarka; Kimby, Eva; Bradley, Colm; Montserrat, Emili

    2015-01-01

    We report the largest retrospective, phase IV non-interventional, observational study of ofatumumab therapy in heavily pre-treated patients with poor-prognosis chronic lymphocytic leukemia. Total number of patients was 103; median age was 65 years (range 39–85). Median number of prior lines of therapy was 4 (range 1–13), including, in most cases, rituximab-, fludarabine- and alemtuzumab-based regimens; 13 patients had been allografted. Of 113 adverse events, 28 (29%) were considered to be directly related to ofatumumab. Grade 3–4 toxicities included neutropenia (10%), thrombocytopenia (5%), anemia (3%), pneumonia (17%), and fever (3%). Two heavily pre-treated patients developed progressive multifocal leukoencephalopathy. On an intention-to-treat analysis, the overall response rate was 22% (3 complete response, 1 incomplete complete response). Median progression-free and overall survival times were 5 and 11 months, respectively. This study confirms in a daily-life setting the feasibility and acceptable toxicity of ofatumumab treatment in advanced chronic lymphocytic leukemia. The complete response rate, however, was low. Therefore, treatment with ofatumumab should be moved to earlier phases of the disease. Ideally, this should be done in combination with other agents, as recently approved for ofatumumab plus chlorambucil as front-line treatment for patients unfit for fludarabine. This study is registered at clinicaltrials.gov identifier:01453062. PMID:25596264

  2. AngioMatrix, a signature of the tumor angiogenic switch-specific matrisome, correlates with poor prognosis for glioma and colorectal cancer patients

    PubMed Central

    Rupp, Tristan; Arnold, Christiane; van der Heyden, Michaël; Orend, Gertraud; Hussenet, Thomas

    2014-01-01

    Angiogenesis represents a rate-limiting step during tumor progression. Targeting angiogenesis is already applied in cancer treatment, yet limits of anti-angiogenic therapies have emerged, notably because tumors adapt and recur after treatment. Therefore, there is a strong need to better understand the molecular and cellular mechanisms underlying tumor angiogenesis. Using the RIP1-Tag2 transgenic murine model, we identified 298 genes that are deregulated during the angiogenic switch, revealing an ingression/expansion of specific stromal cell types including endothelial cells and pericytes, but also macrophages and perivascular mesenchymal cells. Canonical TGF-β signaling is up-regulated during the angiogenic switch, especially in tumor-associated macrophages and fibroblasts. The matrisome, comprising extracellular matrix (ECM) and ECM-associated molecules, is significantly enriched, which allowed us to define the AngioMatrix signature as the 110 matrisomal genes induced during the RIP1-Tag2 angiogenic switch. Several AngioMatrix molecules were validated at expression level. Ablation of tenascin-C, one of the most highly induced ECM molecules during the switch, resulted in reduced angiogenesis confirming its important role. In human glioma and colorectal samples, the AngioMatrix signature correlates with the expression of endothelial cell markers, is increased with tumor progression and finally correlates with poor prognosis demonstrating its diagnostic and therapeutic potential. PMID:25301723

  3. Overexpression of USP39 predicts poor prognosis and promotes tumorigenesis of prostate cancer via promoting EGFR mRNA maturation and transcription elongation

    PubMed Central

    Li, Lin; Chen, Lu; Liu, Xi; Lu, Jian-Lei; Zhu, Xiao-Mei; Huang, Hai; Yang, Qi-Wei; Ye, Jian-Qing; Gan, Si-Shun; Wang, Lin-Hui; Hong, Yi; Xu, Dan-Feng; Cui, Xin-Gang

    2016-01-01

    Castration resistance is a serious problem facing clinical treatment of prostate cancer (PCa). The underlying molecular mechanisms of acquired proliferation ability of tumor cells upon androgen deprivation are largely undetermined. In the present study, we identified that ubiquitin specific peptidase 39 (USP39) was significantly upregulated in PCa samples and cell lines. Elevated USP39 expression was positively correlated with Gleason score, predicted a poor outcome, and functioned as an independent risk factor for biochemical recurrence (BCR) especially in patients with a Gleason score ≤7. Our cell-based study showed that the expression level of USP39 was the highest in AR-negative PCa cell lines. Knockdown of USP39 in PCa cells inhibited cancer colony formation and tumor cell growth, and induced G2/M arrest and cell apoptosis. Microarray analysis suggested that knockdown of USP39 caused a reduced expression of EGFR. Silencing of USP39 inhibited the expression of EGFR 3′-end, and presented a remarkable block to the maturation of EGFR mRNA, suggesting that silencing of USP39 decreased the transcriptional elongation and maturation of EGFR mRNA. Oncomine datasets analysis showed that USP39 expression was positively correlated with EGFR level. The above findings suggest that USP39 plays a vital oncogenic role in the tumorigenesis of PCa and may prove to be a potential biomarker for predicting the prognosis of PCa patients. PMID:26959883

  4. Down-regulation of human leukocyte antigen class I (HLA-I) is associated with poor prognosis in patients with clear cell renal cell carcinoma.

    PubMed

    Yuan, Jinyang; Liu, Sulai; Yu, Qiuxia; Lin, Yang; Bi, Yunke; Wang, Yi; An, Ruihua

    2013-06-01

    Human leukocyte antigen class I (HLA-I) molecules are transmembrane glycoproteins that have been reported to be down-regulated in multiple types of human malignancies, including clear cell renal cell carcinoma (CCRCC). However, only one study has investigated its prognostic value in CCRCC. In the present study, HLA-I protein expression was analyzed in 120 archived, paraffin-embedded CCRCC samples and 10 adjacent normal tissues using immunohistochemistry. The correlation between HLA-I expression and clinicopathological factors was evaluated by the χ(2) test. Patients' overall survival was analyzed by the Kaplan-Meier method. HLA-I down-regulation was observed in 38.3% (46/120) of renal tumor samples, but only in 10% (1/10) of adjacent normal tissues. Statistical analysis showed a significant correlation of HLA-I expression with TNM stage, lymph node metastasis, and Fuhrman grade. Patients with tumors displaying down-regulation of HLA-I showed significantly shorter overall survival (P=0.021, log-rank test). More importantly, multivariate analysis indicated that down-regulation of HLA-I was an independent prognostic factor for CCRCC patients (P=0.033). Overall, our data suggest that HLA-I down-regulation is associated with tumor progression and a poor prognosis in CCRCC patients, and emphasize the importance of HLA-I in natural and therapeutic immune surveillance of patients with CCRCC. PMID:23245688

  5. Elevated expression of IFN-inducible CXCR3 ligands predicts poor prognosis in patients with non-metastatic clear-cell renal cell carcinoma.

    PubMed

    Liu, Weisi; Liu, Yidong; Fu, Qiang; Zhou, Lin; Chang, Yuan; Xu, Le; Zhang, Weijuan; Xu, Jiejie

    2016-03-22

    IFN-inducible CXCR3 ligands (ICL), namely CXCL9, CXCL10 and CXCL11, exhibit pleiotropic roles in orchestrating immunity and angiogenesis. However, the prognosis value of them in renal cell carcinoma (RCC) was still obscure. Thus, we retrospectively used immunohistochemistry approach to evaluate the impact of these ligands on recurrence and survival of non-metastatic clear cell RCC (ccRCC) patients after nephrectomy. We systemically built a prespecified ICL score based on these ligands, and found specimens with high ICL score were prone to possess high Fuhrman grade, necrosis, and high-risk level of SSIGN. Moreover, ICL score stratified patients into different risk subgroups, and remained an independent adverse prognosticator for overall survival (OS) and recurrence-free survival (RFS). Meanwhile, in TCGA database, the increasing ICL mRNA predicted poor survival and early recurrence. Furthermore, after adding ICL score into SSIGN, the C-index for OS and RFS increased from 0.705 to 0.746 and 0.712 to 0.765, respectively. In conclusion, the ICL score based on expression of CXCL9, CXCL10 and CXCL11 stratified non-metastatic ccRCC patients into different risk subgroups of recurrence and death, which might benefit preoperative risk stratification and guide immune therapy in the future. PMID:26910919

  6. High Ki-67 Immunohistochemical Reactivity Correlates With Poor Prognosis in Bladder Carcinoma: A Comprehensive Meta-Analysis with 13,053 Patients Involved.

    PubMed

    Luo, Yihuan; Zhang, Xin; Mo, Meile; Tan, Zhong; Huang, Lanshan; Zhou, Hong; Wang, Chunqin; Wei, Fanglin; Qiu, Xiaohui; He, Rongquan; Chen, Gang

    2016-04-01

    Ki-67 is considered as one of prime biomarkers to reflect cell proliferation and immunohistochemical Ki-67 staining has been widely applied in clinical pathology. To solve the widespread controversy whether Ki-67 reactivity significantly predicts clinical prognosis of bladder carcinoma (BC), we performed a comprehensive meta-analysis by combining results from different literature.A comprehensive search was conducted in the Chinese databases of WanFang, China National Knowledge Infrastructure and Chinese VIP as well as English databases of PubMed, ISI web of science, EMBASE, Science Direct, and Wiley online library. Independent studies linking Ki-67 to cancer-specific survival (CSS), disease-free survival (DFS), overall survival (OS), progression-free survival (PFS), and recurrence-free survival (RFS) were included in our meta-analysis. With the cut-off values literature provided, hazard ratio (HR) values between the survival distributions were extracted and later combined with STATA 12.0.In total, 76 studies (n = 13,053 patients) were eligible for the meta-analysis. It was indicated in either univariate or multivariate analysis for survival that high Ki-67 reactivity significantly predicted poor prognosis. In the univariate analysis, the combined HR for CSS, DFS, OS, PFS, and RFS were 2.588 (95% confidence interval [CI]: 1.623-4.127, P < 0.001), 2.697 (95%CI: 1.874-3.883, P < 0.001), 2.649 (95%CI: 1.632-4.300, P < 0.001), 3.506 (95%CI: 2.231-5.508, P < 0.001), and 1.792 (95%CI: 1.409-2.279, P < 0.001), respectively. The pooled HR of multivariate analysis for CSS, DFS, OS, PFS, and RFS were 1.868 (95%CI: 1.343-2.597, P < 0.001), 2.626 (95%CI: 2.089-3.301, P < 0.001), 1.104 (95%CI: 1.008-1.209, P = 0.032), 1.518 (95%CI: 1.299-1.773, P < 0.001), and 1.294 (95%CI: 1.203-1.392, P < 0.001), respectively. Subgroup analysis of univariate analysis by origin showed that Ki-67 reactivity significantly correlated with all 5 clinical

  7. Anti-factor VIII IgA as a potential marker of poor prognosis in acquired hemophilia A: results from the GTH-AH 01/2010 study.

    PubMed

    Tiede, Andreas; Hofbauer, Christoph J; Werwitzke, Sonja; Knöbl, Paul; Gottstein, Saskia; Scharf, Rüdiger E; Heinz, Jürgen; Groß, Jürgen; Holstein, Katharina; Dobbelstein, Christiane; Scheiflinger, Fritz; Koch, Armin; Reipert, Birgit M

    2016-05-12

    Neutralizing autoantibodies against factor VIII (FVIII), also called FVIII inhibitors, are the cause of acquired hemophilia A (AHA). They are quantified in the Bethesda assay or Nijmegen-modified Bethesda assay by their ability to neutralize FVIII in normal human plasma. However, FVIII inhibitors do not represent the whole spectrum of anti-FVIII autoantibodies. Here, we studied isotypes, immunoglobulin G subclasses, and apparent affinities of anti-FVIII autoantibodies to assess their prognostic value for the outcome in AHA. We analyzed baseline samples from patients enrolled in the prospective GTH-AH 01/2010 study. Our data suggest that anti-FVIII immunoglobulin A (IgA) autoantibodies are predictors of poor outcome in AHA. Anti-FVIII IgA-positive patients achieved partial remission similar to anti-FVIII IgA-negative patients but had a higher risk of subsequent recurrence. Consequently, IgA-positive patients achieved complete remission less frequently (adjusted hazard ratio [aHR], 0.35; 95% confidence interval [CI], 0.18-0.68; P < .01) and had a higher risk of death (aHR, 2.62; 95% CI, 1.11-6.22; P < .05). Anti-FVIII IgA was the strongest negative predictor of recurrence-free survival after achieving partial remission and remained significant after adjustment for baseline demographic and clinical characteristics. In conclusion, anti-FVIII IgA represents a potential novel biomarker that could be useful to predict prognosis and tailor immunosuppressive treatment of AHA. PMID:26912467

  8. HLA haploidentical peripheral blood stem cell transplantation using reduced dose of posttransplantation cyclophosphamide for poor-prognosis or refractory leukemia and myelodysplastic syndrome.

    PubMed

    Nakamae, Hirohisa; Koh, Hideo; Katayama, Takako; Nishimoto, Mitsutaka; Hayashi, Yoshiki; Nakashima, Yasuhiro; Nakane, Takahiko; Nakamae, Mika; Hirose, Asao; Hino, Masayuki

    2015-11-01

    Nonmyeloablative, human leukocyte antigen (HLA) haploidentical, T-cell-replete bone marrow transplantation followed by high-dose posttransplantation cyclophosphamide (PT/Cy) has recently been developed. This transplantation milieu has resulted in favorable outcomes with low transplantation-related mortality, owing to a low incidence of graft-versus-host disease (GVHD), without increased infectious complications. However, the high relapse rate remains a major concern. We therefore performed a prospective pilot study of HLA haploidentical peripheral blood stem cell transplantation (PBSCT) with intensified conditioning, followed by two lower doses of PT/Cy. A total of 20 patients with refractory or poor-prognosis myelodysplastic syndrome (MDS) and leukemia were enrolled in the study. A trend toward a lower incidence of grade III-IV acute GVHD at day 100 in the group receiving 25 mg/kg × 2 doses of PT/Cy, compared with the group receiving 25 mg/kg of PT/Cy (9.1% vs. 33%, p = 0.20), was noted. However, the cumulative incidence of chronic GVHD was low, at 10% irrespective of PT/Cy dose. The number of infused CD34(+) cells significantly correlated with the grade of acute GVHD (p = 0.004). In addition, the occurrence of BK virus hemorrhagic cystitis was significantly more common in the double-dose PT/Cy group (25% vs. 0%, p = 0.043), especially when combined with busulfan. The probability of overall survival at 1 year in the double-dose group tended to be better compared with that in the single-dose group (64% vs. 44%, respectively; p = 0.20). In conclusion, HLA haploidentical, T-cell-replete PBSCT with 25 mg/kg × 2 doses of PT/Cy might be a feasible option for treating high-risk leukemia and MDS. PMID:26284307

  9. Surgical outcomes with 360-degree suture trabeculotomy in poor prognosis primary congenital glaucoma and glaucoma associated with congenital anomalies or cataract surgery

    PubMed Central

    Beck, Allen D.; Lynn, Michael J.; Crandall, James; Mobin-Uddin, Omar

    2011-01-01

    Purpose To evaluate the outcomes of 360-degree suture trabeculotomy in childhood glaucoma with poor prognosis. Subjects and Methods A nonrandomized, retrospective chart review was performed on pediatric patients (under 18 years old) treated with a 360-degree suture trabeculotomy for glaucoma. The cases were categorized into the following groups: (1) primary congenital glaucoma with birth-onset presentation accompanied by corneal clouding noted at birth, (2) primary congenital glaucoma with onset or presentation after 1 year of age, (3) primary congenital glaucoma with prior failed goniotomy surgery, (4) infantile-onset glaucoma following congenital cataract surgery, and (5) infantile-onset glaucoma with associated ocular/systemic anomalies. Results A total of 45 eyes of 33 patients were analyzed. The mean preoperative intraocular pressure (IOP) was 34.3 ± 6.7 mm Hg on an average of 1.5 medications. Median age at time of surgery was 7 months. Mean final IOP (median last follow-up or failure, 12 months) was 22.2 ± 7.1 mm Hg on an average of 1.5 medications. The probability of success according to time after surgery was 87% at 6 months, 63% at 1 year, and 58% at 2 years. Kaplan-Meier analysis of Groups 1-4 versus Group 5 failed to demonstrate a statistically significant difference (p = 0.13). Of 5 eyes with port wine mark–related glaucoma, 2 had a large (>50%), persistent postoperative hyphema and concurrent vitreous hemorrhage. Conclusions Children with a wide range of ocular pathologies can be successfully treated with 360-degree suture trabeculotomy. Further evaluation of this surgical technique in primary congenital glaucoma and open-angle glaucoma following congenital cataract surgery is warranted. PMID:21397807

  10. High levels of Hsp90 co-chaperone p23 promotes tumor progression and poor prognosis in breast cancer by increasing lymph node metastases and drug resistance

    PubMed Central

    Simpson, Natalie E.; Lambert, W. Marcus; Watkins, Renecia; Giashuddin, Shah; Huang, S. Joseph; Oxelmark, Ellinor; Arju, Rezina; Hochman, Tsivia; Goldberg, Judith D.; Schneider, Robert J.; Reiz, Luiz Fernando Lima; Soares, Fernando Augusto; Logan, Susan K.; Garabedian, Michael J.

    2010-01-01

    p23 is an Hsp90 co-chaperone located in both the cytoplasm and nucleus that stabilizes unliganded steroid receptors, controls catalytic activity of certain kinases, regulates protein-DNA dynamics and is upregulated in several cancers. We previously demonstrated that p23-overexpressing MCF-7 cells (MCF-7+p23) exhibit increased invasion without affecting the estrogen-dependent proliferative response, which suggests that p23 differentially regulates genes controlling processes linked to breast tumor metastasis. To gain a comprehensive view of the effects of p23 on estrogen receptor (ER)-dependent and -independent gene expression, we profiled mRNA expression from control versus MCF-7+p23 cells in the absence and presence of estrogen. A number of p23-sensitive target genes involved in metastasis and drug resistance were identified. Most striking is that many of these genes are also misregulated in invasive breast cancers, including PMP22, ABCC3, AGR2, Sox3, TM4SF1, and p8 (NUPR1). Upregulation of the ATP-dependent transporter ABCC3 by p23 conferred resistance to the chemotherapeutic agents etoposide and doxorubicin in MCF-7+p23 cells. MCF-7+p23 cells also displayed higher levels of activated Akt and an expanded phosphoproteome relative to control cells, suggesting that elevated p23 also enhances cytoplasmic signaling pathways. For breast cancer patients, tumor stage together with high cytoplasmic p23 expression more accurately predicted disease recurrence and mortality than stage alone. High nuclear p23 was found to be associated with high cytoplasmic p23, therefore both may promote tumor progression and poor prognosis by increasing metastatic potential and drug resistance in breast cancer patients. PMID:20847343

  11. A Phase I Trial of Vorinostat and Alvocidib in Patients with Relapsed, Refractory or Poor Prognosis Acute Leukemia, or Refractory Anemia with Excess Blasts-2

    PubMed Central

    Holkova, Beata; Supko, Jeffrey G.; Ames, Matthew M.; Reid, Joel M.; Shapiro, Geoffrey I.; Tombes, Mary Beth; Honeycutt, Connie; McGovern, Renee M.; Kmieciak, Maciej; Shrader, Ellen; Wellons, Martha D.; Sankala, Heidi; Roberts, John D.; Grant, Steven

    2013-01-01

    Purpose This phase I study was conducted to identify the MTD of alvocidib when combined vorinostat in patients with relapsed, refractory, or poor prognosis acute leukemia, or refractory anemia with excess blasts-2 (RAEB-2). Secondary objectives included investigating the pharmacokinetic and pharmacodynamic effects of the combination. Experimental Design Patients received vorinostat (200 mg orally, 3 times a day [TID], for 14 days), on a 21-day cycle, combined with 2 different alvocidib administration schedules: a 1-h intravenous infusion, daily x 5; or a 30-min loading infusion followed by a 4-h maintenance infusion, weekly x 2. The alvocidib dose was escalated using a standard 3+3 design. Results Twenty-eight patients were enrolled and treated. The alvocidib MTD was 20 mg/m2 (30-min loading infusion) followed by 20 mg/m2 (4-h maintenance infusion) on days 1 and 8, in combination with vorinostat. The most frequently encountered toxicities were cytopenias, fatigue, hyperglycemia, hypokalemia, hypophosphatemia, and QT prolongation. Dose limiting toxicities (DLTs) were cardiac arrhythmia-atrial fibrillation and QT prolongation. No objective responses were achieved, although 13 of 26 evaluable patients exhibited stable disease. Alvocidib appeared to alter vorinostat pharmacokinetics, whereas alvocidib pharmacokinetics were unaffected by vorinostat. Ex vivo exposure of leukemia cells to plasma obtained from patients after alvocidib treatment blocked vorinostat-mediated p21CIP1 induction and down-regulated Mcl-1 and p-RNA Pol II for some specimens, although parallel in vivo bone marrow responses were infrequent. Conclusions Alvocidib combined with vorinostat is well tolerated. Although disease stabilization occurred in some heavily pretreated patients, objective responses were not obtained with these schedules. PMID:23515411

  12. Elevated levels of urinary prostaglandin e metabolite indicate a poor prognosis in ever smoker head and neck squamous cell carcinoma patients.

    PubMed

    Kekatpure, Vikram D; Boyle, Jay O; Zhou, Xi Kathy; Duffield-Lillico, Anna J; Gross, Neil D; Lee, Nancy Y; Subbaramaiah, Kotha; Morrow, Jason D; Milne, Ginger; Lippman, Scott M; Dannenberg, Andrew J

    2009-11-01

    Cyclooxygenase (COX)-derived prostaglandin E(2) (PGE(2)) plays a role in the development and progression of several tumor types including head and neck squamous cell carcinoma (HNSCC). Measurements of urinary PGE metabolite (PGE-M) can be used as an index of systemic PGE(2) production. In ever smokers, increased levels of urinary PGE-M reflect increased COX-2 activity. In this study, we determined whether baseline levels of urinary PGE-M were prognostic for ever smoker HNSCC patients. A retrospective chart review of ever smoker HNSCC patients treated with curative intent was done. Fifteen of 31 evaluable patients developed progressive disease (recurrence or a second primary tumor) after a median follow-up of 38 months. There were no statistically significant differences between patients with (n = 15) or without disease progression (n = 16) with regard to stage, site, treatment received, smoking status, and aspirin use during follow-up. Median urinary PGE-M levels were significantly higher in HNSCC patients with disease progression (21.7 ng/mg creatinine) compared with patients without (13.35 ng/mg creatinine; P = 0.03). Importantly, patients with high baseline levels of urinary PGE-M had a significantly greater risk of disease progression (hazard ratio, 4.76, 95% CI, 1.31-17.30; P < 0.01) and death (hazard ratio, 9.54; 95% CI, 1.17-77.7; P = 0.01) than patients with low baseline levels of urinary PGE-M. These differences were most evident among patients with early-stage disease. Taken together, our findings suggest that high baseline levels of urinary PGE-M indicate a poor prognosis in HNSCC patients. Possibly, HNSCC patients with high COX-2 activity manifested by elevated urinary PGE-M will benefit from treatment with a COX-2 inhibitor. PMID:19843689

  13. Upregulation of the long non-coding RNA BANCR correlates with tumor progression and poor prognosis in esophageal squamous cell carcinoma.

    PubMed

    Liu, Zihao; Yang, Tongxin; Xu, Zhipeng; Cao, Xiufeng

    2016-08-01

    Esophageal squamous cell cancer was one of the most lethal tumors. The lack of effective early diagnosis and treatment ways brings its mortality quite high. Esophageal squamous dysplasia (ESD), is the only histopathology that predicts the development of ESCC. Recent evidence indicates that long noncoding RNAs (lncRNAs) play a critical role in the tumor progression and poor prognosis. BRAF activated non-coding RNA (BANCR) is a 693-bp transcript with a potential functional role in melanoma cell migration. The clinical significance of BANCR, and its' relationship with precancerous lesion of ESCC are unclear. Expression of BANCR was analyzed in 142 ESCC tissues and eight ESCC cell lines using quantitative polymerase chain reaction (qPCR) assays. We further analyzed the BANCR expression level in plasma and precancerous lesion of ESCC. In our results, BANCR levels in plasma were significantly higher in ESCC patients than in normal controls and correlated well with the presence of tumor status. Besides, BANCR expression increased significantly from low to high-grade intraepithelial neoplasia. Additionally, increased BANCR expression was associated with worse histologic grade, advanced TNM stage, more lymph node metastasis, and shorter survival of ESCC patients. The expression level of BANCR reverts to normal after the tumor has been resected, and the expression level of BANCR increased with the disease progression. Increased BANCR expression was found to be an independent prognostic factor for ESCC. In summary, BANCR may be a novel tumor biomarker for early detection, a prospective prognostic indicator and a potential therapeutic target for ESCC and ESD patients. PMID:27470379

  14. A novel long non-coding RNA FOXCUT and mRNA FOXC1 pair promote progression and predict poor prognosis in esophageal squamous cell carcinoma.

    PubMed

    Pan, Fei; Yao, Jie; Chen, Yang; Zhou, Changxi; Geng, Peiliang; Mao, Hui; Fang, Xiangqun

    2014-01-01

    Accumulating evidences demonstrated that many long non-coding RNAs (lncRNAs) can cooperate with the adjacent coding genes, forming into "lncRNA-mRNA gene pairs" in multiple biological cellular processes. Here, we showed that a novel long non-coding RNA FOXCUT (FOXC1 promoter upstream transcript) and its neighboring gene FOXC1 played a similar important role in the oncogenesis and progression of esophageal squamous cell carcinoma (ESCC). In this study, the expression of FOXCUT/FOXC1 was measured in 82 ESCC tissues and adjacent noncancerous tissues by real-time quantitative PCR (qPCR). The prognostic significance of the lncRNA-mRNA gene pair was evaluated using Kaplan-Meier survival analysis and log-rank test. Cell biological experiments were performed in ESCC cell lines to explore their functions in tumor progression. Notably elevated FOXCUT and FOXC1 expression levels were observed in cancerous tissues compared to adjacent noncancerous tissues (86.6% and 84.1%, respectively; P < 0.01), showing strong correlations with poor differentiation, advanced lymph node classification and metastasis (P < 0.05). Moreover, patients with upregulated FOXCUT or FOXC1 experienced a significantly worse prognosis than those with downregulated FOXCUT or FOXC1 (P < 0.001 and P = 0.014, respectively). In addition, the expression of FOXCUT was positively correlated with expression of FOXC1 in ESCC specimens. And the expression of FOXC1 was also decreased as the FOXCUT expression was silenced by siRNA. Assays in vitro demonstrated that knockdown of either FOXCUT or FOXC1 remarkably inhibited cell proliferation, colony formation, migration, invasion in ESCC cells. In conclusion, FOXCUT may be functionally involved in the tumor progression and survival of ESCC patients, at least in part, by modulating FOXC1. FOXCUT and FOXC1 may function as a lncRNA-mRNA gene pair, which may represent a potential prognostic biomarker and therapeutic target for ESCC patients. PMID:25031703

  15. Lower expression of PH domain leucine-rich repeat protein phosphatase 1 (PHLPP1) association with poor prognosis of gastric cancer

    PubMed Central

    Hou, Yachao; Deng, Jingyu; Zhang, Li; Xie, Xingming; Guo, Xiaofan; Sun, Changyu; Zhang, Rupeng; Liang, Han

    2015-01-01

    Background: The aim of this study was to investigate the expression of PH domain leucine-rich repeat protein phosphatase 1 (PHLPP1) in gastric cancer (GC), and its potential influence on the prognosis of GC patients. Methods: At present study, we examined the immunohistochemical expression of PHLPP1 on tissue microarrays (TMAs) containing 135 gastric adenocarcinoma tissues and 135 matched adjacent non-tumor tissues. In addition, both semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) and western blotting analysis (WB) were adopted to detect of the expression of PHLPP1 in the GC cell lines (AGS, SUN-1, KATO-III, BGC-823, MGC-803, SGC-7901, and HGC-27) and the normal gastric cell line GES-1. Survival analysis was used to investigate the efficiency of the prognostic evaluation of PHLPP1 expression in GC patients. Results: Positive expression rate of PHLPP1 in the primary GC tissues was significantly lower than that in adjacent non-tumor tissues (55.6% vs. 87.4%, P<0.001). Both gene transcription (mRNA) and Protein expression of PHLPP1 in the GC cell lines were significantly lower than those in the GES-1 cell line, respectively. The Kaplan-Meier analysis showed that patients presented PHLPP1 negative expression in the GC tissues had significantly lower overall survival rate than those presented PHLPP1 positive expression in the GC tissues (P=0.008). With the multivariate survival analysis (Cox regression), PHLPP1 expression in the GC tissue was identified as an independent predictor of the survival of patients. Conclusions: This study indicated that aberrant PHLPP1 expression was observed in GC tissues, which was significantly associated with the poor prognostic outcomes of GC patients. PMID:26884964

  16. High expression of vacuolar protein sorting 4B (VPS4B) is associated with accelerated cell proliferation and poor prognosis in human hepatocellular carcinoma.

    PubMed

    Jiang, Dawei; Hu, Baoying; Wei, Lixian; Xiong, Yicheng; Wang, Gang; Ni, Tingting; Zong, Chunyan; Ni, Runzhou; Lu, Cuihua

    2015-03-01

    Vacuolar protein sorting 4B (VPS4B) is a member of ATPase family proteins that have been shown to play important roles in the formation of MVBs, virus budding and abscission of cytokinesis. In this study, we investigated the prognostic role of VPS4B in human hepatocellular carcinoma (HCC) and its effect on the growth of HCC cells. Western blot and immunohistochemistrical analyses revealed that VPS4B was significantly upregulated in 98 HCC tissues, compared with adjacent nontumorous samples. Meanwhile, clinicopathological variables and univariate and multivariate survival analyses showed that high VPS4B expression was correlated with multiple clinicopathological factors, including AJCC stage, microvascular invasion, Ki-67 and a poor prognosis. More importantly, univariate and multivariate survival analyses demonstrated that VPS4B served as an independent prognostic factor for survival in HCC patients. Furthermore, we found that VPS4B was lowly expressed in serum-starved Huh7 and HepG2 HCC cells, and was progressively increased after serum-refeeding. To study whether VPS4B could regulate the proliferation of HCC cells, VPS4B was knocked down in both Huh7 and HepG2 cells through the transfection of VPS4B-siRNA oligos. Flow cytometry and CCK-8 assay results indicated that interference of VPS4B led to cell cycle arrest and reduced cell proliferation of HCC cells. Taken together, our results implied that VPS4B could be a candidate prognostic biomarker as well as a potential therapeutical target of HCC. PMID:25547899

  17. Low expression lncRNA RPLP0P2 is associated with poor prognosis and decreased cell proliferation and adhesion ability in lung adenocarcinoma.

    PubMed

    Chen, Jie; Hu, Lijuan; Chen, Jian; Wu, Fang; Hu, Dongwei; Xu, Gang; Zhu, Peiwu; Wang, Yumin

    2016-09-01

    We investigated the clinical roles and biological function of long non-coding (lncRNA) RPLP0P2 in lung adenocarcinoma (LAD). The expression level of RPLP0P2 was estimated by quantitative reverse transcription-polymerase chain reaction (qPCR) in 57 pairs of LAD and NT samples and the relation of RPLP0P2 to clinical data of LAD patients was analyzed. We overexpressed RPLP0P2 based on the human LAD cell line A549 by lentivirus‑mediated technology, then oncological behavior change was observed of A549 cells and the change of mRNA level of LRRC10B and RPLP0P2 by qPCR. We found that RPLP0P2 expression was lower while LRRC10B mRNA level was higher in LAD than NT by qPCR. RPLP0P2 expression level was negative correlated to LRRC10B mRNA level (Pearson correlation =‑0.754, P=0.0021). The expression of RPLP0P2 in lymph node metastasis of LAD group was significantly lower than LAD without lymph node metastasis group. Survival analysis showed that survival time of high expression of RPLP0P2 was significantly longer than low RPLP0P2 level in LAD patients. After RPLP0P2 was overexpressed, the proliferation rate, adhesion ability, S phase and G2/M phase cells and LRRC10B mRNA significantly reduced, while apoptosis and G0/G1 phase cells obviously increased, but migration ability and invasion did not significantly change. Our study ascertained that low expression of RPLP0P2 in LAD is associated with poor prognosis and decreased proliferation and adhesion ability of tumor cells. LRRC10B may be a downstream gene regulated by RPLP0P2. PMID:27460542

  18. Gallotannin-rich Caesalpinia spinosa fraction decreases the primary tumor and factors associated with poor prognosis in a murine breast cancer model

    PubMed Central

    2013-01-01

    Background Several treatment alternatives are available for primary breast cancer, although those for metastatic disease or inflammation associated with tumor progression are ineffective. Therefore, there is a great need for new therapeutic alternatives capable of generating an immune response against residual tumor cells, thus contributing to eradication of micrometastases and cancer stem cells. The use of complex natural products is an excellent therapeutic alternative widely used by Chinese, Hindu, Egyptian, and ancestral Latin-American Indian populations. Methods The present study evaluated cytotoxic, antitumor, and tumor progression activities of a gallotannin-rich fraction derived from Caesalpinia spinosa (P2Et). The parameters evaluated in vitro were mitochondrial membrane depolarization, phosphatidylserine externalization, caspase 3 activation, DNA fragmentation, and clonogenic activity. The parameters evaluated in vivo were tumor growth, leukocyte number, metastatic cell number, and cytokine production by flow cytometry. Results The in vitro results showed that the P2Et fraction induced apoptosis with mitochondrial membrane potential loss, phosphatidylserine externalization, caspase 3 activation, DNA fragmentation, and decreased clonogenic capacity of 4T1 cells. In vivo, the P2Et fraction induced primary tumor reduction in terms of diameter and weight in BALB/c mice transplanted with 4T1 cells and decreased numbers of metastatic cells, mainly in the spleen. Furthermore, decreases in the number of peripheral blood leukocytes (leukemoid reaction) and interleukin 6 (IL-6) serum levels were found, which are events associated with a poor prognosis. The P2Et fraction exerts its activity on the primary tumor, reduces cell migration to distant organs, and decreases IL-6 serum levels, implying tumor microenvironment mechanisms. Conclusions Overall, the P2Et fraction lessens risk factors associated with tumor progression and diminishes primary tumor size, showing

  19. SPOCK1 Is a Novel Transforming Growth Factor-β-Induced Myoepithelial Marker That Enhances Invasion and Correlates with Poor Prognosis in Breast Cancer.

    PubMed

    Fan, Li-Ching; Jeng, Yung-Ming; Lu, Yueh-Tong; Lien, Huang-Chun

    2016-01-01

    In addition to contraction, myoepithelia have diverse paracrine effects, including a tumor suppression effect. However, certain myoepithelial markers have been shown to contribute to tumor progression. Transforming growth factor-β (TGF-β) is involved in the transdifferentiation of fibroblasts to contractile myofibroblasts. We investigated whether TGF-β can upregulate potential myoepithelial markers, which may have functional and clinicopathological significance in breast cancer. We found that TGF-β induced SPOCK1 expression in MCF10A, MCF12A, and M10 breast cells and demonstrated SPOCK1 as a novel myoepithelial marker that was immunolocalized within or beneath myoepithelia lining ductolobular units. A functional study showed that overexpression of SPOCK1 enhanced invasiveness in mammary immortalized and cancer cells. To further determine the biological significance of SPOCK1 in breast cancer, we investigated the expression of SPOCK1 in 478 invasive ductal carcinoma (IDC) cases through immunohistochemistry and correlated the expression with clinicopathological characteristics. SPOCK1 expression was significantly correlated with high pathological tumor size (P = 0.012), high histological grade (P = 0.013), the triple-negative phenotype (P = 0.022), and the basal-like phenotype (P = 0.026) and was correlated with a significantly poorer overall survival on univariate analysis (P = 0.001, log-rank test). Multivariate Cox regression analysis demonstrated that SPOCK1 expression maintained an independent poor prognostic factor of overall survival. Analysis of SPOCK1 expression on various non-IDC carcinoma subtypes showed an enrichment of SPOCK1 expression in metaplastic carcinoma, which is pathogenetically closely related to epithelial-mesenchymal transition (EMT). In conclusion, we identified SPOCK1 as a novel TGF-β-induced myoepithelial marker and further demonstrated that SPOCK1 enhanced invasion in breast cancer cells and correlated with poor prognosis in breast

  20. Ribosomal Proteins RPS11 and RPS20, Two Stress-Response Markers of Glioblastoma Stem Cells, Are Novel Predictors of Poor Prognosis in Glioblastoma Patients

    PubMed Central

    Yang, Shuai; Tso, Jonathan L.; Menjivar, Jimmy C.; Wei, Bowen; Lucey, Gregory M.; Mareninov, Sergey; Chen, Zugen; Liau, Linda M.; Lai, Albert; Nelson, Stanley F.; Cloughesy, Timothy F.; Tso, Cho-Lea

    2015-01-01

    suggests that TRGC are clinically relevant cells that represent resistant tumorigenic clones from patient tumors and that their properties, at least in part, are reflected in poor-prognosis GBM. The screening of TRGC signatures may represent a novel alternative strategy for identifying new prognostic biomarkers. PMID:26506620

  1. Phosphorylated Mnk1 and eIF4E are associated with lymph node metastasis and poor prognosis of nasopharyngeal carcinoma.

    PubMed

    Zheng, Jun; Li, Jiao; Xu, Lina; Xie, Guiyuan; Wen, Qiuyuan; Luo, Jiadi; Li, Duo; Huang, Donghai; Fan, Songqing

    2014-01-01

    Nasopharyngeal carcinoma (NPC) is a head and neck malignant tumor rare throughout most of the world but common in Southeast Asia, especially in Southern China. The phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) by MAP kinase-interacting kinases (Mnk) on Ser-209 promotes cellular proliferation, survival, malignant transformation and metastasis. However, whether the alterations of the expression of p-eIF4E and p-Mnk1 protein are associated with clinicopathologic/prognostic implication for NPC has not been reported. The purposes of the present study are to examine the expression of p-eIF4E and p-Mnk1 protein in NPC and non-cancerous nasopharyngeal epithelial tissues by immunohistochemistry and evaluate the association between the expression of p-eIF4E and p-Mnk1 protein and clinicopathological characteristics of NPC. The results showed that the positive percentage of p-Mnk1 and p-eIF4E proteins expression in NPC (83.5% and 75.4%, respectively) was significantly higher than that in non-cancerous nasopharyngeal epithelium (40.0% and 32.9%, respectively). The positive expression of p-eIF4E and p-Mnk1 in the NPC with cervical lymph node metastasis was significantly higher than those without lymph node metastasis. Additionally, p-eIF4E expression was more pronouncedly increased in metastatic NPC than the matched primary NPC. Increase of p-eIF4E and p-Mnk1 expression was significantly correlated inversely with overall survival. Spearman's rank correlation test further showed that expression of p-Mnk1 was strongly positive correlated with expression of p-eIF4E in NPC. The expression of p-Mnk1 and p-eIF4E in NPC was proved to be the independent prognostic factors regardless of lymph node metastasis, clinical stages and combination of radiotherapy and chemotherapy, histological type, age and gender by multivariate analysis. Taken together, high expression of p-Mnk1 and p-eIF4E might be novel valuable biomarkers to predict poor prognosis of NPC and

  2. CD146 expression is associated with a poor prognosis in human breast tumors and with enhanced motility in breast cancer cell lines

    PubMed Central

    Zabouo, Gwladys; Imbert, Anne-Marie; Jacquemier, Jocelyne; Finetti, Pascal; Moreau, Thomas; Esterni, Benjamin; Birnbaum, Daniel; Bertucci, François; Chabannon, Christian

    2009-01-01

    Introduction Metastasis is a complex process involving loss of adhesion, migration, invasion and proliferation of cancer cells. Cell adhesion molecules play a pivotal role in this phenomenon by regulating cell–cell and cell–matrix interactions. CD146 (MCAM) is associated with an advanced tumor stage in melanoma, prostate cancer and ovarian cancer. Studies of CD146 expression and function in breast cancer remain scarce except for a report concluding that CD146 could act as a tumor suppressor in breast carcinogenesis. Methods To resolve these apparent discrepancies in the role of CD146 in tumor cells, we looked at the association of CD146 expression with histoclinical features in human primary breast cancers using DNA and tissue microarrays. By flow cytometry, we characterized CD146 expression on different breast cancer cell lines. Using siRNA or shRNA technology, we studied functional consequences of CD146 downmodulation of MDA-MB-231 cells in migration assays. Wild-type, mock-transfected and downmodulated transfected cells were profiled using whole-genome DNA microarrays to identify genes whose expression was modified by CD146 downregulation. Results Microarray studies revealed the association of higher levels of CD146 with histoclinical features that belong to the basal cluster of human tumors. Expression of CD146 protein on epithelial cells was detected in a small subset of cancers with histoclinical features of basal tumors. CD146+ cell lines displayed a mesenchymal phenotype. Downmodulation of CD146 expression in the MDA-MB-231 cell line resulted in downmodulation of vimentin, as well as of a set of genes that include both genes associated with a poor prognosis in a variety of cancers and genes known to promote cell motility. In vitro functional assays revealed decreased migration abilities associated with decreased CD146 expression. Conclusions In addition to its expression in the vascular compartment, CD146 is expressed on a subset of epithelial cells in

  3. KRAS mutation is a weak, but valid predictor for poor prognosis and treatment outcomes in NSCLC: A meta-analysis of 41 studies

    PubMed Central

    Pan, Wei; Yang, Yan; Zhu, Hongcheng; Zhang, Youcheng; Zhou, Rongping; Sun, Xinchen

    2016-01-01

    Mutation of oncogene KRAS is common in non-small cell lung cancer (NSCLC), however, its clinical significance is still controversial. Independent studies evaluating its prognostic and predictive value usually drew inconsistent conclusions. Hence, We performed a meta-analysis with 41 relative publications, retrieved from multi-databases, to reconcile these controversial results and to give an overall impression of KRAS mutation in NSCLC. According to our findings, KRAS mutation was significantly associated with worse overall survival (OS) and disease-free survival (DFS) in early stage resected NSCLC (hazard ratio or HR=1.56 and 1.57, 95% CI 1.39-1.76 and 1.17-2.09 respectively), and with inferior outcomes of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) treatment and chemotherapy (relative risk or RR=0.21 and 0.66 for objective response rate or ORR, 95% CI 0.12-0.39 and 0.54-0.81 respectively; HR=1.46 and 1.30 for progression-free survival or PFS, 95%CI 1.23-1.74 and 1.14-1.50 respectively) in advanced NSCLC. When EGFR mutant patients were excluded, KRAS mutation was still significantly associated with worse OS and PFS of EGFR-TKIs (HR=1.40 and 1.35, 95 % CI 1.21-1.61 and 1.11-1.64). Although KRAS mutant patients presented worse DFS and PFS of chemotherapy (HR=1.33 and 1.11, 95% CI 0.97-1.84 and 0.95-1.30), and lower response rate to EGFR-TKIs or chemotherapy (RR=0.55 and 0.88, 95 % CI 0.27-1.11 and 0.76-1.02), statistical differences were not met. In conclusion, KRAS mutation is a weak, but valid predictor for poor prognosis and treatment outcomes in NSCLC. There's a need for developing target therapies for KRAS mutant lung cancer and other tumors. PMID:26840022

  4. Increased expression of the long noncoding RNA CRNDE-h indicates a poor prognosis in colorectal cancer, and is positively correlated with IRX5 mRNA expression

    PubMed Central

    Liu, Tong; Zhang, Xin; Yang, Yong-mei; Du, Lu-tao; Wang, Chuan-xin

    2016-01-01

    Background The long noncoding RNA (lncRNA) colorectal neoplasia differentially expressed – h (CRNDE-h) plays important roles in the early stages of human development and cancer progression. We investigated the expression and clinical significance of lncRNA CRNDE-h in colorectal cancer (CRC). Methods The expression level of lncRNA CRNDE-h was analyzed in 142 CRC tissues and 142 paired adjacent nontumorous tissues, along with 21 inflammatory bowel diseases, 69 hyperplastic polyp, and 73 colorectal adenoma samples, using quantitative real-time polymerase chain reaction. The association between lncRNA CRNDE-h, and Iroquois homeobox protein 5 (IRX5) mRNA was examined in the same 142 CRC tissues. Results We found that lncRNA CRNDE-h level was elevated in the CRC and adenoma groups compared with the other groups (all at P<0.001). In CRC, upregulation of lncRNA CRNDE-h was significantly correlated with large tumor size, positive regional lymph node metastasis, and distant metastasis (all at P<0.05). Area under the curve for lncRNA CRNDE-h showed diagnostic capability for distinguishing CRC from other groups. Patients with CRC with high lncRNA CRNDE-h expression level had poorer overall survival than those with low lncRNA CRNDE-h expression (log-rank test, P<0.001). Further, multivariable Cox regression analysis suggested that increased expression of lncRNA CRNDE-h was an independent prognostic indicator for CRC (hazard ratio [HR]=2.173; 95% confidence interval [CI], 1.282–3.684, P=0.004). Furthermore, lncRNA CRNDE-h expression was positively correlated with IRX5 mRNA in CRC tissues. Conclusions Our data offers convincing evidence for the first time that lncRNA CRNDE-h is associated with adverse clinical characteristics and poor prognosis, which suggests that it might play an important role in CRC development and progression and might have clinical potential as a useful prognostic predictor. PMID:27042112

  5. SAP domain-dependent Mkl1 signaling stimulates proliferation and cell migration by induction of a distinct gene set indicative of poor prognosis in breast cancer patients

    PubMed Central

    2014-01-01

    -proliferative poor-outcome classes in human breast cancer and a strongly reduced survival rate for patients independent of tumor grade. Conclusions This study highlights a crucial role for the transcriptional regulator Mkl1 and its SAP domain during breast cancer progression. We identified a novel gene set that correlates with bad prognosis and thus may help in deciding the rigor of therapy. PMID:24495796

  6. Upregulation of the Non-Coding RNA OTUB1-isoform 2 Contributes to Gastric Cancer Cell Proliferation and Invasion and Predicts Poor Gastric Cancer Prognosis

    PubMed Central

    Wang, Yi-qin; Zhang, Qiong-yan; Weng, Wei-wei; Wu, Yong; Yang, Yu-si; Shen, Chen; Chen, Xiao-Chen; Wang, Lei; Liu, Kai-jing; Xu, Mi-die; Sheng, Wei-qi

    2016-01-01

    that OTUB1-isoform 2 independently predicts poor prognosis and promotes tumor progression in gastric cancer. The non-coding RNA OTUB1-isoform 2 should be targeted in future molecular therapies. PMID:27019636

  7. Aberrant expression of microRNA-99a and its target gene mTOR associated with malignant progression and poor prognosis in patients with osteosarcoma

    PubMed Central

    Zhao, Jiali; Chen, Fengli; Zhou, Quan; Pan, Wei; Wang, Xinhong; Xu, Jin; Ni, Li; Yang, Huilin

    2016-01-01

    Background The mammalian target of rapamycin (mTOR) has been reported to act as a target gene of microRNA (miR)-99a in various cancer cells and identified as an independent prognostic marker of human osteosarcoma. The aim of this study was to investigate the clinical significance of miR-99a/mTOR axis in human osteosarcoma. Methods A total of 130 pairs of osteosarcoma and matched noncancerous bone tissues were used to detect the expression levels of miR-99a and mTOR mRNA by quantitative real-time polymerase chain reaction. Then, associations of miR-99a and/or mTOR expression with clinico-pathological features and prognosis of patients with osteosarcoma were statistically analyzed. Results The expression levels of miR-99a (tumor vs normal: 2.11±1.03 vs 4.69±1.21, P<0.001) and mTOR mRNA (tumor vs normal: 4.40±1.13 vs 1.74±0.85, P<0.001) in osteosarcoma tissues were, respectively, lower and higher than those in noncancerous bone tissues. The expression levels of miR-99a in osteosarcoma tissues were negatively correlated with those of mTOR mRNA. Additionally, miR-99a-low and/or mTOR-high expression were all significantly associated with advanced surgical stage, positive metastasis and recurrence, and poor response to chemotherapy (all P<0.05). Moreover, patients with osteosarcoma with miR-99a-low and/or mTOR-high expression had shorter overall and disease-free survivals than those in miR-99a-high and/or mTOR-low expression groups. Multivariate Cox analyses showed that miR-99a and/or mTOR expression were all independent prognostic factors of osteosarcoma. Conclusion Our data showed the crucial role of miR-99a/mTOR axis in the malignant progression of human osteosarcoma, implying that conjoined expression of miR-99a and mTOR may offer an attractive novel prognostic marker for this disease. PMID:27073323

  8. Co-expression of the carbamoyl-phosphate synthase 1 gene and its long non-coding RNA correlates with poor prognosis of patients with intrahepatic cholangiocarcinoma

    PubMed Central

    MA, SEN-LIN; LI, AI-JUN; HU, ZHAO-YANG; SHANG, FU-SHENG; WU, MENG-CHAO

    2015-01-01

    The mechanisms leading to high rates of malignancy and recurrence of human intrahepatic cholangiocarcinoma (ICC) remain unclear. It is difficult to diagnose and assess the prognosis of patients with ICC in the clinic due to the lack of specific biomarkers. In addition, long non-coding RNAs (lncRNAs) have been reported to serve important roles in certain types of tumorigenesis however a role in ICC remains to be reported. The aim of the current study was to screen for genes and lncRNAs that are abnormally expressed in ICC and to investigate their biological and clinicopathological significance in ICC. The global gene and lncRNA expression profiles in ICC were measured using bioinformatics analysis. Carbamoyl-phosphate synthase 1 (CPS1) and its lncRNA CPS1 intronic transcript 1 (CPS1-IT1) were observed to be upregulated in ICC. The expression of CPS1 and CPS1-IT1 was measured in 31 tissue samples from patients with ICC and a number of cell lines. The effects of CPS1 and CPS1-IT1 on the proliferation and apoptosis of the ICC-9810 cell line were measured. In addition, the clinicopathological features and survival rates of patients with ICC with respect to the gene and lncRNA expression status were analyzed. CPS1 and CPS1-IT1 were co-upregulated in ICC tissues compared with non-cancerous tissues. Knockdown of CPS1 andor CPS1-IT1 reduced the proliferation and increased the apoptosis of ICC-9810 cells. Additionally, clinical analysis indicated that CPS1 and CPS1-IT1 were associated with poor liver function and reduced survival rates when the relative expression values were greater than 4 in cancer tissues. The comparisons between the high CPS1 expression group and the low expression group indicated significant differences in international normalized ratio (P=0.048), total protein (P=0.049), indirect bilirubin (P=0.025), alkaline phosphatase (P=0.003) and disease-free survival (P=0.034). In addition, there were differential trends in CA19-9 (P=0.068), globulin (P=0

  9. Preimplantation genetic screening for all 24 chromosomes by microarray comparative genomic hybridization significantly increases implantation rates and clinical pregnancy rates in patients undergoing in vitro fertilization with poor prognosis

    PubMed Central

    Majumdar, Gaurav; Majumdar, Abha; Lall, Meena; Verma, Ishwar C.; Upadhyaya, Kailash C.

    2016-01-01

    CONTEXT: A majority of human embryos produced in vitro are aneuploid, especially in couples undergoing in vitro fertilization (IVF) with poor prognosis. Preimplantation genetic screening (PGS) for all 24 chromosomes has the potential to select the most euploid embryos for transfer in such cases. AIM: To study the efficacy of PGS for all 24 chromosomes by microarray comparative genomic hybridization (array CGH) in Indian couples undergoing IVF cycles with poor prognosis. SETTINGS AND DESIGN: A retrospective, case–control study was undertaken in an institution-based tertiary care IVF center to compare the clinical outcomes of twenty patients, who underwent 21 PGS cycles with poor prognosis, with 128 non-PGS patients in the control group, with the same inclusion criterion as for the PGS group. MATERIALS AND METHODS: Single cells were obtained by laser-assisted embryo biopsy from day 3 embryos and subsequently analyzed by array CGH for all 24 chromosomes. Once the array CGH results were available on the morning of day 5, only chromosomally normal embryos that had progressed to blastocyst stage were transferred. RESULTS: The implantation rate and clinical pregnancy rate (PR) per transfer were found to be significantly higher in the PGS group than in the control group (63.2% vs. 26.2%, P = 0.001 and 73.3% vs. 36.7%, P = 0.006, respectively), while the multiple PRs sharply declined from 31.9% to 9.1% in the PGS group. CONCLUSIONS: In this pilot study, we have shown that PGS by array CGH can improve the clinical outcome in patients undergoing IVF with poor prognosis. PMID:27382234

  10. Patients with chronic lymphocytic leukaemia and clonal deletion of both 17p13.1 and 11q22.3 have a very poor prognosis

    PubMed Central

    Greipp, Patricia T.; Smoley, Stephanie A.; Viswanatha, David S.; Frederick, Lori S.; Rabe, Kari G.; Sharma, Ruchi G.; Slager, Susan L.; Van Dyke, Daniel L.; Tschumper, Renee C.; Shanafelt, Tait D.; Zent, Clive S.

    2013-01-01

    Summary Detection of a 17p13.1 deletion (loss of TP53) or 11q22.3 deletion (loss of ATM), by fluorescence in situ hybridization (FISH), in chronic lymphocytic leukaemia (CLL) patients is associated with a poorer prognosis. Because TP53 and ATM are integral to the TP53 pathway, we hypothesized that 17p13.1- (17p-) and 11q22.3- (11q-) occurring in the same cell (clonal 17p-/11q-) would confer a worse prognosis than either 17p- or 11q-. We studied 2184 CLL patients with FISH (1995–2012) for the first occurrence of 17p-, 11q-, or clonal 17p-/11q-. Twenty (1%) patients had clonal 17p-/11q-, 158 (7%) had 17p- (including 4 with 17p- and 11q- in separate clones), 247 (11%) had 11q-, and 1759 (81%) had neither 17p- nor 11q-. Eleven of 15 (73%) tested patients with clonal 17p-/11q- had dysfunctional TP53 mutations. Overall survival for clonal 17p-/11q- was significantly shorter (1.9 years) than 17p- (3.1 years, p = 0.04), 11q- (4.8 years, p = <0.0001), or neither 17p- nor 11q- (9.3 years, p = <0.0001). Clonal 17p-/11q- thus conferred significantly worse prognosis, suggesting that loss of at least one copy of both TP53 and ATM causes more aggressive disease. Use of an ATM/TP53 combination FISH probe set could identify these very-high risk patients. PMID:24032430

  11. MYC protein expression is associated with poor prognosis in primary diffuse large B-cell lymphoma of the central nervous system.

    PubMed

    Tapia, Gustavo; Baptista, Maria-Joao; Muñoz-Marmol, Ana-Maria; Gaafar, Ayman; Puente-Pomposo, Maria; Garcia, Olga; Marginet-Flinch, Ruth; Sanz, Carolina; Navarro, Jose-Tomas; Sancho, Juan-Manuel; Ribera, Josep-Maria; Ariza, Aurelio; Mate, Jose-Luis

    2015-07-01

    MYC and BCL2 gene translocations and protein expression have recently demonstrated to be of prognostic significance in systemic diffuse large B-cell lymphoma (DLBCL). However, their role in primary central nervous system DLBCL (CNS-DLBCL) prognosis has been scarcely analyzed. We studied the immunophenotype, the status of the MYC, BCL2, and BCL6 genes and the clinical features of a series of 42 CNS-DLBCL and evaluated their prognostic significance. We found high MYC protein expression in 43% of cases, and this was associated with lower overall survival (OS). Cases with concurrent expression of MYC and BCL2 showed a lower OS, although the difference did not reach statistical significance. Translocations involving the MYC or BCL2 genes were not detected. The BCL6 gene was frequently translocated, but was unrelated to survival. We conclude that MYC protein expression detected by immunohistochemistry identifies a CNS-DLBCL subset with worse prognosis and may contribute to a more accurate risk stratification of CNS-DLBCL patients. PMID:26010683

  12. High expression of piwi-like RNA-mediated gene silencing 1 is associated with poor prognosis via regulating transforming growth factor-β receptors and cyclin-dependent kinases in breast cancer.

    PubMed

    Cao, Jiwei; Xu, Gang; Lan, Jing; Huang, Qingqing; Tang, Zuxiong; Tian, Liping

    2016-03-01

    Previous studies have demonstrated that abnormal expression levels of PIWI may serve a crucial role in tumorigenesis. However, the pathological role and its association with prognosis remains to be fully elucidated. In the present study, the expression levels of piwi‑like RNA‑mediated gene silencing 1 (HIWI) and piwi‑like RNA‑mediated gene silencing 2 (HILI) in breast cancer tissues were reported to be high. The high expression levels of HIWI are correlated with poor prognosis in detected patients. In addition, by overexpression and interference, it was demonstrated that HIWI promotes the activity of breast cancer cells while depression of HIWI may induce apoptosis of breast cancer cells. It was additionally identified that suppression of HIWI may arrest the cells at the G2/M stage. The expression levels of transforming growth factor‑β receptor (TβR)I, TβRII, cyclin‑dependent kinase (CDK)4, CDK6 and CDK8 were observed to be regulated by HIWI, which indicated a novel mechanism of HIWI in the regulation of breast cancer progression. The present study provides novel insight into the HIWI expression in breast cancer, providing a potential biomarker for assessment of prognosis and therapy of breast cancer. PMID:26847393

  13. Autophagy Defects Suggested by Low Levels of Autophagy Activator MAP1S and High Levels of Autophagy Inhibitor LRPPRC Predict Poor Prognosis of Prostate Cancer Patients

    PubMed Central

    Jiang, Xianhan; Zhong, Weide; Huang, Hai; He, Huichan; Jiang, Funeng; Chen, Yanru; Yue, Fei; Zou, Jing; Li, Xun; He, Yongzhong; You, Pan; Yang, Weiqiang; Lai, Yiming; Wang, Fen; Liu, Leyuan

    2016-01-01

    MAP1S (originally named C19ORF5) is a widely distributed homolog of neuronal-specific MAP1A and MAP1B, and bridges autophagic components with microtubules and mitochondria to affect autophagosomal biogenesis and degradation. Mitochondrion-associated protein LRPPRC functions as an inhibitor for autophagy initiation to protect mitochondria from autophagy degradation. MAP1S and LRPPRC interact with each other and may collaboratively regulate autophagy although the underlying mechanism is yet unknown. Previously, we have reported that LRPPRC levels serve as a prognosis marker of patients with prostate adenocarcinomas (PCA), and that patients with high LRPPRC levels survive a shorter period after surgery than those with low levels of LRPPRC. MAP1S levels are elevated in diethylnitrosamine-induced hepatocelular carcinomas in wildtype mice and the exposed MAP1S-deficient mice develop more malignant hepatocellular carcinomas. We performed immunochemical analysis to evaluate the co-relationship among the levels of MAP1S, LRPPRC, P62, and γ-H2AX. Samples were collected from wildtype and prostate-specific PTEN-deficient mice, 111 patients with PCA who had been followed up for 10 years and 38 patients with benign prostate hyperplasia enrolled in hospitals in Guangzhou, China. The levels of MAP1S were generally elevated so the MAP1S-mediated autophagy was activated in PCA developed in either PTEN-deficient mice or patients than their respective benign tumors. The MAP1S levels among patients with PCA vary dramatically, and patients with low MAP1S levels survive a shorter period than those with high MAP1S levels. Levels of MAP1S in collaboration with levels of LRPPRC can serve as markers for prognosis of prostate cancer patients. PMID:25043940

  14. Up-regulated expression of phospholipase C, β1 is associated with tumor cell proliferation and poor prognosis in hepatocellular carcinoma

    PubMed Central

    Li, Junxiang; Zhao, Xuya; Wang, Dazhi; He, Wei; Zhang, Shuai; Cao, Wei; Huang, Yu; Wang, Ling; Zhou, Shi; Luo, Kaijian

    2016-01-01

    Background Phospholipase C, β1 (PLCB1) plays critical roles in intracellular transduction and regulating signal activation which are important to tumorigenesis. However, the mechanism of PLCB1 in hepatocellular carcinoma (HCC) is still unknown. This study aims to investigate whether its expression is associated with the clinicopathological parameters and prognosis of the patients with HCC. Methods Immunohistochemistry on two tissue microarrays containing 141 cases of HCC tissues and adjacent non-tumorous tissues were performed to analyze the correlation between PLCB1 expression and clinicopathological features. Kaplan–Meier analysis and Cox multivariate analysis were performed to determine the PLCB1 expression in HCC prognosis. Furthermore, effects of PLCB1 on proliferation of HCC cells were explored using a colony formation assay and apoptosis assay. Results We identified that PLCB1 expression was significantly higher in tumor tissues than that in adjacent non-tumorous tissues and associated with advanced tumor stage. Kaplan–Meier survival analysis showed that patients with PLCB1-positive tumors had poorer survival than the patients with PLCB1-negative tumors. In multivariate analyses, PLCB1 expression was an independent prognostic factor. Moreover, overexpression of PLCB1 in HCC cells promoted cell proliferation and inhibited apoptosis, while knocking down PLCB1 reduced cell viability in vitro. Further investigation found that activation of ERK signaling might involve in PLCB1-mediated cell growth. Conclusion Our study suggests that PLCB1 promotes the progression of HCC and can be served as an independent prognostic factor and a promising therapeutic target in HCC. PMID:27051304

  15. High expression of COUP-TF II cooperated with negative Smad4 expression predicts poor prognosis in patients with colorectal cancer

    PubMed Central

    Wang, Chaoqun; Zhou, Yun; Ruan, Ruoyun; Zheng, Maojin; Han, Wencan; Liao, Linchuan

    2015-01-01

    Objective: In order to evaluate whether the role of chicken ovalbumin upstream promoter transcription factor II (COUP-TF II) could sever as a predictor to stratify risk of human colorectal cancer (CRC) patients, and to elucidate the preliminary molecular mechanisms of COUP-TF II involved in the development and advancement of CRC reflected by investigating the relationship of COUP-TF II with PTEN, Smad4. Methods: 112 cases tissue microarray and immunohistochemical SP method were used to detect the expression of COUP-TF II, PTEN and Smad4 in CRC tissues and adjacent non-tumorous tissues. The clinical relevance and prognosis of COUP-TF II, PTEN, Smad4 in CRC patients were analyzed. Furthermore, Cox proportional hazards model was performed to indicate the independent prognostic factors for CRC patients using various clinicopathological parameters and COUP-TF II, PTEN and Smad4. Results: COUP-TF II proteins were positively expressed in 65.2% of CRC tissues and 15.5% paired non-CRC tissues, respectively. The expression of COUP-TF II was significantly correlated with TNM stage and lymph node metastasis and a negative correlation with Smad4 expression. Patients bearing higher levels of COUP-TF II expression showed lower DFS and OS. Most importantly, Cox proportional hazards regression analyses showed COUP-TF II positive/Smad4 negative status (DFS, P=0.001; OS, P=0.005) were independent prognostic factors for CRC patients. Conclusion: Positive COUP-TF II expression levels has significant value in determining CRC stage and metastasis and cooperates with negative Smad4 expression contributing to assess prognosis in patients with colorectal cancer, suggesting Smad4 may be involved in the above regulation progress probably. PMID:26261604

  16. PD-L1 Expression Is Associated with Tumor FOXP3+ Regulatory T-Cell Infiltration of Breast Cancer and Poor Prognosis of Patient

    PubMed Central

    Li, Zhenhua; Dong, Pengzhi; Ren, Meijing; Song, Yawen; Qian, Xiaolong; Yang, Yiling; Li, Shuai; Zhang, Xinmin; Liu, Fangfang

    2016-01-01

    Background: Expression of PD-L1 has been estimated to predict the therapeutic potential of PD-L1 inhibition in solid tumors. Recent studies have demonstrated that PD-L1 plays a critical role in regulatory T-cell (Treg) development and functional maintenance. Although increases in FOXP3+Treg infiltration and PD-L1 expression have been revealed in several malignancies, their correlation in human breast tumors is as yet unclear. Methods: Whole-tissue sections from 501 patients with breast cancer were examined for PD-L1 and FOXP3 expression by immunohistochemistry. Correlation between their expressions and the association with clinicopathological features, intrinsic tumor subtypes and patient's prognosis were studied. Results: PD-L1 expression and FOXP3+Treg infiltrates in tumor tissue demonstrated a high correlation (rs=0.334, p<0.001) in this cohort of breast cancer patients. High PD-L1 expression and increased FOXP3+Treg infiltrates were both associated with high histological grade, negative ER and PR status, and aggressive intrinsic tumor subtypes, especially the basal-like subtype. Tumors with concomitant high expressions of the two markers had the worst prognosis. Multivariate analysis proved both markers to be the independent predictors for decreased overall survival of patients, particularly in the basal-like subtype. Conclusions: The results suggest that PD-L1 and FOXP3+Tregs may work synergistically and their up-regulated expressions promote tumor immune evasion in breast cancer. Combinatorial immunotherapeutic approaches aiming on blocking PD-L1 and depleting Tregs might improve therapeutic efficacy in breast cancer patients, especially those with basal-like carcinoma. PMID:27162536

  17. High-grade B-cell Lymphoma With MYC Rearrangement and Without BCL2 and BCL6 Rearrangements Is Associated With High P53 Expression and a Poor Prognosis.

    PubMed

    Li, Shaoying; Weiss, Vivian L; Wang, Xuan J; Desai, Parth A; Hu, Shimin; Yin, C Cameron; Tang, Guilin; Reddy, Nishitha M; Medeiros, L Jeffrey; Lin, Pei

    2016-02-01

    Patients with MYC/BCL2 double-hit lymphoma (DHL) are known to have an aggressive clinical course and to respond poorly to various therapies including intensive chemotherapy and stem cell transplant. Less is known about high-grade B-cell lymphoma with MYC rearrangement without concomitant BCL2 and BCL6 rearrangement, designated here as single-hit lymphoma (SHL). In this study, we assessed 61 cases of SHL and compared them with 83 cases of DHL, all confirmed by MYC, BCL2, and BCL6 fluorescence in situ hybridization studies. Although many clinicopathologic features overlap between patients with SHL and those with DHL, distinct features were observed in SHL. Patients with SHL had tumors with a higher prevalence of p53 overexpression (P=0.047), less frequent expression of CD10, BCL2, and BCL6 (P<0.05), and less often had a history of low-grade B-cell lymphoma (P=0.01). In addition, MYC was more frequently partnered with IGH in SHL than in DHL (P=0.04). With a median follow-up of 25 months, the overall survival of 61 SHL patients was poor and similar to that of DHL patients (2-y overall survival rate of 41% in SHL vs. 48% in DHL; P=0.35) and significantly worse than patients with diffuse large B-cell lymphoma and B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma, without MYC and BCL2 rearrangements (P<0.0001). In conclusion, patients with SHL have distinct clinicopathologic features but a similar poor prognosis compared with patients with MYC/BCL2 DHL. The poor prognosis of patients with SHL may be partially related to the higher frequency and level of p53 expression in these tumors. PMID:26448193

  18. The Number of Pathologically Positive Lymph Nodes and Pathological Tumor Depth Predicts Prognosis in Patients With Poorly Differentiated Squamous Cell Carcinoma of the Oral Cavity

    SciTech Connect

    Kang, Chung-Jan; Lin, Chien-Yu; Wang, Hung-Ming; Fan, Kang-Hsing; Ng, Shu-Hang; Lee, Li-Yu; Chen, I-How; Huang, Shiang-Fu; and others

    2011-11-15

    Purpose: The objective of this retrospective study was twofold: (1) to investigate prognostic factors for clinical outcomes in patients with poorly differentiated oral cavity squamous cell carcinoma and (2) to identify specific prognostic subgroups that may help to guide treatment decisions. Methods and Materials: We examined 102 patients with poorly differentiated oral cavity squamous cell carcinoma. All patients were followed for at least 24 months after surgery or until death. The 5-year rates of local control, neck control, distant metastasis, disease-free, disease-specific, and overall survival served as main outcome measures. Results: The 5-year rates were as follows: local control (79%), neck control (64%), distant metastases (27%), disease-free survival (48%), disease-specific survival (52%), and overall survival (42%). Multivariable analysis showed that the number of pathologically positive nodes ({>=}4 vs. {<=}3) was a significant predictor of neck control, distant metastasis, and disease-free, disease-specific, and overall survival rates. In addition, the presence of tumor depth of {>=}11 mm (vs. <11 mm) was a significant predictor of distant metastasis, disease-specific survival, and overall survival rates. The combination of the two predictors (26.5%, 27/102) was independently associated with poorer neck control (p = 0.0319), distant metastasis (p < 0.0001), and disease-free (p < 0.0001), disease-specific (p < 0.0001), and overall survival (p < 0.0001) rates. Conclusions: In patients with poorly differentiated oral cavity squamous cell carcinoma, the presence of at least 4 pathologically positive lymph nodes and of a pathological tumor depth {>=}11 mm identifies a subset of subjects with poor clinical outcomes. Patients carrying both risk factors are suitable candidates for the development of novel therapeutic approaches.

  19. Exon array analysis of head and neck cancers identifies a hypoxia related splice variant of LAMA3 associated with a poor prognosis.

    PubMed

    Moller-Levet, Carla S; Betts, Guy N J; Harris, Adrian L; Homer, Jarrod J; West, Catharine M L; Miller, Crispin J

    2009-11-01

    The identification of alternatively spliced transcript variants specific to particular biological processes in tumours should increase our understanding of cancer. Hypoxia is an important factor in cancer biology, and associated splice variants may present new markers to help with planning treatment. A method was developed to analyse alternative splicing in exon array data, using probeset multiplicity to identify genes with changes in expression across their loci, and a combination of the splicing index and a new metric based on the variation of reliability weighted fold changes to detect changes in the splicing patterns. The approach was validated on a cancer/normal sample dataset in which alternative splicing events had been confirmed using RT-PCR. We then analysed ten head and neck squamous cell carcinomas using exon arrays and identified differentially expressed splice variants in five samples with high versus five with low levels of hypoxia-associated genes. The analysis identified a splice variant of LAMA3 (Laminin alpha 3), LAMA3-A, known to be involved in tumour cell invasion and progression. The full-length transcript of the gene (LAMA3-B) did not appear to be hypoxia-associated. The results were confirmed using qualitative RT-PCR. In a series of 59 prospectively collected head and neck tumours, expression of LAMA3-A had prognostic significance whereas LAMA3-B did not. This work illustrates the potential for alternatively spliced transcripts to act as biomarkers of disease prognosis with improved specificity for particular tissues or conditions over assays which do not discriminate between splice variants. PMID:19936049

  20. Long non-coding RNA ATB promotes growth and epithelial-mesenchymal transition and predicts poor prognosis in human prostate carcinoma.

    PubMed

    Xu, Song; Yi, Xiao-Ming; Tang, Chao-Peng; Ge, Jing-Ping; Zhang, Zheng-Yu; Zhou, Wen-Quan

    2016-07-01

    Long non-coding RNAs (lncRNAs) have been identified to be critical mediators in various tumors associated with cancer progression. Long non-coding RNA activated by TGF-β (lncRNA-ATB) is a stimulator of epithelial-mesenchymal transition (EMT) and serves as a novel prognostic biomarker for hepatocellular carcinoma. However, the biological role and clinical significance of lncRNA-ATB in human prostate cancer have yet to be fully elucidated. The present study was designed to explore the expression of lncRNA-ATB in human prostate cancer patients and the role of lncRNA-ATB in prostate cancer cells. We showed that lncRNA-ATB expression was significantly upregulated in tumor tissues in patients with prostate cancer in comparison with adjacent non-tumor tissues. Further analysis indicted that high lncRNA-ATB expression may be an independent prognostic factor for biochemical recurrence (BCR)-free survival in prostate cancer patients. Overexpression of lncRNA-ATB promoted, and knockdown of lncRNA-ATB inhibited the growth of prostate cancer cells via regulations of cell cycle regulatory protein expression levels. In addition, lncRNA-ATB stimulated epithelial-mesenchymal transition (EMT) associated with ZEB1 and ZNF217 expression levels via ERK and PI3K/AKT signaling pathways. These results indicated that lncRNA-ATB may be considered as a new predictor in the clinical prognosis of patients with prostate cancer. Overexpression of lncRNA-ATB exerts mitogenic and EMT effects of prostate cancer via activation of ERK and PI3K/AKT signaling pathways. PMID:27176634

  1. Expression of DDX27 contributes to colony-forming ability of gastric cancer cells and correlates with poor prognosis in gastric cancer

    PubMed Central

    Tsukamoto, Yoshiyuki; Fumoto, Shoichi; Noguchi, Tsuyoshi; Yanagihara, Kazuyoshi; Hirashita, Yuka; Nakada, Chisato; Hijiya, Naoki; Uchida, Tomohisa; Matsuura, Keiko; Hamanaka, Ryoji; Murakami, Kazunari; Seto, Masao; Inomata, Masafumi; Moriyama, Masatsugu

    2015-01-01

    Previously, we have reported that gain at chromosome 20q13 is the most common genomic copy number aberration in gastric cancer (GC) (29/30 cases), and that among the genes located in this region, we have identified DDX27, whose expression level shows the highest correlation with genomic copy number, as a candidate therapeutic target for GC. Here, we analyzed the clinicopathological significance of DDX27 using immunohistochemistry and studied its functions using knockdown assays. We found that DDX27 was frequently upregulated in GC tissues (98 of 140 cases, 70%), and significantly associated with venous invasion and liver metastasis. Furthermore, multivariate analysis of GC patients showed that high expression of DDX27 was independently associated with poorer prognosis. In functional assays, knockdown of DDX27 reduced the ability of GC cells to form colonies both on conventional plates and soft agar, but had little effect on their invasiveness. We also found that knockdown of DDX27 reduced the viability of GC cells through inhibition of cell cycle progression independently of apoptosis. Interestingly, DDX27 depletion induced accumulation of TP53 in a TP53 wild-type cell line, AGS, but not in a TP53-deleted cell line, 44As3, although DDX27 knockdown commonly reduced the viability of both, indicating the TP53-dependent and independent cell cycle control of DDX27. Thus, our results suggest that expression of DDX27 contributes to colony formation by GC cells through cell cycle control and may be a potential therapeutic target for GC patients with chromosome gain at 20q13. PMID:26693055

  2. Long non-coding RNA ATB promotes growth and epithelial-mesenchymal transition and predicts poor prognosis in human prostate carcinoma

    PubMed Central

    XU, SONG; YI, XIAO-MING; TANG, CHAO-PENG; GE, JING-PING; ZHANG, ZHENG-YU; ZHOU, WEN-QUAN

    2016-01-01

    Long non-coding RNAs (lncRNAs) have been identified to be critical mediators in various tumors associated with cancer progression. Long non-coding RNA activated by TGF-β (lncRNA-ATB) is a stimulator of epithelial-mesenchymal transition (EMT) and serves as a novel prognostic biomarker for hepatocellular carcinoma. However, the biological role and clinical significance of lncRNA-ATB in human prostate cancer have yet to be fully elucidated. The present study was designed to explore the expression of lncRNA-ATB in human prostate cancer patients and the role of lncRNA-ATB in prostate cancer cells. We showed that lncRNA-ATB expression was significantly upregulated in tumor tissues in patients with prostate cancer in comparison with adjacent non-tumor tissues. Further analysis indicted that high lncRNA-ATB expression may be an independent prognostic factor for biochemical recurrence (BCR)-free survival in prostate cancer patients. Overexpression of lncRNA-ATB promoted, and knockdown of lncRNA-ATB inhibited the growth of prostate cancer cells via regulations of cell cycle regulatory protein expression levels. In addition, lncRNA-ATB stimulated epithelial-mesenchymal transition (EMT) associated with ZEB1 and ZNF217 expression levels via ERK and PI3K/AKT signaling pathways. These results indicated that lncRNA-ATB may be considered as a new predictor in the clinical prognosis of patients with prostate cancer. Overexpression of lncRNA-ATB exerts mitogenic and EMT effects of prostate cancer via activation of ERK and PI3K/AKT signaling pathways. PMID:27176634

  3. Loss of ARID1A expression predicts poor survival prognosis in gastric cancer: a systematic meta-analysis from 14 studies

    PubMed Central

    Yang, Lin; Wei, Sheng; Zhao, Rongxian; Wu, Yingxing; Qiu, Hong; Xiong, Huihua

    2016-01-01

    The chromatin remodeling gene, AT-rich interactive domain 1A gene (ARID1A), frequently mutates inactively in gastric cancer (GC). However, its prognostic value remains controversial. To address this issue, a comprehensive meta-analysis was performed. Studies published until March 2016 were systematically searched. A total of 15 cohorts from 14 literatures involving 3183 patients were subjected to this meta-analysis. The pooled data showed that ARID1A expression loss predicted poor overall survival (OS) in GC (Hazard Ratio (HR) = 1.60; 95% Confidence Interval (CI) = 1.40–1.81; P < 0.001), with low heterogeneity among these studies (I2 = 21.5%; P = 0.214). Stratification analyses revealed that ARID1A expression loss was associated with poor OS in Asians (HR = 1.65, 95% CI = 1.44–1.89), proportion of proximal disease ≤30% subgroup (HR = 1.80, 95% CI = 1.36–2.38) and Epstein-Barr virus (EBV) (+) > 5% subgroup (HR = 1.59, 95% CI = 1.18–2.15). The robust results were suggested by sensitivity analyses and no evidence of significant publication bias was detected. This study demonstrated a significant relationship between deletion of ARID1A expression and poor OS in GC. Moreover, ethnicity, tumor location and EBV infection status might be potential key factors influencing this correlation. PMID:27354232

  4. The RNA binding protein FXR1 is a new driver in the 3q26-29 amplicon and predicts poor prognosis in human cancers

    PubMed Central

    Qian, Jun; Hassanein, Mohamed; Hoeksema, Megan D.; Harris, Bradford K.; Zou, Yong; Chen, Heidi; Lu, Pengcheng; Eisenberg, Rosana; Wang, Jing; Espinosa, Allan; Ji, Xiangming; Harris, Fredrick T.; Rahman, S. M. Jamshedur; Massion, Pierre P.

    2015-01-01

    Aberrant expression of RNA-binding proteins has profound implications for cellular physiology and the pathogenesis of human diseases such as cancer. We previously identified the Fragile X-Related 1 gene (FXR1) as one amplified candidate driver gene at 3q26-29 in lung squamous cell carcinoma (SCC). FXR1 is an autosomal paralog of Fragile X mental retardation 1 and has not been directly linked to human cancers. Here we demonstrate that FXR1 is a key regulator of tumor progression and its overexpression is critical for nonsmall cell lung cancer (NSCLC) cell growth in vitro and in vivo. We identified the mechanisms by which FXR1 executes its regulatory function by forming a novel complex with two other oncogenes, protein kinase C, iota and epithelial cell transforming 2, located in the same amplicon via distinct binding mechanisms. FXR1 expression is a candidate biomarker predictive of poor survival in multiple solid tumors including NSCLCs. Because FXR1 is overexpressed and associated with poor clinical outcomes in multiple cancers, these results have implications for other solid malignancies. PMID:25733852

  5. High Expression of Leucine Zipper-EF-Hand Containing Transmembrane Protein 1 Predicts Poor Prognosis in Head and Neck Squamous Cell Carcinoma

    PubMed Central

    Chen, Liyan; Yang, Yang; Liu, Shuangping; Piao, Longzhen; Zhang, Yuan; Lin, Zhenhua; Li, Zhuhu

    2014-01-01

    Leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) is a mitochondrial inner membrane protein and plays an important role in mitochondrial ATP production and biogenesis. High expression levels of LETM1 have been correlated with numerous human malignancies. This study explored the clinicopathological significance of LETM1 expression as a prognostic determinant in head and neck squamous cell carcinoma (HNSCC). HNSCC samples from 176 patients were selected for immunohistochemical staining of LETM1 protein. Correlations between LETM1 overexpression and clinicopathological features of HNSCC were evaluated by Chi-squared tests and Fisher's exact tests, and relationships between prognostic factors and patient survival were analyzed using Cox proportional hazards models. Our results demonstrated that the strongly positive rate of LETM1 protein was 65.3% in HNSCC, which was significantly higher than in either adjacent nontumor tissue (25.0%) or normal squamous epithelia (6.7%). LETM1 overexpression correlated with poor differentiation, presence of lymph node metastasis, advanced stage, absence of chemoradiotherapy, and 5-year disease-free survival and overall survival rates in HNSCC. Further analysis showed that high LETM1 expression, advanced stage, and nonchemoradiotherapy were significant independent risk factors for mortality in HNSCC. In conclusion, LETM1 plays an important role in the progression of HNSCC and is an independent poor prognostic factor for HNSCC. PMID:24689060

  6. Overexpression of ribosomal L1 domain containing 1 is associated with an aggressive phenotype and a poor prognosis in patients with prostate cancer

    PubMed Central

    LI, XIAO-PING; JIAO, JU; LU, LI; ZOU, QIONG; ZHU, SHU; ZHANG, YONG

    2016-01-01

    The aim of the present study was to investigate the overexpression and significance of ribosomal L1 domain containing 1 (RSL1D1) in prostate cancer (PCA). The present study performed immunohistochemical analysis on the tissues of 138 patients with pathologically confirmed PCA. The patients were followed up for a median of 87 months. In addition, 50 patients with benign prostatic hyperplasia (BPH) were enrolled in the present study as a control group. Of the 138 PCA tissue samples, 124 (89.9%) expressed RSL1D1, while 4 out of the 50 (8.0%) BPH tissues expressed RSL1D1. The present study defined a high RSL1D1 expression level as the relative gene expression that was equal to or higher than the median, and low expression as the gene expression lower than the median. The pathological stage of patients with PCA (≥pT3a vs. pT2c) and the Gleason scores of patients (≥7 vs. <7) were associated with RSL1D1 expression (χ2=4.809 and 14.703; P=0.028 and P<0.0001, respectively) and a high expression of RSL1D1 (χ2=10.294 and 17.520; P=0.001 and P<0.0001, respectively). Kaplan-Meier curve analysis demonstrated that the biochemical recurrence (BCR)-free survival rate of the patients was increased in patients without RSL1D1 expression (P=0.0046), in those with low RSL1D1 expression (P<0.0001) and in those without RSL1D1 expression in the mesenchyme (P=0.006) compared with those patients with no expression, low expression and no mesenchymal expression, respectively. A high expression level of RSL1D1 was demonstrated to be an independent prognostic factor of BCR in patients with PCA using Cox regression analysis. Overall, the present study demonstrated that RSL1D1 expression was associated with PCA, and that it may aid in the improvement of diagnosis, prognosis and risk stratification of patients with PCA. PMID:27073561

  7. Overexpression of TMPRSS4 in non-small cell lung cancer is associated with poor prognosis in patients with squamous histology

    PubMed Central

    Larzabal, L; Nguewa, P A; Pio, R; Blanco, D; Sanchez, B; Rodríguez, M J; Pajares, M J; Catena, R; Montuenga, L M; Calvo, A

    2011-01-01

    Background: Mortality rates in lung cancer patients have not decreased significantly in recent years, even with the implementation of new therapeutic regimens. One of the main problems is that a large proportion of patients present local or distant metastasis at the time of diagnosis. The need for identification of novel biomarkers and therapeutic targets for a more effective management of lung cancer led us to investigate TMPRSS4, a protease reported to promote tumour growth and metastasis. Material and methods: In all, 34 lung cancer cell lines were used to evaluate the TMPRSS4 expression. Cell migration and clonogenic assays, and an in-vivo lung metastasis model were used for functional analysis of the TMPRSS4 downregulation in H358, H441 and H2170 cell lines. The TMPRSS4 expression analysis in normal and malignant lung tissue samples was performed by qPCR. Five different microarray-based publicly available expression databases were used to validate our results and to study prognosis. Results: The TMPRSS4 knock down in H358, H441 and H2170 cells resulted in a significant reduction in proliferation, clonogenic capacity and invasion. A significant (P<0.05) decrease in the lung colonisation and growth was found when mice were injected with TMPRSS4-depleated H358-derived clones, as compared with controls. Expression of TMPRSS4 showed a >30-fold increase (P<0.001) in tumours in comparison with non-malignant samples. Levels in tumours with squamous cell carcinoma (SCC) histology were found to be significantly higher (P<0.001) than those with adenocarcinoma (AC) histology, which was confirmed in data retrieved from the microarrays. Kaplan–Meier curves demonstrated that high levels of TMPRSS4 were significantly associated (P=0.017) with reduced overall survival in the patients with SCC histology, whereas no correlation was found for the AC histology. Conclusion: Our results demonstrate that TMPRSS4 has a role in the lung cancer development. The potential use of TMPRSS

  8. Membranous expressions of Lewis y and CAM-DR-related markers are independent factors of chemotherapy resistance and poor prognosis in epithelial ovarian cancer

    PubMed Central

    Zhu, Lian-Cheng; Gao, Jian; Hu, Zhen-Hua; Schwab, Carlton L; Zhuang, Hui-Yu; Tan, Ming-Zi; Yan, Li-Mei; Liu, Juan-Juan; Zhang, Dan-Ye; Lin, Bei

    2015-01-01

    Background: Chemotherapy resistance is a common problem faced by patients diagnosed with epithelial ovarian cancer (EOC). Currently there are no specific or sensitive clinical biomarkers that maybe implemented to identify chemotherapy resistance and give insight to prognosis. The aim of this study is to investigate the roles of Lewis y antigen and the markers associated with cell-adhesion-mediated drug resistance (CAM-DR) in patients with EOC. Methods: 92 EOC patients who were treated with systemic chemotherapy after cytoreductive surgery were included in this analysis. Patients were divided into two groups, chemotherapy sensitive (n = 56) and resistant (n = 36). Immunohistochemical (IHC) staining for Lewis y and CAM-DR-related cell surface proteins including CD44, CD147, HE4 (Human epididymis protein 4), integrin α5, β1, αv and β3 were conducted on tissues collected during primary debulking surgery. Using multivariate logistic regressions, IHC results were compared to clinical variables and chemotherapy resistance to determine possible correlations. The relationships between IHC expression and progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan–Meier method and Cox regression analysis. Results: Membranous expression of Lewis y and all these CAM-DR-related markers were significantly higher in the resistant group than that of the sensitive group (all P < 0.01). Multivariate regression analysis revealed that high expression of Lewis y, CD44, HE4, integrin α5 and β1 as well as advanced FIGO stage were independent risk factors for chemotherapy resistance (all P < 0.05). Advanced FIGO stage, lymph node metastasis and high expression of Lewis y, CD44, CD147, HE4, integrin α5, β1 were associated with a shorter PFS and OS (all P < 0.05). Moreover, multivariate COX analysis demonstrated that the following variates were independent predictors of worse PFS and OS survival: late FIGO stage (P = 0.013, 0.049), high expressions of Lewis

  9. Uveal melanoma: estimating prognosis.

    PubMed

    Kaliki, Swathi; Shields, Carol L; Shields, Jerry A

    2015-02-01

    Uveal melanoma is the most common primary malignant tumor of the eye in adults, predominantly found in Caucasians. Local tumor control of uveal melanoma is excellent, yet this malignancy is associated with relatively high mortality secondary to metastasis. Various clinical, histopathological, cytogenetic features and gene expression features help in estimating the prognosis of uveal melanoma. The clinical features associated with poor prognosis in patients with uveal melanoma include older age at presentation, male gender, larger tumor basal diameter and thickness, ciliary body location, diffuse tumor configuration, association with ocular/oculodermal melanocytosis, extraocular tumor extension, and advanced tumor staging by American Joint Committee on Cancer classification. Histopathological features suggestive of poor prognosis include epithelioid cell type, high mitotic activity, higher values of mean diameter of ten largest nucleoli, higher microvascular density, extravascular matrix patterns, tumor-infiltrating lymphocytes, tumor-infiltrating macrophages, higher expression of insulin-like growth factor-1 receptor, and higher expression of human leukocyte antigen Class I and II. Monosomy 3, 1p loss, 6q loss, and 8q and those classified as Class II by gene expression are predictive of poor prognosis of uveal melanoma. In this review, we discuss the prognostic factors of uveal melanoma. A database search was performed on PubMed, using the terms "uvea," "iris," "ciliary body," "choroid," "melanoma," "uveal melanoma" and "prognosis," "metastasis," "genetic testing," "gene expression profiling." Relevant English language articles were extracted, reviewed, and referenced appropriately. PMID:25827538

  10. Epigenetic downregulation of the ISG15–conjugating enzyme UbcH8 impairs lipolysis and correlates with poor prognosis in nasopharyngeal carcinoma

    PubMed Central

    Chen, Fu; Xiao, Xue; Huang, Tingting; He, Qian; Wang, Shumin; Du, Chunping; Mo, Yingxi; Lin, Longde; Xie, Ying; Wei, Lili; Lan, Ying; Murata, Mairiko; Huang, Guangwu; Ernberg, Ingemar; Matskova, Liudmila; Zhang, Zhe

    2015-01-01

    We identified the UBE2L6 gene, encoding the ISG15-conjugating enzyme UbcH8, as one gene significantly downregulated by promoter hypermethylation in nasopharyngeal carcinoma (NPC). Reduced expression of the UbcH8 protein correlated with poor outcome in NPC patients. Restored expression of UBE2L6 suppressed proliferation and colony formation in NPC cells, while inducing apoptosis. Of particular interest, we found that aberrant lipid turnover was controlled by UbcH8 in NPC through ISG15-conjugation of valosin-containing protein (VCP). Tumor tissue and NPC cell lines showed conspicuously strong accumulation of lipid droplets (LDs) compared to control nasopharyngeal epithelium and non-cancerous cell lines. We demonstrated that UbcH8 counteracts degradation of adipocyte triglyceride lipase (ATGL), a key enzyme in lipid catabolism. PMID:26506425

  11. Low miR-143/miR-145 Cluster Levels Induce Activin A Overexpression in Oral Squamous Cell Carcinomas, Which Contributes to Poor Prognosis

    PubMed Central

    Bufalino, Andreia; Cervigne, Nilva K.; de Oliveira, Carine Ervolino; Fonseca, Felipe Paiva; Rodrigues, Priscila Campioni; Macedo, Carolina Carneiro Soares; Sobral, Lays Martin; Miguel, Marcia Costa; Lopes, Marcio Ajudarte; Leme, Adriana Franco Paes; Lambert, Daniel W.; Salo, Tuula A.; Kowalski, Luiz Paulo; Graner, Edgard; Coletta, Ricardo D.

    2015-01-01

    Deregulated expression of activin A is reported in several tumors, but its biological functions in oral squamous cell carcinoma (OSCC) are unknown. Here, we investigate whether activin A can play a causal role in OSCCs. Activin A expression was assessed by qPCR and immunohistochemistry in OSCC tissues. Low activin A-expressing cells were treated with recombinant activin A and assessed for apoptosis, proliferation, adhesion, migration, invasion and epithelial-mesenchymal transition (EMT). Those phenotypes were also evaluated in high activin A-expressing cells treated with follistatin (an activin A antagonist) or stably expressing shRNA targeting activin A. Transfections of microRNA mimics were performed to determine whether the overexpression of activin A is regulated by miR-143/miR-145 cluster. Activin A was overexpressed in OSCCs in comparison with normal oral mucosa, and high activin A levels were significantly associated with lymph node metastasis, tumor differentiation and poor survival. High activin A levels promoted multiple properties associated with malignant transformation, including decreased apoptosis and increased proliferation, migration, invasion and EMT. Both miR-143 and miR-145 were markedly downregulated in OSCC cell lines and in clinical specimens, and inversely correlated to activin A levels. Forced expression of miR-143 and miR-145 in OSCC cells significantly decreased the expression of activin A. Overexpression of activin A in OSCCs, which is controlled by downregulation of miR-143/miR-145 cluster, regulates apoptosis, proliferation and invasiveness, and it is clinically correlated with lymph node metastasis and poor survival. PMID:26317418

  12. Association of Nuclear PIM1 Expression with Lymph Node Metastasis and Poor Prognosis in Patients with Lung Adenocarcinoma and Squamous Cell Carcinoma

    PubMed Central

    Jiang, Richeng; Wang, Xinyue; Jin, Ziliang; Li, Kai

    2016-01-01

    Increasing evidence indicates that aberrant expression of PIM1, p-STAT3 and c-MYC is involved in the pathogenesis of various solid tumors, but its prognostic value is still unclear in non-small cell lung cancer (NSCLC). Here, we sought to evaluate the expression and prognostic role of these markers in patients with lung adenocarcinoma (AD) and squamous cell carcinoma (SCC). Real time RT-PCR and Western blotting was used to analyze the mRNA and protein expression of PIM1 in NSCLC cell lines, respectively. The expression of PIM1, p-STAT3, and c-MYC was immunohistochemically tested in archival tumor samples from 194 lung AD and SCC patients. High nuclear PIM1 expression was detected in 43.3% of ADs and SCCs, and was significantly correlated with lymph node (LN) metastasis (P = 0.028) and histology (P = 0.003). High nuclear PIM1 expression (P = 0.034), locally advanced stage (P < 0.001), AD (P = 0.007) and poor pathologic differentiation (P = 0.002) were correlated with worse disease-free survival (DFS). High nuclear PIM1 expression (P = 0.009), advanced clinical stage (P < 0.001) and poor pathologic differentiation (P = 0.004) were independent unfavorable prognostic factors for overall survival (OS). High p-STAT3 expression was not associated with OS but significantly correlated with LN metastasis, while c-MYC was not significantly correlated with any clinicopathological parameter or survival. Therefore, in AD and SCC patients, nuclear PIM1 expression level is an independent factor for DFS and OS and it might serve as a predictive biomarker for outcome. PMID:26918046

  13. Down-regulation of C12orf59 is associated with a poor prognosis and VHL mutations in renal cell carcinoma

    PubMed Central

    Wu, Jianting; Li, Cailing; Luo, Liya; Xia, Lingling; Li, Xianxin; Gui, Yaoting; Cai, Zhiming; Li, Zesong

    2016-01-01

    C12orf59 is newly identified gene in kidney. However, the relation of C12orf59 expression and clinic features is unknown. Here, our study showed that C12orf59 was broadly expressed in normal human tissues with high expression levels in kidney while its expression is beyond detectable in a panel of cancer cell lines. C12orf59 expression in RCC was significantly decreased compared with corresponding adjacent noncancerous tissues (P < 0.01). The decreased C12orf59 expression was correlated with lymph node status (P < 0.05), distant metastases (P < 0.05), poor survival (P < 0.001) (HR 3.00; 95% CI, 1.29–7.53), VHL non-sense mutations or frame-shift mutations (P < 0.01), and UMPP gene non-sense mutations or frame-shift mutations (P = 0.01). Thus, we propose that the decreased C12orf59 expression status is a prognostic biomarker of ccRCC and cooperates with the loss of VHL all the while promoting renal carcinogenesis. PMID:26758419

  14. LAPTM4B is associated with poor prognosis in NSCLC and promotes the NRF2-mediated stress response pathway in lung cancer cells.

    PubMed

    Maki, Yuho; Fujimoto, Junya; Lang, Wenhua; Xu, Li; Behrens, Carmen; Wistuba, Ignacio I; Kadara, Humam

    2015-01-01

    We recently demonstrated that lysosomal protein transmembrane 4 beta (LAPTM4B) is elevated in non-small cell lung cancers (NSCLCs) and in the surrounding premalignant airway field of cancerization. In the present study, we sought to begin to understand the relevance of LAPTM4B expression and signaling to NSCLC pathogenesis. In situ hybridization analysis of LAPTM4B transcript in tissue microarrays comprised of 368 NSCLCs demonstrated that LAPTM4B expression was significantly increased in smoker compared to non-smoker lung adenocarcinoma tumors (P < 0.001) and was significantly associated with poor overall survival (P < 0.05) in adenocarcinoma patients. Knockdown of LAPTM4B expression inhibited cell growth, induced cellular apoptosis and decreased cellular autophagy in serum starved lung cancer cells. Expression profiling coupled with pathways analysis revealed decreased activation of the nuclear factor erythroid 2-like 2 (NRF2) stress response pathway following LAPTM4B knockdown. Further analysis demonstrated that LAPTM4B augmented the expression and nuclear translocation of the NRF2 transcription factor following serum deprivation as well as increased the expression of NRF2 target genes such as heme oxygenase 1/HMOX1). Our study points to the relevance of LAPTM4B expression to NSCLC pathogenesis as well as to the probable role of LAPTM4B/NRF2 signaling in promoting lung cancer cell survival. PMID:26343532

  15. A CD21 low phenotype, with no evidence of autoantibodies to complement proteins, is consistent with a poor prognosis in CLL

    PubMed Central

    Nichols, Eva-Maria; Jones, Rachel; Watson, Rachael

    2015-01-01

    B-cell chronic lymphocytic leukemia (CLL) is characterized by differential BCR signaling and autoimmune complications. Complement modulates B-cell function via C3d and CD21 cross-linked to the B-cell receptor (BCR). We hypothesized that CD21 contributes to BCR signaling and participates in the autoimmunity associated with CLL. We analyzed CD21 expression on 106 CLL patient samples and matched serum from 50 patients for the presence of soluble CD21 and autoantibodies to CR2, CR1, MCP and FH. CD21 expression on CLL B-cells was significantly lower than that expressed on B-cells from age-matched controls (P < 0.0001) and was inversely correlated with soluble CD21 (r2 = −0.41). We found no evidence of autoantibody to any complement regulator. Low CD21 expression correlated to prognostic subsets of CLL patients, i.e. cases with unmutated IGHV genes (P = 0.0006), high CD38 (P = 0.02) and high ZAP70 expression (P = 0.0017). Low CD21 expression was inversely correlated to the levels of phosphotyrosine induced in CLL cells following BCR ligation with αIgM (r2=–0.21). Importantly, lower CD21 expression was also predictive for reduced overall survival (P = 0.005; HR = 2.7). In conclusion, we showed that reduced expression of CD21 on CLL B-cells appears functionally relevant and was associated with poor clinical outcomes. PMID:26452134

  16. LAPTM4B is associated with poor prognosis in NSCLC and promotes the NRF2-mediated stress response pathway in lung cancer cells

    PubMed Central

    Maki, Yuho; Fujimoto, Junya; Lang, Wenhua; Xu, Li; Behrens, Carmen; Wistuba, Ignacio I.; Kadara, Humam

    2015-01-01

    We recently demonstrated that lysosomal protein transmembrane 4 beta (LAPTM4B) is elevated in non-small cell lung cancers (NSCLCs) and in the surrounding premalignant airway field of cancerization. In the present study, we sought to begin to understand the relevance of LAPTM4B expression and signaling to NSCLC pathogenesis. In situ hybridization analysis of LAPTM4B transcript in tissue microarrays comprised of 368 NSCLCs demonstrated that LAPTM4B expression was significantly increased in smoker compared to non-smoker lung adenocarcinoma tumors (P < 0.001) and was significantly associated with poor overall survival (P < 0.05) in adenocarcinoma patients. Knockdown of LAPTM4B expression inhibited cell growth, induced cellular apoptosis and decreased cellular autophagy in serum starved lung cancer cells. Expression profiling coupled with pathways analysis revealed decreased activation of the nuclear factor erythroid 2-like 2 (NRF2) stress response pathway following LAPTM4B knockdown. Further analysis demonstrated that LAPTM4B augmented the expression and nuclear translocation of the NRF2 transcription factor following serum deprivation as well as increased the expression of NRF2 target genes such as heme oxygenase 1/HMOX1). Our study points to the relevance of LAPTM4B expression to NSCLC pathogenesis as well as to the probable role of LAPTM4B/NRF2 signaling in promoting lung cancer cell survival. PMID:26343532

  17. Baseline Serum Lactate Dehydrogenase Levels for Patients Treated With Intensity-Modulated Radiotherapy for Nasopharyngeal Carcinoma: A Predictor of Poor Prognosis and Subsequent Liver Metastasis

    SciTech Connect

    Zhou Guanqun; Tang Linglong; Mao Yanping; Chen Lei; Li Wenfei; Sun Ying; Liu Lizhi; Li Li; Lin Aihua; Ma Jun

    2012-03-01

    Purpose: To evaluate the prognostic value of baseline serum lactate dehydrogenase (LDH) levels in patients with nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiotherapy (IMRT). Methods and Materials: Cases of NPC (n = 465) that involved treatment with IMRT with or without chemotherapy were retrospectively analyzed. Results: The mean ({+-}SD) and median baseline serum LDH levels for this cohort were 172.77 {+-} 2.28 and 164.00 IU/L, respectively. Levels of LDH were significantly elevated in patients with locoregionally advanced disease (p = 0.016). Elevated LDH levels were identified as a prognostic factor for rates of overall survival (OS), disease-free survival (DFS), and distant metastasis-free survival (DMFS), with p values <0.001 in the univariate analysis and p < 0.001, p = 0.004, and p = 0.003, respectively, in the multivariate analysis. Correspondingly, the prognostic impact of patient LDH levels was found to be statistically significant for rates of OS, DFS, and DMFS (p = 0.028, 0.024, and 0.020, respectively). For patients who experienced subsequent liver failure after treatment, markedly higher pretreatment serum LDH levels were detected compared with patients experiencing distant metastasis events at other sites (p = 0.032). Conclusions: Elevated baseline LDH levels are associated with clinically advanced disease and are a poor prognosticator for OS, DFS, and DMFS for NPC patients. These results suggest that elevated serum levels of LDH should be considered when evaluating treatment options.

  18. Involvement of Difference in Decrease of Hemoglobin Level in Poor Prognosis of Stage I and II Nasopharyngeal Carcinoma: Implication in Outcome of Radiotherapy

    SciTech Connect

    Gao Jin; Tao Yalan; Li Guo; Yi Wei; Xia Yunfei

    2012-03-15

    Purpose: To investigate the effect of hemoglobin (Hb) concentration and the difference in its decrease during treatment on outcome of radiotherapy (RT) alone for patients with Stage I and II nasopharyngeal carcinoma. Methods and Materials: A total of 572 patients with Stage I-II nasopharyngeal carcinoma with RT alone between January 2001 and December 2004 were retrospectively analyzed. Patient characteristics, tumor variables, and Hb level, including pre-RT Hb, mid-RT Hb, and dynamic change of Hb between pre- and post- RT and its difference in decrease ( White-Up-Pointing-Small-Triangle Hb) were subjected to univariate and multivariable analysis to identify factors that predict disease-specific survival (DSS), local regional recurrence-free survival (LRFS), and metastases-free survival (MFS). Results: The 5-year DSS was poorer in the Hb continuous decrease group than in the Hb noncontinuous decrease group (84% vs. 89%; p = 0.008). There was poorer 5-year DSS in patients with White-Up-Pointing-Small-Triangle Hb of >11.5 g/L than in those with White-Up-Pointing-Small-Triangle Hb of {<=}11.5 g/L (82% vs. 89%; p = 0.001), and poorer LRFS (79% vs. 83%; p = 0.035). Univariate and multivariate analysis showed that Hb decrease difference with greater than 11.5 g/L was an independent prognostic factor for DSS and LRFS. Conclusions: The difference in decrease of Hb level during the course of radiation treatment appeared as a poor prognostic factor in Stage I and II nasopharyngeal carcinoma patients.

  19. Microenvironment-Modulated Metastatic CD133+/CXCR4+/EpCAM- Lung Cancer-Initiating Cells Sustain Tumor Dissemination and Correlate with Poor Prognosis.

    PubMed

    Bertolini, Giulia; D'Amico, Lucia; Moro, Massimo; Landoni, Elena; Perego, Paola; Miceli, Rosalba; Gatti, Laura; Andriani, Francesca; Wong, Donald; Caserini, Roberto; Tortoreto, Monica; Milione, Massimo; Ferracini, Riccardo; Mariani, Luigi; Pastorino, Ugo; Roato, Ilaria; Sozzi, Gabriella; Roz, Luca

    2015-09-01

    Metastasis is the main reason for lung cancer-related mortality, but little is known about specific determinants of successful dissemination from primary tumors and metastasis initiation. Here, we show that CD133(+)/CXCR4(+) cancer-initiating cells (CIC) directly isolated from patient-derived xenografts (PDX) of non-small cell lung cancer are endowed with superior ability to seed and initiate metastasis at distant organs. We additionally report that CXCR4 inhibition successfully prevents the increase of cisplatin-resistant CD133(+)/CXCR4(+) cells in residual tumors and their metastatization. Immunophenotypic analysis of lung tumor cells intravenously injected or spontaneously disseminated to murine lungs demonstrated the survival advantage and increased colonization ability of a specific subset of CD133(+)/CXCR4(+) with reduced expression of epithelial cell adhesion molecule (EpCAM(-)), which also shows the greatest in vitro invasive potential. We next prove that recovered disseminated cells from lungs of PDX-bearing mice enriched for CD133(+)/CXCR4(+)/EpCAM(-) CICs are highly tumorigenic and metastatic. Importantly, microenvironment stimuli eliciting epithelial-to-mesenchymal transition, including signals from cancer-associated fibroblasts, are able to increase the dissemination potential of lung cancer cells through the generation of the CD133(+)/CXCR4(+)/EpCAM(-) subset. These findings also have correlates in patient samples where disseminating CICs are enriched in metastatic lymph nodes (20-fold, P = 0.006) and their detection in primary tumors is correlated with poor clinical outcome (disease-free survival: P = 0.03; overall survival: P = 0.05). Overall, these results highlight the importance of specific cellular subsets in the metastatic process, the need for in-depth characterization of disseminating tumor cells, and the potential of therapeutic strategies targeting both primary tumor and tumor-microenvironment interactions. PMID:26141860

  20. High frequency of additional gene mutations in acute myeloid leukemia with MLL partial tandem duplication: DNMT3A mutation is associated with poor prognosis

    PubMed Central

    Kao, Hsiao-Wen; Liang, Der-Cherng; Kuo, Ming-Chung; Wu, Jin-Hou; Dunn, Po; Wang, Po-Nan; Lin, Tung-Liang; Shih, Yu-Shu; Liang, Sung-Tzu; Lin, Tung-Huei; Lai, Chen-Yu; Lin, Chun-Hui; Shih, Lee-Yung

    2015-01-01

    The mutational profiles of acute myeloid leukemia (AML) with partial tandem duplication of mixed-lineage leukemia gene (MLL-PTD) have not been comprehensively studied. We studied 19 gene mutations for 98 patients with MLL-PTD AML to determine the mutation frequency and clinical correlations. MLL-PTD was screened by reverse-transcriptase PCR and confirmed by real-time quantitative PCR. The mutational analyses were performed with PCR-based assays followed by direct sequencing. Gene mutations of signaling pathways occurred in 63.3% of patients, with FLT3-ITD (44.9%) and FLT3-TKD (13.3%) being the most frequent. 66% of patients had gene mutations involving epigenetic regulation, and DNMT3A (32.7%), IDH2 (18.4%), TET2 (18.4%), and IDH1 (10.2%) mutations were most common. Genes of transcription pathways and tumor suppressors accounted for 23.5% and 10.2% of patients. RUNX1 mutation occurred in 23.5% of patients, while none had NPM1 or double CEBPA mutation. 90.8% of MLL-PTD AML patients had at least one additional gene mutation. Of 55 MLL-PTD AML patients who received standard chemotherapy, age older than 50 years and DNMT3A mutation were associated with inferior outcome. In conclusion, gene mutations involving DNA methylation and activated signaling pathway were common co-existed gene mutations. DNMT3A mutation was a poor prognostic factor in MLL-PTD AML. PMID:26375248

  1. Analyses of resected human brain metastases of breast cancer reveal the association between up-regulation of hexokinase 2 and poor prognosis.

    PubMed

    Palmieri, Diane; Fitzgerald, Daniel; Shreeve, S Martin; Hua, Emily; Bronder, Julie L; Weil, Robert J; Davis, Sean; Stark, Andreas M; Merino, Maria J; Kurek, Raffael; Mehdorn, H Maximilian; Davis, Gary; Steinberg, Seth M; Meltzer, Paul S; Aldape, Kenneth; Steeg, Patricia S

    2009-09-01

    Brain metastases of breast cancer seem to be increasingin incidence as systemic therapy improves. Metastatic disease in the brain is associated with high morbidity and mortality. We present the first gene expression analysis of laser-captured epithelial cells from resected human brain metastases of breast cancer compared with unlinked primary breast tumors. The tumors were matched for histology, tumor-node-metastasis stage, and hormone receptor status. Most differentially expressed genes were down-regulated in the brain metastases, which included, surprisingly, many genes associated with metastasis. Quantitative real-time PCR analysis confirmed statistically significant differences or strong trends in the expression of six genes: BMP1, PEDF, LAMgamma3, SIAH, STHMN3, and TSPD2. Hexokinase 2 (HK2) was also of interest because of its increased expression in brain metastases. HK2 is important in glucose metabolism and apoptosis. In agreement with our microarray results, HK2 levels (both mRNA and protein) were elevated in a brain metastatic derivative (231-BR) of the human breast carcinoma cell line MDA-MB-231 relative to the parental cell line (231-P) in vitro. Knockdown of HK2 expression in 231-BR cells using short hairpin RNA reduced cell proliferation when cultures were maintained in glucose-limiting conditions. Finally, HK2 expression was analyzed in a cohort of 123 resected brain metastases of breast cancer. High HK2 expression was significantly associated with poor patient survival after craniotomy (P = 0.028). The data suggest that HK2 overexpression is associated with metastasis to the brain in breast cancer and it may be a therapeutic target. PMID:19723875

  2. Analyses of Resected Human Brain Metastases of Breast Cancer Reveal the Association between Up-regulation of Hexokinase 2 and Poor Prognosis

    PubMed Central

    Palmieri, Diane; Fitzgerald, Daniel; Shreeve, S. Martin; Hua, Emily; Bronder, Julie L.; Weil, Robert J.; Davis, Sean; Stark, Andreas M.; Merino, Maria J.; Kurek, Raffael; Mehdorn, H. Maximilian; Davis, Gary; Steinberg, Seth M.; Meltzer, Paul S.; Aldape, Kenneth; Steeg, Patricia S.

    2009-01-01

    Brain metastases of breast cancer appear to be increasing in incidence as systemic therapy improves. Metastatic disease in the brain is associated with high morbidity and mortality. We present the first gene expression analysis of laser captured epithelial cells from resected human brain metastases of breast cancer compared to unlinked primary breast tumors. The tumors were matched for histology, TNM stage and hormone receptor status. Most differentially expressed genes were down-regulated in the brain metastases which included, surprisingly, many genes associated with metastasis. Q-PCR analysis confirmed statistically significant differences or strong trends in the expression of six genes: BMP1, PEDF, LAMγ3, SIAH, STHMN3 and TSPD2. Hexokinase 2 (HK2) was also of interest because of its increased expression in brain metastases. HK2 is important in glucose metabolism and apoptosis. In agreement with our microarray results, HK2 levels (both mRNA and protein) were elevated in a brain metastatic derivative (231-BR) of the human breast carcinoma cell line MDA-MB-231 relative to the parental cell line (231-P), in vitro. Knockdown of HK2 expression in 231-BR cells using shRNA reduced cell proliferation when cultures were maintained in glucose limiting conditions. Finally, HK2 expression was analyzed in a cohort of 123 resected brain metastases of breast cancer. High HK2 expression was significantly associated with poor patient survival post-craniotomy (P=0.028). The data suggest that HK2 overexpression is associated with metastasis to the brain in breast cancer and it may be a therapeutic target. PMID:19723875

  3. High expression of S100A8 gene is associated with drug resistance to etoposide and poor prognosis in acute myeloid leukemia through influencing the apoptosis pathway

    PubMed Central

    Yang, Xiao-yan; Zhang, Ming-ying; Zhou, Qi; Wu, Shui-yan; Zhao, Ye; Gu, Wei-ying; Pan, Jian; Cen, Jian-nong; Chen, Zi-xing; Guo, Wen-ge; Chen, Chien-shing; Yan, Wen-hua; Hu, Shao-yan

    2016-01-01

    S100A8 has been increasingly recognized as a biomarker in multiple solid tumors and has played pivotal roles in hematological malignancies. S100A8 is potentially an indicator for poor survival in acute myeloid leukemia (AML) in retrospective studies. However, the mechanisms of S100A8 are diverse in cancers. In this study, we investigated the correlation of S100A8 at the transcription level with clinical parameters in 91 de novo AML patients and explored its mechanisms of chemoresistance to etoposide in vitro. The transcription level of S100A8 was significantly lower at initial and relapse stages of AML samples than at complete remission (P<0.001) and than in the control group (P=0.0078), while no significant difference could be found between initial and relapse stages (P=0.257). Patients with high transcription levels of S100A8 exhibited a shorter overall survival (P=0.0012). HL-60 cells transfected with S100A8 showed resistance to etoposide with a higher level IC50 value and lower apoptosis rate compared with HL-60 cells transfected with empty vector. Thirty-six genes were significantly downregulated and 12 genes were significantly upregulated in S100A8 overexpression group compared with control group in which 360 genes involved in apoptotic genes array were performed by real-time reverse transcriptase polymerase chain reaction. Among them, the caspase-3, Bcl-2, and Bax were verified by Western blot analysis which indicated that the role of S100A8 in resistance to chemotherapy was closely related with antiapoptosis. In conclusion, critical S100A8 provided useful clinical information in predicting the outcome of AML. The main mechanism of S100A8 which promoted chemoresistance was antiapoptosis. PMID:27540302

  4. ELMO1 is upregulated in AML CD34+ stem/progenitor cells, mediates chemotaxis and predicts poor prognosis in normal karyotype AML.

    PubMed

    Capala, Marta E; Vellenga, Edo; Schuringa, Jan Jacob

    2014-01-01

    Both normal as well leukemic hematopoietic stem cells critically depend on their microenvironment in the bone marrow for processes such as self-renewal, survival and differentiation, although the exact pathways that are involved remain poorly understood. We performed transcriptome analysis on primitive CD34+ acute myeloid leukemia (AML) cells (n = 46), their more differentiated CD34- leukemic progeny, and normal CD34+ bone marrow cells (n = 31) and focused on differentially expressed genes involved in adhesion and migration. Thus, Engulfment and Motility protein 1 (ELMO1) was identified amongst the top 50 most differentially expressed genes. ELMO1 is a crucial link in the signaling cascade that leads to activation of RAC GTPases and cytoskeleton rearrangements. We confirmed increased ELMO1 expression at the mRNA and protein level in a panel of AML samples and showed that high ELMO1 expression is an independent negative prognostic factor in normal karyotype (NK) AML in three large independent patient cohorts. Downmodulation of ELMO1 in human CB CD34+ cells did not significantly alter expansion, progenitor frequency or differentiation in stromal co-cultures, but did result in a decreased frequency of stem cells in LTC-IC assays. In BCR-ABL-transduced human CB CD34+ cells depletion of ELMO1 resulted in a mild decrease in proliferation, but replating capacity of progenitors was severely impaired. Downregulation of ELMO1 in a panel of primary CD34+ AML cells also resulted in reduced long-term growth in stromal co-cultures in two out of three cases. Pharmacological inhibition of the ELMO1 downstream target RAC resulted in a severely impaired proliferation and survival of leukemic cells. Finally, ELMO1 depletion caused a marked decrease in SDF1-induced chemotaxis of leukemic cells. Taken together, these data show that inhibiting the ELMO1-RAC axis might be an alternative way to target leukemic cells. PMID:25360637

  5. Prognostic Relevance of Cytokine Receptor Expression in Acute Myeloid Leukemia: Interleukin-2 Receptor α-Chain (CD25) Expression Predicts a Poor Prognosis.

    PubMed

    Nakase, Kazunori; Kita, Kenkichi; Kyo, Taiichi; Ueda, Takanori; Tanaka, Isao; Katayama, Naoyuki

    2015-01-01

    A variety of cytokine/cytokine receptor systems affect the biological behavior of acute leukemia cells. However, little is known about the clinical relevance of cytokine receptor expression in acute myeloid leukemia (AML). We quantitatively examined the expression of interleukin-2 receptor α-chain (IL-2Rα, also known as CD25), IL-2Rβ, IL-3Rα, IL-4Rα, IL-5Rα, IL-6Rα, IL-7Rα, the common β-chain (βc), γc, granulocyte-macrophage colony-stimulating factor (GM-CSF)Rα, G-CSFR, c-fms, c-mpl, c-kit, FLT3, and GP130 in leukemia cells from 767 adult patients with AML by flow cytometry and determined their prevalence and clinical significance. All cytokine receptors examined were expressed at varying levels, whereas the levels of IL-3Rα, GM-CSFRα, IL-2Rα, γc, c-kit, and G-CSFR exhibited a wide spectrum of ≥10,000 sites/cell. In terms of their French-American-British classification types, GM-CSFRα and c-fms were preferentially expressed in M4/M5 patients, G-CSF in M3 patients, and IL-2Rα in non-M3 patients. Elevated levels of IL-3Rα, GM-CSFRα, and IL-2Rα correlated with leukocytosis. In patients ≤60 years old, higher levels of these 3 receptors correlated with poor responses to conventional chemotherapy, but only IL-2Rα was associated with a shorter overall survival. By incorporating IL-2Rα status into cytogenetic risk stratification, we could sort out a significantly adverse-risk cohort from the cytogenetically intermediate-risk group. Analyses with various phenotypical risk markers revealed the expression of IL-2Rα as an independent prognostic indicator in patients with intermediate-risk cytogenetics. These findings were not observed in patients >60 years old. Our results indicate that several cytokine receptors were associated with certain cellular and clinical features, but IL-2Rα alone had prognostic value that provides an additional marker to improve current risk evaluation in AML patients ≤60 years old. PMID:26375984

  6. Prognostic Relevance of Cytokine Receptor Expression in Acute Myeloid Leukemia: Interleukin-2 Receptor α-Chain (CD25) Expression Predicts a Poor Prognosis

    PubMed Central

    Nakase, Kazunori; Kita, Kenkichi; Kyo, Taiichi; Ueda, Takanori; Tanaka, Isao; Katayama, Naoyuki

    2015-01-01

    A variety of cytokine/cytokine receptor systems affect the biological behavior of acute leukemia cells. However, little is known about the clinical relevance of cytokine receptor expression in acute myeloid leukemia (AML). We quantitatively examined the expression of interleukin-2 receptor α-chain (IL-2Rα, also known as CD25), IL-2Rβ, IL-3Rα, IL-4Rα, IL-5Rα, IL-6Rα, IL-7Rα, the common β-chain (βc), γc, granulocyte-macrophage colony-stimulating factor (GM-CSF)Rα, G-CSFR, c-fms, c-mpl, c-kit, FLT3, and GP130 in leukemia cells from 767 adult patients with AML by flow cytometry and determined their prevalence and clinical significance. All cytokine receptors examined were expressed at varying levels, whereas the levels of IL-3Rα, GM-CSFRα, IL-2Rα, γc, c-kit, and G-CSFR exhibited a wide spectrum of ≥10,000 sites/cell. In terms of their French-American-British classification types, GM-CSFRα and c-fms were preferentially expressed in M4/M5 patients, G-CSF in M3 patients, and IL-2Rα in non-M3 patients. Elevated levels of IL-3Rα, GM-CSFRα, and IL-2Rα correlated with leukocytosis. In patients ≤60 years old, higher levels of these 3 receptors correlated with poor responses to conventional chemotherapy, but only IL-2Rα was associated with a shorter overall survival. By incorporating IL-2Rα status into cytogenetic risk stratification, we could sort out a significantly adverse-risk cohort from the cytogenetically intermediate-risk group. Analyses with various phenotypical risk markers revealed the expression of IL-2Rα as an independent prognostic indicator in patients with intermediate-risk cytogenetics. These findings were not observed in patients >60 years old. Our results indicate that several cytokine receptors were associated with certain cellular and clinical features, but IL-2Rα alone had prognostic value that provides an additional marker to improve current risk evaluation in AML patients ≤60 years old. PMID:26375984

  7. Secretory Phospholipase A2-IIa is a Target Gene of the HER/HER2-Elicited Pathway and a Potential Plasma Biomarker for Poor Prognosis of Prostate Cancer

    PubMed Central

    Oleksowicz, Leslie; Liu, Yin; Bracken, R. Bruce; Gaitonde, Krishnanath; Burke, Barbara; Succop, Paul; Levin, Linda; Dong, Zhongyun; Lu, Shan

    2012-01-01

    BACKGROUND Our previous study showed that prostate cancer cells overexpress and secrete secretory phospholipases A2 group IIa (sPLA2-IIa) and plasma sPLA2-IIa was elevated in prostate cancer patients. The current study further explored the underlying mechanism of sPLA2-IIa overexpression and the potential role of sPLA2-IIa as a prostate cancer biomarker. METHODS Plasma and tissue specimens from prostate cancer patients were analyzed for sPLA2-IIa levels. Regulation of sPLA2-IIa expression by Heregulin-α was determined by western blot and reporter assay. RESULTS We found that Heregulin-α enhanced expression of the sPLA2-IIa gene via the HER2/HER3-elicited pathway. The EGFR/HER2 dual inhibitor Lapatinib and the NF-kB inhibitor Bortezomib inhibited sPLA2-IIa expression induced by Heregulin-α. Heregulin-α upregulated expression of the sPLA2-IIa gene at the transcriptional level. We further confirmed that plasma sPLA2-IIa secreted by mouse bearing human prostate cancer xenografts reached detectable plasma concentrations. A Receiver Operating Characteristic (ROC) analysis of patient plasma specimens revealed that high levels of plasma sPLA2-IIa, with the optimum cutoff value of 2.0 ng/ml, were significantly associated with high Gleason score (8~10) relative to intermediate Gleason score (6~7) prostate cancers and advanced relative to indolent cancers. The area under the ROC curve (AUC) was 0.73 and 0.74, respectively. CONCLUSION We found that Heregulin-α, in addition to EGF, contributes to sPLA2-IIa overexpression in prostate cancer cells. Our findings support the notion that high levels of plasma sPLA2-IIa may serve as a poor prognostic biomarker capable of distinguishing aggressive from indolent prostate cancers, which may improve decision making and optimize patient management. PMID:22127954

  8. ALDH1-High Ovarian Cancer Stem-Like Cells Can Be Isolated from Serous and Clear Cell Adenocarcinoma Cells, and ALDH1 High Expression Is Associated with Poor Prognosis

    PubMed Central

    Kuroda, Takafumi; Hirohashi, Yoshihiko; Torigoe, Toshihiko; Yasuda, Kazuyo; Takahashi, Akari; Asanuma, Hiroko; Morita, Rena; Mariya, Tasuku; Asano, Takuya; Mizuuchi, Masahito; Saito, Tsuyoshi; Sato, Noriyuki

    2013-01-01

    Cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) are defined as a small population of cancer cells that have high tumorigenicity. Furthermore, CSCs/CICs are resistant to several cancer therapies, and CSCs/CICs are therefore thought to be responsible for cancer recurrence after treatment and distant metastasis. In epithelial ovarian cancer (EOC) cases, disease recurrence after chemotherapy is frequently observed, suggesting ovarian CSCs/CICs are involved. There are four major histological subtypes in EOC, and serous adenocarcinoma and clear cell adenocarcinoma are high-grade malignancies. We therefore analyzed ovarian CSCs/CICs from ovarian carcinoma cell lines (serous adenocarcinoma and clear cell adenocarcinoma) and primary ovarian cancer cells in this study. We isolated ovarian CSCs/CICs as an aldehyde dehydrogenase 1 high (ALDH1high) population from 6 EOC cell lines (3 serous adenocarcinomas and 3 clear cell adenocarcinomas) by the ALDEFLUOR assay. ALDH1high cells showed greater sphere-forming ability, higher tumorigenicity and greater invasive capability, indicating that ovarian CSCs/CICs are enriched in ALDH1high cells. ALDH1high cells could also be isolated from 8 of 11 primary ovarian carcinoma samples. Immunohistochemical staining revealed that higher ALDH1 expression levels in ovary cancer cases are related to poorer prognosis in both serous adenocarcinoma cases and clear cell adenocarcinoma cases. Taken together, the results indicate that ALDH1 is a marker for ovarian CSCs/CICs and that the expression level of ALDH1 might be a novel biomarker for prediction of poor prognosis. PMID:23762304

  9. Regulation of COX-2 expression and epithelial-to-mesenchymal transition by hypoxia-inducible factor-1α is associated with poor prognosis in hepatocellular carcinoma patients post TACE surgery

    PubMed Central

    HUANG, MINGSHENG; WANG, LONG; CHEN, JUNWEI; BAI, MINGJUN; ZHOU, CHUREN; LIU, SUJUAN; LIN, QU

    2016-01-01

    Currently, it is not entirely clear whether hypoxia-inducible factor-1α (HIF-1α) is involved in the regulation of COX-2 expression and epithelial-to-mesenchymal transition (EMT), and whether these events affect the prognosis of hepatocellular carcinoma (HCC) patients treated with transcatheter arterial chemoembolization (TACE). In this report the relationship between HIF-1α and COX-2 protein expression, EMT in tumor specimens from HCC patients after TACE surgery and the clinical significance of HIF-1α and COX-2 expression were analyzed using statistical approaches. HepG2 cells treated with CoCl2 was employed as a hypoxia cell model in vitro to study hypoxia-induced HIF-1α, COX-2 expression, and EMT alteration. The results showed that HIF-1α and COX-2 protein expression increased in HCC tissues after TACE surgery. Moreover, there was positive correlation between upregulation of HIF-1α and COX-2. Elevated expression of HIF-1α increased both Snail and Vimentin protein expression, while it reduced E-cadherin protein expression. It was further verified that hypoxia enhanced protein expression of HIF-1α and COX-2 in HepG2 cells treated with CoCl2. Upregulation of HIF-1α and COX-2, together with EMT alteration resulted in increased migration and invasion of HepG2 cells under hypoxia. In conclusion, TACE surgery results in aggravated hypoxia status, leading to increased HIF-1α protein expression in HCC tissue. To adapt to hypoxic environment, HIF-1α stimulates COX-2 protein expression and promotes EMT process in hepatocellular cancer cells, which enhances HCC invasion and metastasis, and might contribute to poor prognosis in HCC patients post TACE treatment. PMID:26984380

  10. [AORTOENTERIC FISTULA, A POOR PROGNOSIS FINDING].

    PubMed

    Benoit, A; Thai, M; Medart, L; Desiron, Q; Fraipont, V

    2016-05-01

    We report the case of a patient admitted with upper gastrointestinal bleeding. The CT scan revealed an aorto-duodenal fistula. This case highlights the progression of radiological imaging in parallel with the clinical course. We take this opportunity to write a brief literature review mainly focused on the description and diagnostic modalities of aortoenteric fistulas. PMID:27337841

  11. Uveal melanoma: Estimating prognosis

    PubMed Central

    Kaliki, Swathi; Shields, Carol L; Shields, Jerry A

    2015-01-01

    Uveal melanoma is the most common primary malignant tumor of the eye in adults, predominantly found in Caucasians. Local tumor control of uveal melanoma is excellent, yet this malignancy is associated with relatively high mortality secondary to metastasis. Various clinical, histopathological, cytogenetic features and gene expression features help in estimating the prognosis of uveal melanoma. The clinical features associated with poor prognosis in patients with uveal melanoma include older age at presentation, male gender, larger tumor basal diameter and thickness, ciliary body location, diffuse tumor configuration, association with ocular/oculodermal melanocytosis, extraocular tumor extension, and advanced tumor staging by American Joint Committee on Cancer classification. Histopathological features suggestive of poor prognosis include epithelioid cell type, high mitotic activity, higher values of mean diameter of ten largest nucleoli, higher microvascular density, extravascular matrix patterns, tumor-infiltrating lymphocytes, tumor-infiltrating macrophages, higher expression of insulin-like growth factor-1 receptor, and higher expression of human leukocyte antigen Class I and II. Monosomy 3, 1p loss, 6q loss, and 8q and those classified as Class II by gene expression are predictive of poor prognosis of uveal melanoma. In this review, we discuss the prognostic factors of uveal melanoma. A database search was performed on PubMed, using the terms “uvea,” “iris,” “ciliary body,” “choroid,” “melanoma,” “uveal melanoma” and “prognosis,” “metastasis,” “genetic testing,” “gene expression profiling.” Relevant English language articles were extracted, reviewed, and referenced appropriately. PMID:25827538

  12. The p53 Codon 72 Pro/Pro Genotype Identifies Poor-Prognosis Neuroblastoma Patients: Correlation with Reduced Apoptosis and Enhanced Senescence by the p53-72P Isoform12

    PubMed Central

    Cattelani, Sara; Ferrari-Amorotti, Giovanna; Galavotti, Sara; Defferrari, Raffaella; Tanno, Barbara; Cialfi, Samantha; Vergalli, Jenny; Fragliasso, Valentina; Guerzoni, Clara; Manzotti, Gloria; Soliera, Angela Rachele; Menin, Chiara; Bertorelle, Roberta; McDowell, Heather P; Inserra, Alessandro; Belli, Maria Luisa; Varesio, Luigi; Tweddle, Deborah; Tonini, Gian Paolo; Altavista, Pierluigi; Dominici, Carlo; Raschellà, Giuseppe; Calabretta, Bruno

    2012-01-01

    The p53 gene is rarely mutated in neuroblastoma, but codon 72 polymorphism that modulates its proapoptotic activity might influence cancer risk and clinical outcome. We investigated whether this polymorphism affects neuroblastoma risk and disease outcome and assessed the biologic effects of the p53-72R and p53-72P isoforms in p53-null cells. Comparison of 288 healthy subjects and 286 neuroblastoma patients revealed that the p53-72 polymorphism had no significant impact on the risk of developing neuroblastoma; however, patients with the Pro/Pro genotype had a shorter survival than those with the Arg/Arg or the Arg/Pro genotypes even in the stage 3 and 4 subgroup without MYCN amplification. By Cox regression analysis, the p53 Pro/Pro genotype seems to be an independent marker of poor prognosis (hazard ratio = 2.74; 95% confidence interval = 1.14–6.55, P = .014) together with clinical stage, MYCN status, and age at diagnosis. In vitro, p53-72P was less effective than p53-72R in inducing apoptosis and inhibiting survival of p53-null LAN-1 cells treated with etoposide, topotecan, or ionizing radiation but not taxol. By contrast, p53-72P was more effective in promoting p21-dependent accelerated senescence, alone or in the presence of etoposide. Thus, the p53-72 Pro/Pro genotype might be a marker of poor outcome independent of MYCN amplification, possibly improving risk stratification. Moreover, the lower apoptosis and the enhanced accelerated senescence by the p53-72P isoform in response to DNA damage suggest that patients with neuroblastoma with the p53-72 Pro/Pro genotype may benefit from therapeutic protocols that do not rely only on cytotoxic drugs that function, in part, through p53 activation. PMID:22904680

  13. Mutant p53 determines pancreatic cancer poor prognosis to pancreatectomy through upregulation of cavin-1 in patients with preoperative serum CA19-9 ≥ 1,000 U/mL

    PubMed Central

    Xiang, Jin-Feng; Wang, Wen-Quan; Liu, Liang; Xu, Hua-Xiang; Wu, Chun-Tao; Yang, Jing-Xuan; Qi, Zi-Hao; Wang, Ya-Qi; Xu, Jin; Liu, Chen; Long, Jiang; Ni, Quan-Xing; Li, Min; Yu, Xian-Jun

    2016-01-01

    Patients with pancreatic ductal adenocarcinoma (PDAC) and preoperative CA19-9 ≥ 1,000 U/mL that does not decrease postresection have the worst prognosis, but the mechanism is unclear. Here, we elucidated the relationship between this signature and driver-gene mutations, and the cavins/caveolin-1 axis. Four major driver-genes (KRAS, TP53, CDKN2A/p16, and SMAD4/DPC4) that are associated with PDAC and five critical molecules (cavin-1/-2/-3/-4 and caveolin-1) in the cavins/caveolin-1 axis were screened by immunohistochemistry in tumor tissue microarrays. Additionally, six pancreatic cancer cell lines and a spleen subcapsular inoculation nude mouse model were also used. Overexpression of mutant p53 was the major mutational event in patients with the CA19-9 signature. Cavin-1 was also overexpressed, and mutant p53 correlated directly with high cavin-1 expression in pancreatic cancer cell lines and tumor specimens (P < 0.01). Furthermore, mutant p53R172H upregulated cavin-1 and promoted invasiveness and metastasis of pancreatic cancer cells in vitro and in vivo. Finally, combination of mutant p53 and high cavin-1 density indicated the shortest survival for patients with PDAC after resection (P < 0.001). Mutant p53-driven upregulation of cavin-1 represents the major mechanism of poor outcome for PDAC patients with the CA19-9 signature after resection, indicating that inhibition of cavin-1 may improve the long-term efficacy of pancreatectomy. PMID:26753987

  14. Tissue expression levels of miR-29b and miR-422a in children, adolescents, and young adults' age groups and their association with prediction of poor prognosis in human osteosarcoma.

    PubMed

    Bahador, Reza; Taheriazam, Afshin; Mirghasemi, Alireza; Torkaman, Ali; Shakeri, Mohammadreza; Yahaghi, Emad; Goudarzi, Peyman Karimi

    2016-03-01

    Osteosarcoma is the most common type of bone cancer in children and adolescents. MicroRNAs (miRNAs) play important roles in the development, differentiation, and function of different cell types and in the pathogenesis of various human diseases. miRNAs are differentially expressed in normal and cancer cells. The investigation of miRNA expression between healthy subjects and patients with osteosarcoma is crucial for future clinical trials. In this study, the expression levels of miRNAs were detected by qRT-PCR. Correlation between expression levels of tow miRNAs and different clinicopathological characteristics were analyzed using the χ (2) test. Survival rate was detected using the log-rank test and Kaplan-Meier method. qRT-PCR was shown that expression levels of miR-29b and miR-422a were strongly decreased in osteosarcoma bone tissue compared with noncancerous bone tissues. Our result indicated that the low expression levels of miR-29b and miR-422a showed strong correlation with large tumor size (P = 0.20; 0.029), advanced TNM stage (P = 0.001; 0.012), distant metastasis (P = 0.008; 0.019), and grade of tumor (P = 0.009; 0.016). Kaplan-Meier survival analysis showed that the low expressions of miR-29b/miR-422a were correlated with shorter time overall survival (log-rank test, P = 0.009; P = 0.013). Moreover, multivariate Cox proportional hazards model indicated that miR-29b and miR-422a (P = 0.024; P = 0.016) were independent prognostic markers of overall survival of patients. Our result indicated that downregulation of miR-29b and miR-422a may be linked to the prediction of poor prognosis, indicating that miR-29b and miR-422a may be a valuable prognostic marker for osteosarcoma patients. PMID:26423405

  15. Downregulation of BRAF activated non-coding RNA is associated with poor prognosis for non-small cell lung cancer and promotes metastasis by affecting epithelial-mesenchymal transition

    PubMed Central

    2014-01-01

    . Conclusion We determined that BANCR actively functions as a regulator of EMT during NSCLC metastasis, suggesting that BANCR could be a biomarker for poor prognosis of NSCLC. PMID:24655544

  16. Increased Levels of β-catenin, LEF-1, and HPA-1 Correlate with Poor Prognosis for Acral Melanoma with Negative BRAF and NRAS Mutation in BRAF Exons 11 and 15 and NRAS Exons 1 and 2

    PubMed Central

    Xu, Sanxiong; Zhang, Jinyu; Jiang, Yongxin; Chen, Yongbin; Li, Hongjun; Liu, Xuefeng; Xu, Da; Chen, Yanjin; Yang, Yihao; Zhang, Ya; Li, Dongxu; Xia, Junfeng

    2015-01-01

    To determine the expression of β-catenin, lymphoid enhancer-binding protein-1 (LEF-1), and heparanase-1 (HPA-1) and to evaluate these proteins' potential prognostic values in malignant acral melanoma without mutations in BRAF exons 11 and 15 and NRAS exons 1 and 2, specimens from 90 patients with wild-type BRAF and NRAS were assessed and analyzed by immunohistochemistry and western blotting. The positive expression of β-catenin, lymphoid enhancer-binding protein-1, and heparanase-1 was observed in 36 (72%), 31 (62%), and 32 (64%) of the detected acral melanomas, respectively. The expression of β-catenin, lymphoid enhancer-binding protein-1, and heparanase-1 was not correlated with gender, age, or diseased body parts (p>0.05), but was significantly positively correlated with the tumor node metastasis (TNM) stage and metastasis (correlation=0.406 and 0.716, 0.397 and 0.582, 0.353 and 0.579; p=0.040 and 0.0001, 0.0040 and 0.0001, 0.0120 and 0.0001, respectively). We also observed that the increased expression of β-catenin, lymphoid enhancer-binding protein-1, and heparanase-1 was significantly correlated with decreased survival and poor prognosis (p=0.001, 0.010, and 0.023, respectively). A multifactorial analysis using Cox's regression model revealed that β-catenin, lymphoid enhancer-binding protein-1, heparanase-1, and the TNM stage were all independent factors in malignant melanoma (risk ratios were 7.294, 5.550, 5.622, and 4.794; p-values were 0.007, 0.018, 0.018, and 0.029, respectively). This study may provide the basis for the use of β-catenin, lymphoid enhancer-binding protein-1, and heparanase-1 as novel targets in the treatment of malignant invasion and metastasis in acral melanoma cancer. The expression of β-catenin, LEF-1, and HPA-1 was assessed and compared in malignant melanoma with that of peritumoral tissue and benign nevus in the patients with negative mutations in BRAF exons 11 and 15 and NRAS exons 1 and 2. The study may provide the basis for

  17. Co‑expression of the carbamoyl‑phosphate synthase 1 gene and its long non‑coding RNA correlates with poor prognosis of patients with intrahepatic cholangiocarcinoma.

    PubMed

    Ma, Sen-Lin; Li, Ai-Jun; Hu, Zhao-Yang; Shang, Fu-Sheng; Wu, Meng-Chao

    2015-12-01

    The mechanisms leading to high rates of malignancy and recurrence of human intrahepatic cholangiocarcinoma (ICC) remain unclear. It is difficult to diagnose and assess the prognosis of patients with ICC in the clinic due to the lack of specific biomarkers. In addition, long non‑coding RNAs (lncRNAs) have been reported to serve important roles in certain types of tumorigenesis however a role in ICC remains to be reported. The aim of the current study was to screen for genes and lncRNAs that are abnormally expressed in ICC and to investigate their biological and clinicopathological significance in ICC. The global gene and lncRNA expression profiles in ICC were measured using bioinformatics analysis. Carbamoyl‑phosphate synthase 1 (CPS1) and its lncRNA CPS1 intronic transcript 1 (CPS1‑IT1) were observed to be upregulated in ICC. The expression of CPS1 and CPS1‑IT1 was measured in 31 tissue samples from patients with ICC and a number of cell lines. The effects of CPS1 and CPS1‑IT1 on the proliferation and apoptosis of the ICC‑9810 cell line were measured. In addition, the clinicopathological features and survival rates of patients with ICC with respect to the gene and lncRNA expression status were analyzed. CPS1 and CPS1‑IT1 were co‑upregulated in ICC tissues compared with non‑cancerous tissues. Knockdown of CPS1 andor CPS1‑IT1 reduced the proliferation and increased the apoptosis of ICC‑9810 cells. Additionally, clinical analysis indicated that CPS1 and CPS1‑IT1 were associated with poor liver function and reduced survival rates when the relative expression values were greater than 4 in cancer tissues. The comparisons between the high CPS1 expression group and the low expression group indicated significant differences in international normalized ratio (P=0.048), total protein (P=0.049), indirect bilirubin (P=0.025), alkaline phosphatase (P=0.003) and disease‑free survival (P=0.034). In addition, there were differential trends in CA19‑9

  18. Nuclear expression of Y-box binding protein-1 is associated with poor prognosis in patients with pancreatic cancer and its knockdown inhibits tumor growth and metastasis in mice tumor models.

    PubMed

    Shinkai, Kentaro; Nakano, Kenji; Cui, Lin; Mizuuchi, Yusuke; Onishi, Hideya; Oda, Yoshinao; Obika, Satoshi; Tanaka, Masao; Katano, Mitsuo

    2016-07-15

    The objective of this study was to examine the implication of Y-box-binding protein-1 (YB-1) for the aggressive phenotypes, prognosis and therapeutic target in pancreatic ductal adenocarcinoma (PDAC). YB-1 expression in PDAC, pancreatic intraepithelial neoplasia (PanIN) and normal pancreas specimens was evaluated by immunohistochemistry, and its correlation with clinicopathological features was assessed in patients with PDAC. The effects of YB-1 on proliferation, invasion and expressions of cell cycle-related proteins and matrix metalloproteinases (MMPs) were analyzed by WST-8, cell cycle and Matrigel invasion assays, Western blotting and quantitative RT-PCR in PDAC cells transfected with YB-1-siRNAs. To verify the significance of YB-1 for tumor progression in vivo, the growth and metastasis were monitored after intrasplenic implantation of ex vivo YB-1 siRNA-transfected PDAC cells, and YB-1-targeting antisense oligonucleotides were intravenously administered in nude mice harboring subcutaneous tumor. The intensity of YB-1 expression and positivity of nuclear YB-1 expression were higher in PDAC than PanIN and normal pancreatic tissues. Nuclear YB-1 expression was significantly associated with dedifferentiation, lymphatic/venous invasion and unfavorable prognosis. YB-1 knockdown inhibited cell proliferation via cell cycle arrest by S-phase kinase-associated protein 2 downregulation and consequent p27 accumulation, and decreased the invasion due to downregulated membranous-type 2 MMP expression in PDAC cells. Tumor growth and liver metastasis formation were significantly suppressed in nude mice after implantation of YB-1-silenced PDAC cells, and the YB-1 targeting antisense oligonucleotide significantly inhibited the growth of subcutaneous tumors. In conclusion, YB-1 may be involved in aggressive natures of PDAC and a promising therapeutic target. PMID:26939718

  19. Phase 2 Study of Concurrent Cetuximab Plus Definitive Thoracic Radiation Therapy Followed by Consolidation Docetaxel Plus Cetuximab in Poor Prognosis or Elderly Patients With Locally Advanced Non-Small Cell Lung Cancer

    SciTech Connect

    Dilling, Thomas J.; Extermann, Martine; Kim, Jongphil; Thompson, Lora M.; Yue, Binglin; Stevens, Craig W.; Antonia, Scott; Gray, Jhanelle; Williams, Charles; Haura, Eric; Pinder-Schenck, Mary; Tanvetyanon, Tawee; Kim, Sungjune; Chiappori, Alberto

    2014-11-15

    Background: Recursive partitioning analysis has shown that Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≥2, male sex, and age ≥70 years are prognostic of poor outcome in locally advanced non-small cell lung cancer (LA-NSCLC) patients. Concurrent chemoradiation therapy (CRT) improves survival, but toxicity is a concern in this frail patient cohort. We therefore opened this trial of concurrent definitive thoracic radiation therapy (XRT) and cetuximab, followed by consolidation docetaxel plus cetuximab. Methods and Materials: Eligible patients had pathologically proven, unresectable LA-NSCLC (stage IIA-“dry” IIIB). They had ECOG PS 2 or weight loss ≥5% in 3 months or were aged ≥70 years. The primary objective was progression-free survival (PFS). Secondary objectives included overall survival (OS) and overall response rate (ORR). Results: From May 2008 to November 2010, a total of 32 patients were evaluated in our single-institution, institutional review board–approved prospective clinical trial. Three patients were screen failures and 2 more withdrew consent before treatment, leaving 27 evaluable patients. One was removed because of poor therapy compliance, and 2 were taken off trial because of grade 3 cetuximab-related toxicities but were followed up under intent-to-treat analysis. The median follow-up and OS were 10.5 months. The median PFS was 7.5 months. The ORR was 59.3%. Eight early/sudden deaths were reported. Upon review, 6 patients developed severe pulmonary complications. Conclusions: Patients enrolled in this trial had improved OS compared with poor-PS historical controls (10.5 vs 6.4 months) and comparable OS to good-PS historical controls (10.5 vs 11.9 months) treated with XRT alone. However, pulmonary toxicity is a concern. Consolidative cetuximab/docetaxel, in conjunction with high-dose radiation therapy, is a putative cause.

  20. Zipper-interacting protein kinase promotes epithelial-mesenchymal transition, invasion and metastasis through AKT and NF-kB signaling and is associated with metastasis and poor prognosis in gastric cancer patients.

    PubMed

    Li, Jian; Deng, Zhijuan; Wang, Zhu; Wang, Dong; Zhang, Longjuan; Su, Qiao; Lai, Yingrong; Li, Bin; Luo, Zexing; Chen, Xu; Chen, Yu; Huang, Xiaohui; Ma, Jieyi; Wang, Wenjian; Bi, Jiong; Guan, Xinyuan

    2015-04-10

    Zipper-interacting Protein Kinase (ZIPK) belongs to the death-associated protein kinase family. ZIPK has been characterized as a tumor suppressor in various tumors, including gastric cancer. On the other hand, ZIPK also promotes cell survival. In this study, both in vitro and in vivo assays indicated that ZIPK promoted cell growth, proliferation, migration, invasion, tumor formation and metastasis in nude mice. ZIPK induced epithelial-mesenchymal transition (EMT) with increasing expression of β-catenin, mesenchymal markers, Snail and Slug, and with decreasing expression of E-cadherin. Furthermore, ZIPK activated the AKT/IκB/NF-κB pathway, which can promote EMT and metastasis. Additionally, ZIPK expression was detected in human primary gastric cancer and their matched metastatic lymph node samples by immunohistochemistry. Increased expression of ZIPK in lymph node metastases was significantly associated with stage VI and abdominal organ invasion. Survival analysis revealed that patients with increased ZIPK expression in metastatic lymph nodes had poor disease-specific survival. Taken together, our study reveals that ZIPK is a pro-oncogenic factor, which promotes cancer metastasis. PMID:25831050

  1. CD34 expression on bone marrow blasts is a novel predictor of poor prognosis independent of FlT3-ITD in acute myeloid leukemia with the NPM1-mutation.

    PubMed

    Zhu, Hong-Hu; Liu, Yan-Rong; Jiang, Hao; Lu, Jin; Qin, Ya-Zhen; Jiang, Qian; Bao, Li; Ruan, Guo-Rui; Jiang, Bin; Huang, Xiaojun

    2013-06-01

    To explore the prognostic value of CD34 expression in NPM1-mutated acute myeloid leukemia (NPM1m+AML), seventy-one NPM1m+AML patients were retrospectively analyzed. The patients with >7% CD34 expression (according to the ROC analysis) had a lower complete remission (CR) rate after 1 course of induction, disease-free survival (DFS), and overall survival (OS) compared to those with ≤7% CD34 expression (p=0.0038; p=0.001; p<0.0001). A multivariate analysis revealed that CD34 expression is a prognostic factor that is independent of FlT3-ITD for relapse, DFS and OS. We established a novel prognostic model based on the CD34 and FLT3 status at diagnosis, which could facilitate the segregation of patients into three prognostically different subgroups. We demonstrate that CD34 expression on blasts is a novel, poor predictor independent of FlT3-ITD in NPM1-mutated patients and established a new prognostic model based on the CD34 and FLT3 status at diagnosis, which may facilitate immediate clinical utility for prognostic stratification and risk-adapted therapeutic choices. PMID:23473998

  2. Membranous Insulin-like Growth Factor-1 Receptor (IGF1R) Expression Is Predictive of Poor Prognosis in Patients with Epidermal Growth Factor Receptor (EGFR)-Mutant Lung Adenocarcinoma

    PubMed Central

    Park, Eunhyang; Park, Soo Young; Kim, Hyojin; Sun, Ping-Li; Jin, Yan; Cho, Suk Ki; Kim, Kwhanmien; Lee, Choon-Taek; Chung, Jin-Haeng

    2015-01-01

    Background: Insulin-like growth factor-1 receptor (IGF1R) is a membrane receptor-type tyrosine kinase that has attracted considerable attention as a potential therapeutic target, although its clinical significance in non-small cell lung cancer (NSCLC) is controversial. This study aimed to clarify the clinical significance of IGF1R expression in human NSCLC. Methods: IGF1R protein expression was evaluated using immunohistochemistry in 372 patients with NSCLC who underwent curative surgical resection (146 squamous cell carcinomas [SqCCs] and 226 adenocarcinomas [ADCs]). We then analyzed correlations between expression of IGF1R and clinicopathological and molecular features and prognostic significance. Results: Membranous and cytoplasmic IGF1R expression were significantly higher in SqCCs than in ADCs. In patients with SqCC, membranous IGF1R expression was associated with absence of vascular, lymphatic, and perineural invasion; lower stage; and better progression-free survival (PFS) (hazard ratio [HR], 0.586; p = .040). In patients with ADC, IGF1R expression did not have a significant prognostic value; however, in the subgroup of epidermal growth factor receptor (EGFR)-mutant ADC, membranous IGF1R expression was associated with lymphatic and perineural invasion, solid predominant histology, and higher cancer stage and was significantly associated with worse PFS (HR, 2.582; p = .009). Conclusions: Lung ADC and SqCC showed distinct IGF1R expression profiles that demonstrated prognostic significance. High membranous IGF1R expression was predictive of poor PFS in EGFR-mutant lung ADC, while it was predictive of better PFS in SqCC. These findings will help improve study design for subsequent investigations and select patients for future anti-IGF1R therapy. PMID:26265685

  3. Biological Markers May Indicate Poor Breast Cancer Prognosis

    Cancer.gov

    A team of researchers has found an association between breast cancer survival and two proteins that, when present in the blood in high levels, are indicators of inflammation. Using data from the Health, Eating, Activity and Lifestyle (HEAL) study sponsor

  4. Nonendemic HPV-Positive Nasopharyngeal Carcinoma: Association With Poor Prognosis

    SciTech Connect

    Stenmark, Matthew H.; McHugh, Jonathan B.; Schipper, Matthew; Walline, Heather M.; Komarck, Christine; Feng, Felix Y.; Worden, Francis P.; Wolf, Gregory T.; Chepeha, Douglas B.; Prince, Mark E.; Bradford, Carol R.; Mukherji, Suresh K.; Eisbruch, Avraham; Carey, Thomas E.

    2014-03-01

    Purpose: To investigate the relationship between human papillomavirus (HPV) and Epstein-Barr virus (EBV) in nonendemic nasopharyngeal carcinoma (NPC) and assess the prognostic implications of viral status. Methods and Materials: Paraffin-embedded tumor specimens from 62 patients with primary NPC diagnosed between 1985 and 2011 were analyzed for EBV and high-risk HPV. EBV status was determined by the use of in situ hybridization for EBV encoded RNA. HPV status was assessed with p16 immunohistochemistry and multiplex polymerase chain reaction MassArray for determination of HPV type. Proportional hazards models were used to compare the risk of death among patients as stratified by viral status. Results: Of 61 evaluable tumors, 26 (43%) were EBV-positive/HPV-negative, 18 (30%) were HPV-positive/EBV-negative, and 17 (28%) were EBV/HPV-negative. EBV and HPV infection was mutually exclusive. HPV positivity was significantly correlated with World Health Organization grade 2 tumors, older age, and smoking (all P<.001). The racial distribution of the study population was 74% white, 15% African American, and 11% Asian/Middle Eastern. Among HPV-positive patients, 94% were white. At a median follow-up time of 7 years, HPV-positive and EBV/HPV-negative tumors exhibited worse outcomes than did EBV-positive tumors, including decreased overall survival (hazard ratio [HR] 2.98, P=.01; and HR 3.89, P=.002), progression-free survival (HR 2.55, P=.02; and HR 4.04, P<.001), and locoregional control (HR 4.01, P=.03; and HR 6.87, P=.001). Conclusion: In our Midwestern population, high-risk HPV infection may play an etiologic role in the development of nonendemic, EBV-negative NPC. Compared with EBV-positive NPC, HPV-positive and EBV/HPV-negative NPC are associated with worse outcomes. A larger confirmatory study is needed to validate these findings.

  5. Nonendemic HPV-Positive Nasopharyngeal Carcinoma: Association With Poor Prognosis

    PubMed Central

    Stenmark, Matthew H.; McHugh, Jonathan B.; Schipper, Matthew; Walline, Heather M.; Komarck, Christine; Feng, Felix Y.; Worden, Francis P.; Wolf, Gregory T.; Chepeha, Douglas B.; Prince, Mark E.; Bradford, Carol R.; Mukherji, Suresh K.; Eisbruch, Avraham; Carey, Thomas E.

    2014-01-01

    Purpose To investigate the relationship between human papillomavirus (HPV) and Epstein-Barr virus (EBV) in non-endemic nasopharyngeal carcinoma (NPC) and assess the prognostic implications of viral status. Methods and Materials Paraffin-embedded tumor specimens from 62 patients with primary NPC diagnosed between 1985 and 2011 were analyzed for EBV and high-risk HPV. EBV status was determined using in situ hybridization for EBV encoded RNA. HPV status was assessed with p16 immunohistochemistry and multiplex PCR-MassArray for determination of HPV type. Proportional hazards models were used to compare the risk of death among patients as stratified by viral status. Results Of 61 evaluable tumors, 26 (43%) were EBV-positive/HPV-negative, 18 (30%) were HPV-positive/EBV-negative, and 17 (28%) were EBV/HPV-negative. EBV and HPV infection was mutually exclusive. HPV-positivity was significantly correlated with WHO grade II tumors, older age, and smoking (all p <0.001). The racial distribution of the study population was 74% Caucasian, 15% African American, and 11% Asian/Middle Eastern. Among HPV-positive patients, 94% were Caucasian. At a median follow-up of 7 years, HPV-positive and EBV/HPV-negative tumors exhibited worse outcomes as compared to EBV-positive tumors, including decreased overall survival (hazard ratio [HR] 2.98, p=0.01 and HR 3.89, p=0.002], progression-free survival (HR 2.55, p=0.02 and HR 4.04, p <0.001], and locoregional control (HR 4.01, p=0.03 and HR 6.87, p=0.001). Conclusion In our Midwestern population high-risk HPV infection may play an etiologic role in the development of non-endemic, EBV-negative NPC. Compared with EBV-positive NPC, HPV positive and EBV/HPV-negative NPC are associated with worse outcomes. A larger confirmatory study is needed to validate these findings. PMID:24521676

  6. Understanding Your Cancer Prognosis Video

    Cancer.gov

    Understanding Your Cancer Prognosis is the main video in the NCI Prognosis Video Series, which offers the perspectives of three cancer patients and their doctor, an oncologist who is also a national expert in doctor-patient communication.

  7. Prognosis of occupational asthma.

    PubMed

    Paggiaro, P L; Vagaggini, B; Bacci, E; Bancalari, L; Carrara, M; Di Franco, A; Giannini, D; Dente, F L; Giuntini, C

    1994-04-01

    Several studies on the prognosis of occupational asthma have shown that a significant proportion of patients continue to experience asthmatic symptoms and nonspecific bronchial hyperresponsiveness after cessation of work. The determinants of this unfavourable prognosis of asthma are: long duration of exposure before the onset of asthma; long duration of symptoms before diagnosis; baseline airway obstruction; dual response after specific challenge test; and the persistence of markers of airway inflammation in bronchoalveolar lavage fluid and bronchial biopsy. The relevance of immunological markers in the outcome of occupational asthma has not yet been assessed. Further occupational exposure in sensitized subjects leads to persistence and sometimes to progressive deterioration of asthma, irrespective of the reduction of exposure to the specific sensitizer, and only the use of particular protective devices effectively prevents the progression of the disease. A long-term follow-up study of toluene diisocyanate (TDI)-induced asthma showed that the improvement in bronchial hyperresponsiveness to methacholine occurred in a small percentage of subjects and only a long time after work cessation. Bronchial sensitivity to TDI may disappear, but non-specific bronchial hyperresponsiveness often persists unchanged, suggesting a permanent deregulation of airway tone. Steroid treatment significantly reduces nonspecific bronchial hyperresponsiveness only when started immediately after diagnosis. PMID:8005260

  8. Factors affecting epilepsy development and epilepsy prognosis in cerebral palsy.

    PubMed

    Mert, Gulen Gul; Incecik, Faruk; Altunbasak, Sakir; Herguner, Ozlem; Mert, Mustafa Kurthan; Kiris, Nurcihan; Unal, Ilker

    2011-08-01

    A study was conducted between November 2006 and October 2009 to determine the factors predicting the presence and prognosis of epilepsy in patients with cerebral palsy. We enrolled 2 groups of patients: 42 with cerebral palsy in group 1 and 56 patients with cerebral palsy and epilepsy in group 2. The subjects in group 2 were considered to have good epilepsy prognosis if they were free of seizures for the previous year; otherwise they were considered to have poor epilepsy prognosis. In group 2, neonatal epilepsy, family history of epilepsy, and moderate to severe mental retardation were significantly higher than in group 1 (P < 0.05). In univariate analysis, neonatal seizures, epileptic activity as measured by electroencephalography, and polytherapy were found to be predictors of poor epilepsy prognosis. Additionally, the need for long-term medication to control seizures unfavorably affects prognosis. In logistic regression analysis, neonatal seizure and interictal epileptic activity in electroencephalography were found to be independent predictors of poor epilepsy outcome. In addition, logistic regression analysis revealed that increasing age reduces the success of epilepsy treatment. Neonatal seizures, family history of epilepsy, and mental retardation were found to be important and independent predictors of development of epilepsy in patients with cerebral palsy. PMID:21763948

  9. Prognosis in diabetic nephropathy.

    PubMed Central

    Parving, H. H.; Hommel, E.

    1989-01-01

    OBJECTIVE--To assess the effect of long term antihypertensive treatment on prognosis in diabetic nephropathy. DESIGN--Prospective study of all insulin dependent diabetic patients aged under 50 with onset of diabetes before the age of 31 who developed diabetic nephropathy between 1974 and 1978 at Steno Memorial Hospital. SETTING--Outpatient diabetic clinic in tertiary referral centre. PATIENTS--Forty five patients (20 women) with a mean age of 30 (SD 7) years and a mean duration of diabetes of 18 (7) years at onset of persistent proteinuria were followed until death or for at least 10 years. INTERVENTIONS--Antihypertensive treatment was started a median of three (0-13) years after onset of nephropathy. Four patients (9%) received no treatment, and 9 (20%), 13 (29%), and 19 (42%) were treated with one, two, or three drugs, respectively. The median follow up was 12 (4-15) years. MAIN OUTCOME MEASURES--Arterial blood pressure and death. RESULTS--Mean blood pressure at start of antihypertensive treatment was 148/95 (15/50) mm Hg. Systolic blood pressure remained almost unchanged (slope -0.01 (95% confidence interval -0.39 to 0.37) mm Hg a year) while diastolic blood pressure decreased significantly (0.87 (0.65 to 1.10) mm Hg a year) during antihypertensive treatment. The cumulative death rate was 18% (8 to 32%) 10 years after onset of nephropathy, in contrast to previous reports of 50% to 77% 10 years after onset of nephropathy. As in previous studies, uraemia was the main cause of death (9 patients; 64%). CONCLUSIONS--The prognosis of diabetic nephropathy has improved during the past decade largely because of effective antihypertensive treatment. PMID:2504376

  10. [Laron syndrome: Presentation, treatment and prognosis].

    PubMed

    Latrech, Hanane; Polak, Michel

    2016-01-01

    Laron syndrome is a rare cause of short stature due to an abnormality of growth hormone receptor (GHR). It is characterized by poor phenotype-genotype correlation and geographic predilection essentially in the Mediterranean rim, the Middle East and Indian subcontinent. This syndrome corresponds to an endogenous and exogenous complete insensitivity of GH and manifests by early hypoglycemia, an extremely severe short stature and dysmorphic features contrasting with high levels of circulating GH. To date, treatment with recombinant IGF1 is the only treatment option that has improved the terrible prognosis in these patients but does not actually realize the conditions for genuine replacement therapy. PMID:26564390

  11. Clinicopathologic and gene expression parameters predict liver cancer prognosis

    PubMed Central

    2011-01-01

    Background The prognosis of hepatocellular carcinoma (HCC) varies following surgical resection and the large variation remains largely unexplained. Studies have revealed the ability of clinicopathologic parameters and gene expression to predict HCC prognosis. However, there has been little systematic effort to compare the performance of these two types of predictors or combine them in a comprehensive model. Methods Tumor and adjacent non-tumor liver tissues were collected from 272 ethnic Chinese HCC patients who received curative surgery. We combined clinicopathologic parameters and gene expression data (from both tissue types) in predicting HCC prognosis. Cross-validation and independent studies were employed to assess prediction. Results HCC prognosis was significantly associated with six clinicopathologic parameters, which can partition the patients into good- and poor-prognosis groups. Within each group, gene expression data further divide patients into distinct prognostic subgroups. Our predictive genes significantly overlap with previously published gene sets predictive of prognosis. Moreover, the predictive genes were enriched for genes that underwent normal-to-tumor gene network transformation. Previously documented liver eSNPs underlying the HCC predictive gene signatures were enriched for SNPs that associated with HCC prognosis, providing support that these genes are involved in key processes of tumorigenesis. Conclusion When applied individually, clinicopathologic parameters and gene expression offered similar predictive power for HCC prognosis. In contrast, a combination of the two types of data dramatically improved the power to predict HCC prognosis. Our results also provided a framework for understanding the impact of gene expression on the processes of tumorigenesis and clinical outcome. PMID:22070665

  12. The Prognosis of Child Abuse

    ERIC Educational Resources Information Center

    Lynch, Margaret A.

    1978-01-01

    Reviews the prognosis for abused children in terms of death, re-injury, permanent physical damage, growth failure, intellectual retardation, and personality and behavior problems. Discusses problems of collecting data and inadequacies of intervention treatments. (JB)

  13. Poor Americans: How the Poor White Live.

    ERIC Educational Resources Information Center

    Pilisuk, Marc; Pilisuk, Phyllis

    Contents of this book include the following essays which originally appeared in "Transaction" magazine: (1) "Poor Americans: an introduction," Marc Pilisuk and Phyllis Pilisuk; (2) "How the white poor live," Marc Pilisuk and Phyllis Pilisuk; (3) "The culture of poverty," Oscar Lewis; (4) "Life in Appalachia--the case of Hugh McCaslin," Robert…

  14. Sterilizing the Poor

    ERIC Educational Resources Information Center

    Rothman, Sheila M.

    1977-01-01

    Suggests that freedom for the middle classes may mean vulnerability for the poor. The enthusiasm for sterilization may be so intense as to deprive the poor of their right not to be sterilized. (Author/AM)

  15. [Paresthesia of the inferior dental nerve: clinical signs, etiological diagnosis and prognosis 1].

    PubMed

    Yana, Y; Boukobza, F; Mardam-Bey, W; Derycke, R

    1990-01-01

    This article is about the different iatrogenic (or others) mechanical and/or chemical trauma that can affect the mandibular nerve and which can lead to paresthesia. Depending on the different causes of the paresthesia, the prognosis for nerve sensitivity regeneration will vary: In some cases treatment is necessary to make the symptoms disappear, in others expectation will be the rull and the prognosis is very poor. PMID:2237104

  16. Exercise hypertension: an adverse prognosis?

    PubMed

    Smith, Ryan G; Rubin, Stanley A; Ellestad, Myrvin H

    2009-01-01

    We sought to clarify the prognostic importance of an "exaggerated" or "hypertensive" systolic blood pressure response to exercise during an exercise test. Studies evaluating the prognosis for cardiovascular events and cardiovascular mortality in those with hypertension during exercise testing were systematically reviewed. Fourteen studies were identified. Six studies were of healthy volunteers or hypertensives. Eight studies were in subjects with known or suspected heart disease. Without established heart disease, exercise hypertension predicted cardiovascular events and cardiovascular death. However, two of the six studies included a multivariate analysis; both demonstrated no independent association. Studies in subjects with known or suspected heart disease demonstrated that exercise hypertension predicted fewer cardiac events and lesser mortality or, after multivariate adjustment, no associated risk. In a healthy population, a higher exercise blood pressure may indicate hypertension or prehypertension, instead of normal vascular function, and an associated long-term adverse prognosis. In a population with a high burden of heart disease, the highest risk subjects with the most extensive cardiac disease may not be capable of generating pressure or workload to allow the manifestation of exercise systolic hypertension. By comparison, therefore, those with exercise hypertension have a better prognosis. PMID:20409979

  17. Rich Donors, Poor Countries

    ERIC Educational Resources Information Center

    Thomas, M. A.

    2012-01-01

    The shifting ideological winds of foreign aid donors have driven their policy towards governments in poor countries. Donors supported state-led development policies in poor countries from the 1940s to the 1970s; market and private-sector driven reforms during the 1980s and 1990s; and returned their attention to the state with an emphasis on…

  18. Inference in `poor` languages

    SciTech Connect

    Petrov, S.

    1996-10-01

    Languages with a solvable implication problem but without complete and consistent systems of inference rules (`poor` languages) are considered. The problem of existence of finite complete and consistent inference rule system for a ``poor`` language is stated independently of the language or rules syntax. Several properties of the problem arc proved. An application of results to the language of join dependencies is given.

  19. PSMB8 and PBK as potential gastric cancer subtype-specific biomarkers associated with prognosis

    PubMed Central

    Kwon, Chae Hwa; Park, Hye Ji; Choi, Yu Ri; Kim, Ahrong; Kim, Hye Won; Choi, Jin Hwa; Hwang, Chung Su; Lee, So Jung; Choi, Chang In; Jeon, Tae Yong; Kim, Dae Hwan; Kim, Gwang Ha; Park, Do Youn

    2016-01-01

    Gastric adenocarcinoma is a common form of cancer associated with a poor prognosis. We analyzed microarray profiling data from 48 patients with gastric adenocarcinoma to characterize gastric cancer subtypes and identify biomarkers associated with prognosis. We identified two major subtypes of gastric adenocarcinoma differentially associated with overall survival (P = 0.025). Genes that were differentially expressed were identified using specific criteria (P < 0.001 and >1.5-fold); expression of 294 and 116 genes was enriched in good and poor prognosis subtypes, respectively. Genes related to translational elongation and cell cycle were upregulated in the poor prognosis group. Of these genes, upregulation of proteasome subunit beta type 8 PSMB8 and PDZ binding kinase PBK was confirmed by real-time reverse transcription-PCR analysis. PSMB8 or PBK knockdown had no effect on gastric cancer cell proliferation but suppressed cell migration and invasion, respectively. Furthermore, immunohistochemistry analysis of 385 gastric cancer patients revealed that increased nuclear expression of PSMB8 and PBK was correlated with depth of invasion, lymph node metastasis, and lower survival rates. Taken together, two gastric adenocarcinoma subtypes were predictive of prognosis. PSMB8 and PBK were predictive of gastric cancer prognosis and could be potential gastric cancer subtype-specific biomarkers. PMID:26894977

  20. Poorly controlled gout: who is doing poorly?

    PubMed Central

    Chia, Faith Li-Ann

    2016-01-01

    Gout, an inflammatory arthritis caused by the deposition of monosodium urate crystals, is commonly seen in primary care and specialist clinics. In recent years, there has been a resurgence of interest in gout due to advances in therapies and the understanding of pathophysiology, with new guidelines being published by international bodies. However, there is still a gap between the goals of treatment and actual day-to-day practice. Barriers that result in poorly controlled gout include patient factors such as lack of understanding of the disease, stigma and nonadherence to treatment, as well as physician factors such as knowledge gaps, inadequate use of allopurinol and lack of ownership of the disease. The medical profession needs to do more to bridge the gap through physician and patient education, identification of treatment targets with appropriate use of drugs, and dissemination of guidelines. PMID:27549096

  1. Poorly controlled gout: who is doing poorly?

    PubMed

    Chia, Faith Li-Ann

    2016-08-01

    Gout, an inflammatory arthritis caused by the deposition of monosodium urate crystals, is commonly seen in primary care and specialist clinics. In recent years, there has been a resurgence of interest in gout due to advances in therapies and the understanding of pathophysiology, with new guidelines being published by international bodies. However, there is still a gap between the goals of treatment and actual day-to-day practice. Barriers that result in poorly controlled gout include patient factors such as lack of understanding of the disease, stigma and nonadherence to treatment, as well as physician factors such as knowledge gaps, inadequate use of allopurinol and lack of ownership of the disease. The medical profession needs to do more to bridge the gap through physician and patient education, identification of treatment targets with appropriate use of drugs, and dissemination of guidelines. PMID:27549096

  2. [Prognosis factors of cholangiocarcinoma: contribution of recent molecular biology tools].

    PubMed

    Malouf, G; Dreyer, C; Guedj, N; Paradis, V; Degos, F; Belghiti, J; Le Tourneau, C; Faivre, S; Raymond, E

    2009-04-01

    Cholangiocarcinoma represents the second most common primary hepatobiliary cancer. Although few patients are candidates for surgery, surgical resection represents the only potential curative option. The prognosis for patients remains poor, despite advances in the understanding of mechanisms involved in carcinogenesis. This review aims to assess clinicopathological factors and biological markers for the ability to predict prognosis. Clinicopathologic factors most often cited are tumor size, lymph node involvement, resecability and surgical margins involvement. Molecular biomarkers have been examined and a number of these, including mdm2, p27, matrix metalloproteinases and vitamin D receptor appear to have prognostic utility. The advent of 'omic'-based profiling offers the potential to assess many different biomarkers at the same time. This 'protein/gene signature' could open the way for developing valid and reproducible predictors of survival based on protein or gene profiles. PMID:19357015

  3. Liver Cirrhosis: Evaluation, Nutritional Status, and Prognosis.

    PubMed

    Nishikawa, Hiroki; Osaki, Yukio

    2015-01-01

    The liver is the major organ for the metabolism of three major nutrients: protein, fat, and carbohydrate. Chronic hepatitis C virus infection is the major cause of chronic liver disease. Liver cirrhosis (LC) results from different mechanisms of liver injury that lead to necroinflammation and fibrosis. LC has been seen to be not a single disease entity but one that can be graded into distinct clinical stages related to clinical outcome. Several noninvasive methods have been developed for assessing liver fibrosis and these methods have been used for predicting prognosis in patients with LC. On the other hand, subjects with LC often have protein-energy malnutrition (PEM) and poor physical activity. These conditions often result in sarcopenia, which is the loss of skeletal muscle volume and increased muscle weakness. Recent studies have demonstrated that PEM and sarcopenia are predictive factors for poorer survival in patients with LC. Based on these backgrounds, several methods for evaluating nutritional status in patients with chronic liver disease have been developed and they have been preferably used in the clinical field practice. In this review, we will summarize the current knowledge in the field of LC from the viewpoints of diagnostic method, nutritional status, and clinical outcomes. PMID:26494949

  4. Liver Cirrhosis: Evaluation, Nutritional Status, and Prognosis

    PubMed Central

    Nishikawa, Hiroki; Osaki, Yukio

    2015-01-01

    The liver is the major organ for the metabolism of three major nutrients: protein, fat, and carbohydrate. Chronic hepatitis C virus infection is the major cause of chronic liver disease. Liver cirrhosis (LC) results from different mechanisms of liver injury that lead to necroinflammation and fibrosis. LC has been seen to be not a single disease entity but one that can be graded into distinct clinical stages related to clinical outcome. Several noninvasive methods have been developed for assessing liver fibrosis and these methods have been used for predicting prognosis in patients with LC. On the other hand, subjects with LC often have protein-energy malnutrition (PEM) and poor physical activity. These conditions often result in sarcopenia, which is the loss of skeletal muscle volume and increased muscle weakness. Recent studies have demonstrated that PEM and sarcopenia are predictive factors for poorer survival in patients with LC. Based on these backgrounds, several methods for evaluating nutritional status in patients with chronic liver disease have been developed and they have been preferably used in the clinical field practice. In this review, we will summarize the current knowledge in the field of LC from the viewpoints of diagnostic method, nutritional status, and clinical outcomes. PMID:26494949

  5. Poor school performance.

    PubMed

    Karande, Sunil; Kulkarni, Madhuri

    2005-11-01

    Education is one of the most important aspects of human resource development. Poor school performance not only results in the child having a low self-esteem, but also causes significant stress to the parents. There are many reasons for children to under perform at school, such as, medical problems, below average intelligence, specific learning disability, attention deficit hyperactivity disorder, emotional problems, poor socio-cultural home environment, psychiatric disorders and even environmental causes. The information provided by the parents, classroom teacher and school counselor about the child's academic difficulties guides the pediatrician to form an initial diagnosis. However, a multidisciplinary evaluation by an ophthalmologist, otolaryngologist, counselor, clinical psychologist, special educator, and child psychiatrist is usually necessary before making the final diagnosis. It is important to find the reason(s) for a child's poor school performance and come up with a treatment plan early so that the child can perform up to full potential. PMID:16391452

  6. Morphosyntax in Poor Comprehenders

    ERIC Educational Resources Information Center

    Adlof, Suzanne M.; Catts, Hugh W.

    2015-01-01

    Children described as "poor comprehenders" (PCs) have reading comprehension difficulties in spite of adequate word reading abilities. PCs are known to display weakness with semantics and higher-level aspects of oral language, but less is known about their grammatical skills, especially with regard to morphosyntax. The purpose of this…

  7. Follicular Lymphoma: The Role of the Tumor Microenvironment in Prognosis.

    PubMed

    Sugimoto, Takumi; Watanabe, Takashi

    2016-01-01

    The microenvironment of follicular lymphoma (FL) is composed of tumor-infiltrating CD8(+) T cells, follicular regulatory T cells, lymphoma-associated macrophages and mast cells, follicular helper T cells, follicular dendritic cells, and follicular reticular cells, all of which have been reported to have relevance in the prognosis of FL patients. In addition, some of these cells play a role in the histologic transformation of FL. Macrophages contribute to a poor prognosis in FL patients treated in the pre-rituximab era, but are associated with good prognosis in those treated in the rituximab era. T-cell immunoglobulin and mucin domain protein (TIM) 3 are markers of T-cell exhaustion, and T cells co-expressing programed death 1 (PD1) in peripheral blood and lymph nodes secrete interleukin (IL)-12 in the serum. Serum CXCL9, IL-2 receptor, and IL-1 receptor agonist are associated with shorter survival of FL patients. Agents for manipulation of the microenvironment surrounding FL cells include the immunomodulatory drug lenalidomide, immune check-point inhibitors, and cyclophosphamide prior to rituximab. To battle FL and to improve the outcomes of FL patients, understanding the relationship between neoplastic cells and the various microenvironmental cellular components is crucial for developing therapeutics against the microenvironment. PMID:27334853

  8. Predicting Prognosis for the Conduct-Problem Boy: Can Family History Help?

    ERIC Educational Resources Information Center

    Odgers, Candice L.; Milne, Barry J.; Caspi, Avshalom; Crump, Raewyn; Poulton, Richie; Moffitt, Terrie E.

    2007-01-01

    Objective: Many children with conduct disorder develop life-course persistent antisocial behavior; however, other children exhibit childhood-limited or adolescence-limited conduct disorder symptoms and escape poor adult outcomes. Prospective prediction of long-term prognosis in pediatric and adolescent clinical settings is difficult. Improved…

  9. Prognosis of occupational chromate dermatitis.

    PubMed

    Halbert, A R; Gebauer, K A; Wall, L M

    1992-10-01

    To elucidate further the natural history and prognosis of occupational chromate dermatitis, 120 affected patients, diagnosed between 1980 and 1989, were reviewed. The incidence of chromate dermatitis in Western Australia appeared to remain unchanged over the decade. 65% of patients were construction workers with cement-induced chromate dermatitis. Workers at greatest risk of sensitization were those mixing bagged cement at the work site. The median age at onset of symptoms was 34 years, with 48% having been exposed to chromate for 5 years or less. Only 37% presented to the dermatologist within 12 months of developing symptoms. 76% of patients had ongoing dermatitis at the time of review. Although 48% of the study population had completely changed their occupation to avoid chromate exposure, symptoms persisted in 69%. A delayed diagnosis of chromate sensitivity was noted to be a predictor of chronicity. In view of the potential chronicity of chromate dermatitis and its associated social and occupational impairment, we recommend the addition of ferrous sulphate while mixing bagged cement at the work site. This simple technique targets the workers at greatest risk of becoming sensitized. PMID:1451485

  10. Developmental dyscalculia: prevalence and prognosis.

    PubMed

    Shalev, R S; Auerbach, J; Manor, O; Gross-Tsur, V

    2000-01-01

    The prevalence of developmental dyscalculia (DC) in the school population ranges from 3-6 %, a frequency similar to that of developmental dyslexia and ADHD. These studies fulfilled the criteria for an adequate prevalence study, i.e., were population based, using standardized measures to evaluate arithmetic function. Although the variation in prevalence is within a narrow range, the differences are probably due to which definition of dyscalculia was used, the age the diagnosis was made and the instrument chosen to test for DC. The relative predominance of girls with DC may reflect a greater vulnerability to environmental influences alone or in addition to a biological predisposition. DC is not only encountered as a specific learning disability but also in diverse neurological disorders, examples of which include ADHD, developmental language disorder, epilepsy, treated phenylketonuria and Fragile X syndrome. Although the long-term prognosis of DC is as yet unknown, current data indicate that DC is a stable learning disability persisting, at least for the short term, in about half of affected children. The long-term consequences of DC and its impact on education, employment and psychological well-being have yet to be determined. PMID:11138905

  11. Overexpression of fatty acid synthase predicts a poor prognosis for human gastric cancer

    PubMed Central

    DUAN, JIANGMAN; SUN, LI; HUANG, HONGXIANG; WU, ZHENZHEN; WANG, LIN; LIAO, WANGJUN

    2016-01-01

    Fatty acid synthase (FASN), a lipogenic multi-enzyme complex, is reported to be overexpressed in various types of of tumor tissues and serves an important role in tumor development and progression. However, the expression of FASN and its possible role in gastric cancer (GC) remains to be defined. In the present study, FASN expression in a group sample of 167 GC tissues was detected by immunohistochemistry and its correlation with clinicopathological features was analyzed. By clinical analysis, it was identified that FASN overexpression was positively correlated with the overall survival [P=0.008; hazard ratio (HR), 4.412; 95% confidence interval (CI), 1.463–13.305] and recurrence rate (P=0.014; HR, 1.705; 95% CI, 1.116–2.606) in patients with GC. In addition, expression of the FASN protein in GC tissues was correlated with age (P=0.032), clinical stage (P<0.001), gastric wall invasion (P=0.014), lymph node metastasis (P<0.001) and distant metastasis (P<0.001), however not with gender (P>0.05). In addition, FASN was observed to be overexpressed in GC tissues at an mRNA and protein level, compared with the adjacent non-cancerous tissues (P<0.05). Taken together, it was suggested that FASN was closely associated with GC metastasis and survival, which further provided evidence that FASN may be a promising prognostic biomarker for patients with GC. PMID:26936091

  12. Low cytoplasmic casein kinase 1 epsilon expression predicts poor prognosis in patients with hepatocellular carcinoma.

    PubMed

    Lin, Shu-Hui; Yeh, Chung-Min; Hsieh, Ming-Ju; Lin, Yueh-Min; Chen, Mei-Wen; Chen, Chih-Jung; Lin, Cheng-Yu; Hung, Hsiao-Fang; Yeh, Kun-Tu; Yang, Shun-Fa

    2016-03-01

    Casein kinase 1 epsilon (CK1ε) is a member of the casein kinase 1 (CK1) family, which comprises highly conserved and ubiquitous serine/threonine protein kinases. Recent studies have demonstrated that CK1ε plays a role in human cancers; however, the role of CK1ε in hepatocellular carcinoma (HCC) remains unclear. The study used immunohistochemistry to examine CK1ε expression in 230 HCC specimens by tissue microarray (TMA) and assessed the effect of CK1ε knockdown on migration of human hepatoma cells in vitro. The immunohistochemical analyses showed that low CK1ε expression was significantly correlated with tumor differentiation (p = 0.008), T classification (p = 0.016), tumor vascular invasion (p = 0.002), and cancer stage (p = 0.010). The univariate and multivariate analyses showed that patients with low CK1ε expression had a considerably lower OS rate than that of the patients with high CK1ε expression (p = 0.041, hazard ratio = 1.4; p = 0.039, hazard ratio = 1.4). Moreover, CK1ε small interfering RNA (siRNA) treatment exerted an invasion-promoting effect in human hepatoma cells. In conclusion, our data indicated that low CK1ε expression is correlated with a low survival rate and CK1ε may play a role as a tumor suppressor in hepatocarcinogenesis. PMID:26482619

  13. OTUB1 promotes tumor invasion and predicts a poor prognosis in gastric adenocarcinoma

    PubMed Central

    Weng, Weiwei; Zhang, Qiongyan; Xu, Midie; Wu, Yong; Zhang, Meng; Shen, Chen; Chen, Xiaochen; Wang, Yiqin; Sheng, Weiqi

    2016-01-01

    Backgrounds: The deubiquitinating enzyme OTUB1 participates in multiple cellular processes. However, its expression and functions in gastric adenocarcinoma remains unknown. The aim of this study was to investigate the expression of OTUB1 and its biological role in gastric adenocarcinoma. Methods: We used immunohistochemistry to analyze OTUB1 expressions levels in 80 paired samples of gastric adenocarcinoma and adjacent normal tissue (ANT) and 30 samples of intraepithelial neoplasia (IN). We also analyzed the correlation between OTUB1 expression and clinicopathological parameters and patient survival status. Moreover, we performed wound-healing, transwell, RT-qPCR and Western blot assays to evaluate the impact of OTUB1 on tumor migration and invasion. Results: In gastric adenocarcinomas, staining for OTUB1 was localized in the cytoplasm. The proportion of samples that expressed OTUB1 and the intensity of its expression were much higher in gastric adenocarcinoma tissues (61 out of 80, 76.25%) than that in either IN (10 out of 30, 33.33%, p<0.001) or ANT (7 out of 80, 8.75%, p<0.001) samples. In malignant cases, higher expression OTUB1 levels were significantly associated with deeper tumor invasion depths (p=0.02), advanced lymph node status (p=0.008) and TNM stage (p=0.001), lymph duct invasion (p<0.001) and nerve invasion (p=0.013). Univariate and multivariate Cox regression analyses revealed that OTUB1 was an independent risk factor for disease-specific survival but not disease-free survival. In vitro wound-healing and transwell assays showed that OTUB1 overexpression promoted tumor cell migration and invasion in gastric cancer cells. Conclusion: OTUB1 contributes to gastric cancer development by enhancing tumor invasiveness. Targeting OTUB1 should be considered in future molecular therapies. PMID:27347330

  14. Multimodal Cancer Care in Poor Prognosis Cancers: Resection Drives Long-Term Outcomes

    PubMed Central

    Healy, Mark A.; Yin, Huiying; Wong, Sandra L.

    2016-01-01

    Background and Objectives Hospitals with high complex oncologic surgical volume have improved short-term outcomes. However, for long-term outcomes, the influence of other therapies must be considered. We compared effects of resection with other therapies on long-term outcomes across U.S. hospitals. Methods We examined claims in the Surveillance, Epidemiology, and End Results (SEER)-Medicare dataset for patients with esophageal (EC) and pancreatic (PC) cancers between 2005–2009, with follow-up through 2011, performing multivariable Cox proportional hazards analyses. We stratified hospitals by volume and compared rates of treatments in the context of survival. Results We studied 905 EC and 3,293 PC patients at 138 and 375 hospitals, respectively. For EC, resection rates were significantly higher (32.9% vs. 9.5%, P<0.001) in the highest versus lowest volume hospitals. Adjusted survival was also statistically significantly better (48.5% vs. 43.1%, P<0.001). For PC, resection rates were also statistically significantly higher (30.1% vs. 12.0%, P<0.001) with higher adjusted survival (21.5% vs. 19.9%, P = 0.01). We did not find variation in rates of other cancer treatments across hospitals. Conclusions A significant association exists between long-term survival and rates of cancer-directed surgery across hospitals, without variation in rates of other therapies. Access to resection appears to be key to reducing variation in long-term survival. PMID:26953166

  15. Coexpression of CXCR4 and MMP9 predicts lung metastasis and poor prognosis in resected osteosarcoma.

    PubMed

    Ren, Zhiwu; Liang, Shoulei; Yang, Jilong; Han, Xiuxin; Shan, Luling; Wang, Biying; Mu, Tianyang; Zhang, Yanqin; Yang, Xueli; Xiong, Shunbin; Wang, Guowen

    2016-04-01

    Osteosarcoma is a highly aggressive bone disease with a tendency to metastasize to the lung. The 5-year survival of patients with metastatic osteosarcoma is only 20 %. Many studies have demonstrated SDF-1/CXCR4 and MMP9 play important roles in the metastasis of malignant tumors, including osteosarcoma. The aim of this study was to investigate the association of CXCR4 and MMP9 expression with clinicopathological features and pulmonary metastasis in osteosarcoma. Using tumor tissue microarrays, we analyzed the expression of CXCR4 and MMP9 among 34 primary osteosarcomas with pulmonary metastasis and 62 primary osteosarcomas without metastasis. A median time of 57.5 months (range: 6 to 171 months) follow-up was performed to evaluate tumor metastasis and the patient survival. The prognostic values were determined by univariate Kaplan-Meier survival analysis and multivariate Cox proportional hazard model analysis. The accuracy of oncologic outcome prediction was evaluated by receiver-operating characteristics (ROC) curves (AUC). The expression of CXCR4 and MMP9 was significantly correlated in tumor tissues (P = 0.026). Both CXCR4 and MMP9 were independent predictors for overall survival and metastasis-free survival by Cox multivariate analysis, and high expression for both CXCR4 and MMP9 were even more significant and better biomarkers for osteosarcoma metastasis and survival. The combination of CXCR4 and MMP9 high expression is very likely to be a valuable independent predictor of lung metastasis and survival in osteosarcoma patients. PMID:26546437

  16. Increased expression of formin-like 3 contributes to metastasis and poor prognosis in colorectal carcinoma.

    PubMed

    Zeng, Yuan-Feng; Xiao, Yi-Sheng; Lu, Ming-Zhi; Luo, Xiao-Jiang; Hu, Guo-Zhu; Deng, Ke-Yu; Wu, Xiao-Mu; Xin, Hong-Bo

    2015-04-01

    Formin-like 3 (FMNL3), a member of diaphanous-related formins subfamily, plays an important role in cytoskeleton reorganization, cell adhesion and cancer cell invasion in vitro. This study aimed to explore the expression of FMNL3 in colorectal carcinoma (CRC) cell-lines and tissues, and further evaluate its prognostic value and correlation with the clinicopathological parameters, and also investigate the effects of FMNL3 gene silencing on the growth and metastasis of CRC in vivo. Immunohistochemical analysis showed that FMNL3 protein was distributed in a punctuate aggregation pattern and located mainly in the cytoplasm of glandular cavity side, close to the nucleus of CRC cells. The positive rate of FMNL3 expression was 87.5% (84/96) in CRC, which was significantly higher than that in adjacent normal mucosa (30%, 9/30). Moreover, FMNL3 protein expressed far more in primary CRC with metastasis and corresponding lymph nodes metastatic CRC than in primary CRC without metastasis. Increased expression of FMNL3 was closely correlated with tumor size, differentiation, serosal invasion, and both lymph node metastasis and distant metastasis. However, it was not correlated with patients' age and gender. According to Kaplan-Meier survival analyses, patients with FMNL3 high expression level had lower overall survival rate than that with FMNL3 low expression level. Univariate and multivariate analyses revealed that high FMNL3 expression was a significant and independent prognostic predictor of patients with CRC. In addition, FMNL3 mRNA and protein levels were substantially up-regulated in CRC-metastasis-derived cell lines, as compared to those in primary-CRC-derived ones. FMNL3 gene silencing suppressed the growth and metastasis of CRC in vivo. In conclusion, FMNL3 plays an important role in the progression and metastasis of CRC and may be a novel potential prognostic predictor and therapeutic target for patients with CRC. PMID:25758200

  17. High expression of TRPM8 predicts poor prognosis in patients with osteosarcoma

    PubMed Central

    Zhao, Wei; Xu, Huimian

    2016-01-01

    The transient receptor potential melastatin member 8 (TRPM8) is a newly characterized oncoprotein involved in various malignant tumors. However, its expression pattern and biological function in osteosarcoma remain unclear. The present study aimed to explore the expression and prognostic significance of TRPM8 in osteosarcoma (OS). The results revealed that the expression of TRPM8 mRNA and protein in OS tissue was significantly higher than that in paired normal bone tissue (P<0.05). Additionally, the level of TRPM8 mRNA and protein in patients with a higher clinical stage and with distant metastasis was markedly higher than in those with a lower clinical stage and no metastasis (P<0.05). Furthermore, a high TRPM8 level was closely associated with clinical stage and distant metastasis (P=0.007 and 0.030), but not associated with the patient age (P=0.481), gender (P=0.905), tumor size (P=0.429), histological subtype (P=0.207) or anatomical location (P=0.369). In addition, OS patients with high TRPM8 expression had significantly shorter overall survival (P=0.008) and disease-free survival times (P=0.008) when compared with patients with low expression of TRPM8. In Cox multivariate analysis, TRPM8 overexpression was identified to be an independent and significant prognostic factor for overall survival (P=0.040), but not for disease-free survival (P=0.051). Collectively, the present data suggest that TRPM8 may play a crucial role in the development and progression of OS, and thus may be considered as a novel molecular target for therapy in patients with OS. PMID:27446440

  18. Malnutrition Identified by the Nutritional Risk Index and Poor Prognosis in Advanced Epithelial Ovarian Carcinoma.

    PubMed

    Yim, Ga Won; Eoh, Kyung Jin; Kim, Sang Wun; Nam, Eun Ji; Kim, Young Tae

    2016-07-01

    Ovarian cancer is a chronic disease with a risk of malnutrition. Nutritional Risk Index (NRI) has been reported as a simple and accurate tool to assess the nutritional status. We sought to explore the prevalence of malnutrition and its association with survival in ovarian cancer. A retrospective study was conducted in 213 advanced ovarian cancer patients. NRI was calculated before and at the end of treatment using patients' body weight and serum albumin level. Overall survival (OS) and progression-free survival (PFS) were estimated by Kaplan-Meier method, and associations were assessed using a Cox proportional hazards analysis adjusted for known prognostic variables. Moderate to severely malnourished patients had lower 5-yr OS (45.3%) compared to normal to mild group (64.0%), respectively (P = 0.024). Adjusted for covariates, the relative risk of death was 5.8 times higher in moderate/severely malnourished group identified at the last course of chemotherapy (HR = 5.896, 95% CI = 2.723-12.764, P < 0.001). Similarly, this cohort had shorter PFS compared with normal to mild risk group (median 15 vs. 28 months, P = 0.011). Malnutrition is prevalent among ovarian cancer patients and is found to be a significant predictor for mortality. PMID:27044606

  19. Downregulation of SASH1 correlates with tumor progression and poor prognosis in ovarian carcinoma

    PubMed Central

    REN, XIAOYAN; LIU, YIFEI; TAO, YUMEI; ZHU, GUOXIANG; PEI, MEILAN; ZHANG, JIANGUO; LIU, JIAN

    2016-01-01

    SAM- and SH3-domain containing 1 (SASH1) is a recently identified tumor suppressor gene that is required in the tumorigenesis of breast and other solid carcinomas. The SASH1 protein contains SH3 and SAM domains, indicating that it may serve an important role in intracellular signal transduction. The purpose of the present study was to investigate the expression of SASH1 in ovarian carcinoma and the correlation between its expression with clinical pathological features and clinical significance, and the effect of SASH1 on cell proliferation, apoptosis and migration of ovarian SKOV3 cells. The human ovarian carcinoma tissues and adjacent normal tissues were collected following surgery. Reverse transcription-quantitative polymerase chain reaction and western blot analysis were used to detect the expression levels of SASH1 mRNA and protein, respectively. The expression levels of SASH1 mRNA and protein in ovarian carcinoma tissues were significantly lower than that observed in adjacent normal tissues (P<0.05). The expression levels of SASH1 in samples from patients without lymph nodes metastasis and patients with early FIGO stage was lower than those with lymph nodes metastasis and patients with advanced FIGO stage (P<0.05). Flow cytometry analysis and Transwell invasion chamber experiments were used to investigate the effect of SASH1 on the cell proliferation, apoptosis and migration of SKOV3 cells. The recombinant plasmid pcDNA3.1-SASH1 was constructed and transfected into SKOV3 cells. In addition, the SKOV3 cells in the pcDNA3.1-SASH1 group exhibited significantly reduced cell growth, proliferation, and migration ability compared to the empty vector group and normal group (P<0.01). There were a greater number of apoptotic cells in the pcDNA3.1-SASH1 group compared to the empty vector group and normal group (P<0.01). Taken together, these results indicated that SASH1 may be a tumor suppressor gene in ovarian carcinoma, and SASH1 expression inhibited growth, proliferation and migration, and enhanced apoptosis of SKOV3 cells. PMID:27123075

  20. ISG15 predicts poor prognosis and promotes cancer stem cell phenotype in nasopharyngeal carcinoma

    PubMed Central

    Han, Ping; Wang, Hong-Bo; Liang, Fa-Ya; Feng, Guo-Kai; Zhou, Ai-Jun; Cai, Mu-Yan; Zhong, Qian; Zeng, Mu-Sheng; Huang, Xiao-Ming

    2016-01-01

    Interferon-stimulated gene 15 (ISG15), the first identified ubiquitin-like protein, is known for its anti-viral capacity. However, its role in tumorigenesis remains controversial. Here, using RNA-seq profiling analysis, we identified ISG15 as a differentially expressed gene in nasopharyngeal carcinoma (NPC) and validated its overexpression in NPC samples and cells. High ISG15 levels in NPC tissues were correlated with more frequent local recurrence and shorter overall survival and disease-free survival. ISG15 overexpression promoted a cancer stem cell phenotype in NPC cells, including increased colony and tumorsphere formation abilities, pluripotency-associated genes expression, and in vivo tumorigenicity. By contrast, knockdown of ISG15 attenuated stemness characteristics in NPC cells. Furthermore, overexpression of ISG15 increased NPC cell resistance to radiation and cisplatin (DDP) treatment. Our study demonstrates a protumor role of ISG15, and suggests that ISG15 is a prognostic predictor and a potential therapeutic target for NPC. PMID:26919245

  1. Serpin peptidase inhibitor clade A member 1 is a biomarker of poor prognosis in gastric cancer

    PubMed Central

    Kwon, C H; Park, H J; Lee, J R; Kim, H K; Jeon, T Y; Jo, H-J; Kim, D H; Kim, G H; Park, D Y

    2014-01-01

    Background: In a previous study, we reported that serpin peptidase inhibitor clade A member 1 (serpinA1) is upregulated in Snail-overexpressing gastric cancer. Although serpinA1 has been studied in several types of cancer, little is known about its roles and mechanisms of action. In this study, we examined the role of serpinA1 in the migration and invasion of gastric cancers and determined its underlying mechanism. Methods: Expression levels were assessed by western blot analyses and real-time PCR. Snail binding to serpinA1 promoter was analysed by chromatin immunoprecipitation (ChIP) assays. The roles of serpinA1 were studied using cell invasion and migration assays. In addition, the clinicopathologic and prognostic significance of serpinA1 expression were validated in 400 gastric cancer patients using immunohistochemical analysis. Results: Overexpression of Snail resulted in upregulation of serpinA1 in gastric cancer cell lines, AGS and MKN45, whereas knockdown of Snail inhibited serpinA1 expression. Chromatin immunoprecipitation analysis showed that overexpression of Snail increased Snail recruitment to the serpinA1 promoter. Overexpression of serpinA1 increased the migration and invasion of gastric cancer cells, whereas knockdown of serpinA1 decreased invasion and migration. Moreover, serpinA1 increased mRNA levels and release of metalloproteinase-8 in gastric cancer cells. Serpin peptidase inhibitor clade A member 1 was observed in the cytoplasm of tumour cells and the stroma by immunohistochemistry. Enhanced serpinA1 expression was significantly associated with increased tumour size, advanced T stage, perineural invasion, lymphovascular invasion, lymph node metastases, and shorter overall survival. Conclusions: Serpin peptidase inhibitor clade A member 1 induces the invasion and migration of gastric cancer cells and its expression is associated with the progression of gastric cancer. These results may provide a potential target to prevent invasion and metastasis in gastric cancer. PMID:25211665

  2. 5-hydroxymethylcytosine loss is associated with poor prognosis for patients with WHO grade II diffuse astrocytomas

    PubMed Central

    Zhang, Feng; Liu, Yifan; Zhang, Zhiwen; Li, Jie; Wan, Yi; Zhang, Liying; Wang, Yangmei; Li, Xia; Xu, Yuqiao; Fu, Xin; Zhang, Xiumin; Zhang, Ming; Zhang, Zhekai; Zhang, Jing; Yan, Qingguo; Ye, Jing; Wang, Zhe; Chen, Charlie Degui; Lin, Wei; Li, Qing

    2016-01-01

    Currently, the reliable prognostic biomarkers for WHO grade II diffuse astrocytomas (DA) are still limited. We investigated the relations between the level of 5-Hydroxymethylcytosine (5hmC), an oxidated production of 5-methylcytosine (5mC) by the ten eleven translocated (TET) enzymes, and clinicopathological features of glioma patients. With an identified anti-5hmC antibody, we performed immunohistochemistry in 287 glioma cases. We detected that 5hmC variably reduced in most gliomas and 5hmC reduction was closely associated with higher pathological grades and shortened survival of glioma patients. In multivariate analysis, 5hmC had no independent prognostic value in the entire patient cohort. However, multivariate analysis within subtypes of gliomas revealed that 5hmC was still a prognostic marker confined to DA. In addition, we detected that IDH1 mutation by DNA sequencing was associated with favorable survival within DA. Lastly, we detected that the combination of 5hmC/KI67 was a useful prognostic marker for restratification of DA. PMID:26864347

  3. 5-hydroxymethylcytosine loss is associated with poor prognosis for patients with WHO grade II diffuse astrocytomas.

    PubMed

    Zhang, Feng; Liu, Yifan; Zhang, Zhiwen; Li, Jie; Wan, Yi; Zhang, Liying; Wang, Yangmei; Li, Xia; Xu, Yuqiao; Fu, Xin; Zhang, Xiumin; Zhang, Ming; Zhang, Zhekai; Zhang, Jing; Yan, Qingguo; Ye, Jing; Wang, Zhe; Chen, Charlie Degui; Lin, Wei; Li, Qing

    2016-01-01

    Currently, the reliable prognostic biomarkers for WHO grade II diffuse astrocytomas (DA) are still limited. We investigated the relations between the level of 5-Hydroxymethylcytosine (5hmC), an oxidated production of 5-methylcytosine (5mC) by the ten eleven translocated (TET) enzymes, and clinicopathological features of glioma patients. With an identified anti-5hmC antibody, we performed immunohistochemistry in 287 glioma cases. We detected that 5hmC variably reduced in most gliomas and 5hmC reduction was closely associated with higher pathological grades and shortened survival of glioma patients. In multivariate analysis, 5hmC had no independent prognostic value in the entire patient cohort. However, multivariate analysis within subtypes of gliomas revealed that 5hmC was still a prognostic marker confined to DA. In addition, we detected that IDH1 mutation by DNA sequencing was associated with favorable survival within DA. Lastly, we detected that the combination of 5hmC/KI67 was a useful prognostic marker for restratification of DA. PMID:26864347

  4. Loss of CSMD1 or 2 may contribute to the poor prognosis of colorectal cancer patients.

    PubMed

    Zhang, Rui; Song, Chun

    2014-05-01

    CUB and sushi multiple domain protein 1 (CSMD1) is a candidate tumor suppressor gene. The three members of CSMD family have very similar structures, each consisting of 14 CUB domains separated from one another by a sushi domain, an additional uninterrupted array of sushi domains, a single transmembrane domain, and a short cytoplasmic tail. In this work, we aimed to study the protein and mRNA levels of the CSMD1, CSMD2, and CSMD3 and evaluate their prognostic importance in colorectal cancer. Reduced expressions of these three proteins were detected in colorectal cancer tissues by comparing matched normal tissues. Low CSMD2 expression was significantly associated with differentiation, lymphatic invasion, and tumor size. CSMD3 was associated with differentiation and lymphatic invasion. CSMD1 and CSMD2 expressions were associated with overall survival. This study offers convincing evidence for the first time that the three genes of CSMD family were downregulated in the patients with colorectal cancer and may be used as predictors of colorectal cancer. PMID:24408017

  5. Azacitidine, Mitoxantrone Hydrochloride, and Etoposide in Treating Older Patients With Poor-Prognosis Acute Myeloid Leukemia

    ClinicalTrials.gov

    2015-08-18

    Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Adult Acute Basophilic Leukemia; Adult Acute Eosinophilic Leukemia; Adult Acute Megakaryoblastic Leukemia; Adult Acute Monoblastic Leukemia; Adult Acute Monocytic Leukemia; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With Maturation; Adult Acute Myeloid Leukemia With Minimal Differentiation; Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL; Adult Acute Myeloid Leukemia Without Maturation; Adult Acute Myelomonocytic Leukemia; Adult Erythroleukemia; Adult Pure Erythroid Leukemia; Alkylating Agent-Related Acute Myeloid Leukemia; Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

  6. True Local Recurrences after Breast Conserving Surgery have Poor Prognosis in Patients with Early Breast Cancer

    PubMed Central

    Sarsenov, Dauren; Ilgun, Serkan; Ordu, Cetin; Alco, Gul; Bozdogan, Atilla; Elbuken, Filiz; Nur Pilanci, Kezban; Agacayak, Filiz; Erdogan, Zeynep; Eralp, Yesim; Dincer, Maktav

    2016-01-01

    Background: This study was aimed at investigating clinical and histopathologic features of ipsilateral breast tumor recurrences (IBTR) and their effects on survival after breast conservation therapy. Methods: 1,400 patients who were treated between 1998 and 2007 and had breast-conserving surgery (BCS) for early breast cancer (cT1-2/N0-1/M0) were evaluated. Demographic and pathologic parameters, radiologic data, treatment, and follow-up related features of the patients were recorded. Results: 53 patients (3.8%) had IBTR after BCS within a median follow-up of 70 months. The mean age was 45.7 years (range, 27-87 years), and 22 patients (41.5%) were younger than 40 years. 33 patients (62.3%) had true recurrence (TR) and 20 were classified as new primary (NP). The median time to recurrence was shorter in TR group than in NP group (37.0 (6-216) and 47.5 (11-192) months respectively; p = 0.338). Progesterone receptor positivity was significantly higher in the NP group (p = 0.005). The overall 5-year survival rate in the NP group (95.0%) was significantly higher than that of the TR group (74.7%, p < 0.033). Multivariate analysis showed that younger age (<40 years), large tumor size (>20 mm), high grade tumor and triple-negative molecular phenotype along with developing TR negatively affected overall survival (hazard ratios were 4.2 (CI 0.98-22.76), 4.6 (CI 1.07-13.03), 4.0 (CI 0.68-46.10), 6.5 (CI 0.03-0.68), and 6.5 (CI 0.02- 0.80) respectively, p < 0.05). Conclusions: Most of the local recurrences after BCS in our study were true recurrences, which resulted in a poorer outcome as compared to new primary tumors. Moreover, younger age (<40), large tumor size (>2 cm), high grade, triple negative phenotype, and having true recurrence were identified as independent prognostic factors with a negative impact on overall survival in this dataset of patients with recurrent breast cancer. In conjunction with a more intensive follow-up program, the role of adjuvant therapy strategies should be explored further in young patients with large and high-risk tumors to reduce the risk of TR. PMID:27158571

  7. The Overexpression of CCAR1 in Hepatocellular Carcinoma Associates with Poor Prognosis

    PubMed Central

    Ha, Sang Yun; Kim, Jeong Hoon; Yang, Jung Wook; Kim, Jimin; Kim, Binnari; Park, Cheol-Keun

    2016-01-01

    Purpose Cell division cycle and apoptosis regulator 1 (CCAR1) plays a dynamic role in regulation of cell growth and apoptosis by serving as a cofactor of steroid/thyroid nuclear receptors, β-catenin, and p53 in a variety of cell types including different cancer cells. However, whether CCAR1 protein is overexpressed in hepatocellular carcinoma (HCC) and the prognostic significance of CCAR1 protein expression in HCC have not been reported. Materials and Methods In 167 HCC patients with long-term follow-up, CCAR1 protein expression was examined by immunohistochemistry. Results High CCAR1 protein expression was observed in 149 of the 167 HCC cases (89.2%) and showed significant correlation with microvascular invasion, intrahepatic metastasis, higher American Joint Committee on Cancer (AJCC) T stage, and early recurrence. High CCAR1 expression showed an unfavorable effect on recurrence-free survival (RFS) (p=0.002). In subgroup analysis, among patients with α-fetoprotein ≤ 20 ng/mL (n=54) and patients with AJCC T stage 1 (n=62), significant differences in RFS were observed between high CCAR1 expression groups and low CCAR1 expression groups (p=0.015 and p=0.004, respectively). High CCAR1 expression tended to be an independent predictor of shorter RFS (p=0.054) and showed an unfavorable effect on overall survival (OS) (p=0.015). In subgroup analysis, among patients with α-fetoprotein ≤ 20 ng/mL (n=54), significant difference in OS was observed between high CCAR1 expression group and low CCAR1 expression group (p=0.046). Conclusion CCAR1 protein could be a potential biomarker predicting RFS in HCC patients after curative hepatectomy. In addition, CCAR1 had prognostic values in HCC patients with normal serum α-fetoprotein levels or early stage HCC. PMID:26511806

  8. Cool seasons are related to poor prognosis in patients with infective endocarditis

    NASA Astrophysics Data System (ADS)

    Chen, Su-Jung; Chao, Tze-Fan; Lin, Yenn-Jiang; Lo, Li-Wei; Hu, Yu-Feng; Tuan, Ta-Chuan; Hsu, Tsui-Lieh; Yu, Wen-Chung; Leu, Hsin-Bang; Chang, Shih-Lin; Chen, Shih-Ann

    2012-09-01

    Many cardiac diseases demonstrate seasonal variations in the incidence and mortality. This study was designed to investigate whether the mortality of infective endocarditis (IE) was higher in cool seasons and to evaluate the effects of cool climate for IE. We enrolled 100 IE patients with vegetations in our hospital. The temperatures of the IE episodes were defined as the monthly average temperatures of the admission days. The average temperatures in the cool (fall/winter) and warm seasons (spring/summer) were 19.2°C and 27.6°C, respectively. In addition, patients admitted with the diagnosis of IE were identified from the National Health Insurance Research Database (NHIRD) and the in-hospital mortality rates in cool and warm seasons were compared to validate the findings derived from the data of our hospital. The mortality rate for IE was significantly higher in fall/winter than in spring/summer which presents consistently in the patient population of our hospital (32.7% versus 12.5%, p = 0.017) and from NHIRD (10.4% versus 4.6%, p = 0.019). IE episodes which occurred during cool seasons presented with a higher rate of heart failure (44.2% versus 22.9%, p = 0.025) and D-dimer level (5.5 ± 3.8 versus 2.4 ± 1.8 μg/ml, p = 0.017) at admission than that of warm seasons. These results may reflect the impact of temperatures during the pre-hospitalized period on the disease process. In the multivariate analysis, Staphylococcal infection, left ventricular hypertrophy, left ventricular systolic dysfunction and temperature were the independent predictors of mortalities in IE patients.

  9. High expression of KIF26B in breast cancer associates with poor prognosis.

    PubMed

    Wang, Qun; Zhao, Zong-Bin; Wang, Geng; Hui, Zhen; Wang, Ming-Hua; Pan, Jun-Feng; Zheng, Hong

    2013-01-01

    To date, a great number of studies have demonstrated that altered expression of kinesins is associated with development and progression of various human cancers. Kinesin family member 26B (KIF26B), a member of the kinesin superfamily proteins (KIFs), is essential for kidney development. However, the role of KIF26B during tumorigenesis and progression is limited. Here, we demonstrate that both KIF26B mRNA and protein are overexpression in breast cancer tissues by RT-qPCR and western blot. Immunohistochemistry revealed that KIF26B expression significantly correlated with clinicopathological factors, including tumor size (P = 0.011), grade (P = 0.017), lymph node status (P = 0.009) and ER status (P = 0.012). Moreover, the Kaplan-Meier analysis indicated that breast cancer patients with high KIF26B expression had a shorter survival than those with low KIF26B expression. In addition, multivariate analysis indicated that KIF26B is an independent prognostic for outcome in breast cancer (HR, 2.356; 95%CI, 1.268-4.378; P = 0.007). Collectively, our study demonstrated that KIF26B was overexpression in breast cancer and could be served as a potential prognostic marker. PMID:23585914

  10. High Expression of KIF26B in Breast Cancer Associates with Poor Prognosis

    PubMed Central

    Wang, Qun; Zhao, Zong-Bin; Wang, Geng; Hui, Zhen; Wang, Ming-Hua; Pan, Jun-Feng; Zheng, Hong

    2013-01-01

    To date, a great number of studies have demonstrated that altered expression of kinesins is associated with development and progression of various human cancers. Kinesin family member 26B (KIF26B), a member of the kinesin superfamily proteins (KIFs), is essential for kidney development. However, the role of KIF26B during tumorigenesis and progression is limited. Here, we demonstrate that both KIF26B mRNA and protein are overexpression in breast cancer tissues by RT-qPCR and western blot. Immunohistochemistry revealed that KIF26B expression significantly correlated with clinicopathological factors, including tumor size (P = 0.011), grade (P = 0.017), lymph node status (P = 0.009) and ER status (P = 0.012). Moreover, the Kaplan-Meier analysis indicated that breast cancer patients with high KIF26B expression had a shorter survival than those with low KIF26B expression. In addition, multivariate analysis indicated that KIF26B is an independent prognostic for outcome in breast cancer (HR, 2.356; 95%CI, 1.268–4.378; P = 0.007). Collectively, our study demonstrated that KIF26B was overexpression in breast cancer and could be served as a potential prognostic marker. PMID:23585914

  11. Poor ovarian reserve.

    PubMed

    Jirge, Padma Rekha

    2016-01-01

    Poor ovarian reserve (POR) is an important limiting factor for the success of any treatment modality for infertility. It indicates a reduction in quantity and quality of oocytes in women of reproductive age group. It may be age related as seen in advanced years of reproductive life or may occur in young women due to diverse etiological factors. Evaluating ovarian reserve and individualizing the therapeutic strategies are very important for optimizing the success rate. Majority or women with POR need to undergo in vitro fertilization to achieve pregnancy. However, pregnancy rate remains low despite a plethora of interventions and is associated with high pregnancy loss. Early detection and active management are essential to minimize the need for egg donation in these women. PMID:27382229

  12. Poor ovarian reserve

    PubMed Central

    Jirge, Padma Rekha

    2016-01-01

    Poor ovarian reserve (POR) is an important limiting factor for the success of any treatment modality for infertility. It indicates a reduction in quantity and quality of oocytes in women of reproductive age group. It may be age related as seen in advanced years of reproductive life or may occur in young women due to diverse etiological factors. Evaluating ovarian reserve and individualizing the therapeutic strategies are very important for optimizing the success rate. Majority or women with POR need to undergo in vitro fertilization to achieve pregnancy. However, pregnancy rate remains low despite a plethora of interventions and is associated with high pregnancy loss. Early detection and active management are essential to minimize the need for egg donation in these women. PMID:27382229

  13. Prognosis research and risk of bias.

    PubMed

    D'Amico, Gennaro; Malizia, Giuseppe; D'Amico, Mario

    2016-03-01

    The interest in prognosis research has been steadily growing during the past few decades because of its impact on clinical decision making. However, since the methodology of prognosis research is still incompletely defined, the quality of published prognosis studies is largely unsatisfactory. Seven major domain for risk of bias in prognosis research have been identified, including study participation, attrition, selection of candidate predictors, outcome definition, confounding factors, analysis, and interpretation of results. The methodology for performing prognostic studies is currently aimed at avoiding such potential biases. Amongst methodologic requirements in prognosis research, the following should be considered most relevant: beforehand publication of the study protocol including the full statistical plan; inclusion of patients at a similar point along the course of the disease; rationale and biological plausibility of candidate predictors; complete information; control of overfitting and underfitting; adequate data handling and analysis; publication of the original data. Validation and analysis of the impact that prediction models have on patient management, are key steps for translation of prognosis research into clinical practice. Finally, transparent reporting of prognostic studies is essential for assessing reliability, applicability and generalizability of study results, and recommendations are now available for this aim. PMID:26910239

  14. Standardized EEG interpretation accurately predicts prognosis after cardiac arrest

    PubMed Central

    Rossetti, Andrea O.; van Rootselaar, Anne-Fleur; Wesenberg Kjaer, Troels; Horn, Janneke; Ullén, Susann; Friberg, Hans; Nielsen, Niklas; Rosén, Ingmar; Åneman, Anders; Erlinge, David; Gasche, Yvan; Hassager, Christian; Hovdenes, Jan; Kjaergaard, Jesper; Kuiper, Michael; Pellis, Tommaso; Stammet, Pascal; Wanscher, Michael; Wetterslev, Jørn; Wise, Matt P.; Cronberg, Tobias

    2016-01-01

    Objective: To identify reliable predictors of outcome in comatose patients after cardiac arrest using a single routine EEG and standardized interpretation according to the terminology proposed by the American Clinical Neurophysiology Society. Methods: In this cohort study, 4 EEG specialists, blinded to outcome, evaluated prospectively recorded EEGs in the Target Temperature Management trial (TTM trial) that randomized patients to 33°C vs 36°C. Routine EEG was performed in patients still comatose after rewarming. EEGs were classified into highly malignant (suppression, suppression with periodic discharges, burst-suppression), malignant (periodic or rhythmic patterns, pathological or nonreactive background), and benign EEG (absence of malignant features). Poor outcome was defined as best Cerebral Performance Category score 3–5 until 180 days. Results: Eight TTM sites randomized 202 patients. EEGs were recorded in 103 patients at a median 77 hours after cardiac arrest; 37% had a highly malignant EEG and all had a poor outcome (specificity 100%, sensitivity 50%). Any malignant EEG feature had a low specificity to predict poor prognosis (48%) but if 2 malignant EEG features were present specificity increased to 96% (p < 0.001). Specificity and sensitivity were not significantly affected by targeted temperature or sedation. A benign EEG was found in 1% of the patients with a poor outcome. Conclusions: Highly malignant EEG after rewarming reliably predicted poor outcome in half of patients without false predictions. An isolated finding of a single malignant feature did not predict poor outcome whereas a benign EEG was highly predictive of a good outcome. PMID:26865516

  15. Morphosyntax in Poor Comprehenders

    PubMed Central

    Adlof, Suzanne M.; Catts, Hugh W.

    2016-01-01

    Children described as poor comprehenders (PCs) have reading comprehension difficulties in spite of adequate word reading abilities. PCs are known to display weakness with semantics and higher-level aspects of oral language, but less is known about their grammatical skills, especially with regard to morphosyntax. The purpose of this study was to examine morphosyntax in fourth grade PCs and typically developing readers (TDs), using three experimental tasks involving finiteness marking. Participants also completed standardized, norm-referenced assessments of phonological memory, vocabulary, and broader language skills. PCs displayed weakness relative to TDs on all three morphosyntax tasks and on every other assessment of oral language except phonological memory, as indexed by nonword repetition. These findings help to clarify the linguistic profile of PCs, suggesting that their language weaknesses include grammatical weaknesses that cannot be fully explained by semantic factors. Because finiteness markers are usually mastered prior to formal schooling in typical development, we call for future studies to examine whether assessments of morphosyntax could be used for the early identification of children at risk for future reading comprehension difficulty.

  16. Mortality after hip fracture with vertebral compression fracture is poor.

    PubMed

    Imai, Norio; Endo, Naoto; Hoshino, Tadashi; Suda, Ken; Miyasaka, Dai; Ito, Tomoyuki

    2016-01-01

    Due to the increasing elderly population, the prevalence of osteoporotic hip fractures in Japanese patients continues to rise. It is well established that patients with either hip fracture or both symptomatic and asymptomatic morphometric vertebral compression fracture (VCF) have a poor health prognosis compared with the general population. The purpose of this study was to retrospectively investigate vertebral fracture rates among patients with hip fracture and their influence on mortality. We examined 182 cases of osteoporotic hip fracture in patients admitted to our institution between January 2009 and May 2011. The average age at the time of fracture was 85 years. Radiographs of the lumbar spine were obtained from all of the participants and the lateral spinal radiographs were examined for evidence of VCF. The patients were classified into two groups, those with VCF and those without. A VCF was identified in approximately 78 % of the patients. The mortality rate 1 year after the hip fracture was approximately 22 % and it was significantly higher in patients with VCF. Through multivariate statistics we found that VCF, post-operative complication, loss of ambulation after operation and medication for osteoporosis were statistically significant. In other words, VCF, post-operative complication and loss of ambulation were considered to be poor prognostic factors and medication for osteoporosis was likely to improve the prognosis. We concluded that the risk of mortality after hip fracture is significantly greater in patients who also have VCF compared to patients without VCF, and that medication for osteoporosis is likely to improve prognosis. PMID:25501699

  17. Impact of Non-Pulmonary Visceral Metastases in the Prognosis and Practice of Metastatic Testicular Germ Cell Tumors

    PubMed Central

    Rossi, Lorena; Martignano, Filippo; Gallà, Valentina; Maugeri, Antonio; Schepisi, Giuseppe

    2016-01-01

    Non-pulmonary visceral metastases, in bones, brain and liver, represent nearly the 10% of metastatic sites of advanced germ cell tumors and are associated with poor prognosis. This review article summarizes major evidences on the impact of different visceral sites on the prognosis, treatment and clinical outcome of patients with germ cell tumors. The clinic-biological mechanisms by which these metastatic sites are associated with poor clinical outcome remain unclear. The multimodality treatment showed a potential better survival, in particular in patients with relapsed disease. Patients with advanced germ cell tumors with visceral metastases should be referred to centers with high expertise in the clinical management of such disease. PMID:27471579

  18. Impact of Non-Pulmonary Visceral Metastases in the Prognosis and Practice of Metastatic Testicular Germ Cell Tumors.

    PubMed

    Rossi, Lorena; Martignano, Filippo; Gallà, Valentina; Maugeri, Antonio; Schepisi, Giuseppe

    2016-04-15

    Non-pulmonary visceral metastases, in bones, brain and liver, represent nearly the 10% of metastatic sites of advanced germ cell tumors and are associated with poor prognosis. This review article summarizes major evidences on the impact of different visceral sites on the prognosis, treatment and clinical outcome of patients with germ cell tumors. The clinic-biological mechanisms by which these metastatic sites are associated with poor clinical outcome remain unclear. The multimodality treatment showed a potential better survival, in particular in patients with relapsed disease. Patients with advanced germ cell tumors with visceral metastases should be referred to centers with high expertise in the clinical management of such disease. PMID:27471579

  19. Sarcopenia in COPD: relationship with COPD severity and prognosis

    PubMed Central

    Costa, Tatiana Munhoz da Rocha Lemos; Costa, Fabio Marcelo; Moreira, Carolina Aguiar; Rabelo, Leda Maria; Boguszewski, César Luiz; Borba, Victória Zeghbi Cochenski

    2015-01-01

    Objective: To evaluate the prevalence of sarcopenia in COPD patients, as well as to determine whether sarcopenia correlates with the severity and prognosis of COPD. Methods: A cross-sectional study with COPD patients followed at the pulmonary outpatient clinic of our institution. The patients underwent dual-energy X-ray absorptiometry. The diagnosis of sarcopenia was made on the basis of the skeletal muscle index, defined as appendicular lean mass/height2 only for low-weight subjects and adjusted for fat mass in normal/overweight subjects. Disease severity (COPD stage) was evaluated with the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria. The degree of obstruction and prognosis were determined by the Body mass index, airflow Obstruction, Dyspnea, and Exercise capacity (BODE) index. Results: We recruited 91 patients (50 females), with a mean age of 67.4 ± 8.7 years and a mean BMI of 25.8 ± 6.1 kg/m2. Sarcopenia was observed in 36 (39.6%) of the patients, with no differences related to gender, age, or smoking status. Sarcopenia was not associated with the GOLD stage or with FEV1 (used as an indicator of the degree of obstruction). The BMI, percentage of body fat, and total lean mass were lower in the patients with sarcopenia than in those without (p < 0.001). Sarcopenia was more prevalent among the patients in BODE quartile 3 or 4 than among those in BODE quartile 1 or 2 (p = 0.009). The multivariate analysis showed that the BODE quartile was significantly associated with sarcopenia, regardless of age, gender, smoking status, and GOLD stage. Conclusions: In COPD patients, sarcopenia appears to be associated with unfavorable changes in body composition and with a poor prognosis. PMID:26578132

  20. [Prognosis of childhood mediastinal lymphoma].

    PubMed

    Okamura, J; Ikuno, Y; Sakata, N; Kai, T; Tasaka, H

    1990-11-01

    Between 1973 and 1989, 16 children with non-Hodgkins lymphoma (NHL) with a mediastinal mass (MM) were treated at our institution with multi-agent chemotherapy and radiotherapy. They also received central nervous system (CNS) prophylaxis including intrathecal methotrexate administration (14 cases) and cranial irradiation (7 cases). Twelve were boys and 4 girls. Median age was 11 +/- 3. One patient died of air way obstruction one day after admission. Fourteen of 15 patients entered into complete remission (CR) and one patient partial remission. Five remains in CR 7 to 175 months after diagnosis (median 76 months). Nine patients relapsed in the bone marrow (3 cases), CNS (3), testicles (1), neck lymph node (1) and bones plus kidneys (1). Of these, 7 patients died within 13 months after initial relapse. The disease free survival (DFS) and overall survival of all patients were 27% and 33%, respectively. Analysis of the prognostic factors among patients with MM+ -NHL revealed that the serum LDH level below 1,000IU/l was a good prognostic sign. Other factors such as age, stage, initial WBC count, size of MM and response of the MM to the initial treatment did not correlate with DFS. Because of its rarity and the poor treatment result, we need more aggressive treatment program by a multiinstitutional study for MM+ -NHL. PMID:2287064

  1. Lung Cancer Staging and Prognosis.

    PubMed

    Woodard, Gavitt A; Jones, Kirk D; Jablons, David M

    2016-01-01

    The seventh edition of the non-small cell lung cancer (NSCLC) TNM staging system was developed by the International Association for the Staging of Lung Cancer (IASLC) Lung Cancer Staging Project by a coordinated international effort to develop data-derived TNM classifications with significant survival differences. Based on these TNM groupings, current 5-year survival estimates in NSLCC range from 73 % in stage IA disease to 13 % in stage IV disease. TNM stage remains the most important prognostic factor in predicting recurrence rates and survival times, followed by tumor histologic grade, and patient sex, age, and performance status. Molecular prognostication in lung cancer is an exploding area of research where interest has moved beyond TNM stage and into individualized genetic tumor analysis with immunohistochemistry, microarray, and mutation profiles. However, despite intense research efforts and countless publications, no molecular prognostic marker has been adopted into clinical use since most fail in subsequent cross-validation with few exceptions. The recent interest in immunotherapy for NSCLC has identified new biomarkers with early evidence that suggests that PD-L1 is a predictive marker of a good response to new immunotherapy drugs but a poor prognostic indicator of overall survival. Future prognostication of outcomes in NSCLC will likely be based on a combination of TNM stage and molecular tumor profiling and yield more precise, individualized survival estimates and treatment algorithms. PMID:27535389

  2. An Omics Perspective on Molecular Biomarkers for Diagnosis, Prognosis, and Therapeutics of Cholangiocarcinoma

    PubMed Central

    Seeree, Pattaya; Pearngam, Phorutai; Kumkate, Supeecha; Janvilisri, Tavan

    2015-01-01

    Cholangiocarcinoma (CCA) is an aggressive biliary tract malignancy arising from the epithelial bile duct. The lack of early diagnostic biomarkers as well as therapeutic measures results in severe outcomes and poor prognosis. Thus, effective early diagnostic, prognostic, and therapeutic biomarkers are required to improve the prognosis and prolong survival rates in CCA patients. Recent advancement in omics technologies combined with the integrative experimental and clinical validations has provided an insight into the underlying mechanism of CCA initiation and progression as well as clues towards novel biomarkers. This work highlights the discovery and validation of molecular markers in CCA identified through omics approaches. The possible roles of these molecules in various cellular pathways, which render CCA carcinogenesis and progression, will also be discussed. This paper can serve as a reference point for further investigations to yield deeper understanding in the complex feature of this disease, potentially leading to better approaches for diagnosis, prognosis, and therapeutics. PMID:26421274

  3. Consequences of Growing Up Poor.

    ERIC Educational Resources Information Center

    Duncan, Greg J., Ed.; Brooks-Gunn, Jeanne, Ed.

    The consequences and correlates of growing up poor as well as the mechanisms through which poverty influences children are explored. This book is organized with a primary focus on research findings and a secondary concern with policy implications. The chapters are: (1) "Poor Families, Poor Outcomes: The Well-Being of Children and Youth" (Jeanne…

  4. Clinical Prognosis in Neonatal Bacterial Meningitis: The Role of Cerebrospinal Fluid Protein

    PubMed Central

    Zhao, Dongying; Ren, Fang; Luo, Zhongcheng; Zhang, Yongjun

    2015-01-01

    Neonates are at high risk of meningitis and of resulting neurologic complications. Early recognition of neonates at risk of poor prognosis would be helpful in providing timely management. From January 2008 to June 2014, we enrolled 232 term neonates with bacterial meningitis admitted to 3 neonatology departments in Shanghai, China. The clinical status on the day of discharge from these hospitals or at a postnatal age of 2.5 to 3 months was evaluated using the Glasgow Outcome Scale (GOS). Patients were classified into two outcome groups: good (167 cases, 72.0%, GOS = 5) or poor (65 cases, 28.0%, GOS = 1–4). Neonates with good outcome had less frequent apnea, drowsiness, poor feeding, bulging fontanelle, irritability and more severe jaundice compared to neonates with poor outcome. The good outcome group also had less pneumonia than the poor outcome group. Besides, there were statistically significant differences in hemoglobin, mean platelet volume, platelet distribution width, C-reaction protein, procalcitonin, cerebrospinal fluid (CSF) glucose and CSF protein. Multivariate logistic regression analyses suggested that poor feeding, pneumonia and CSF protein were the predictors of poor outcome. CSF protein content was significantly higher in patients with poor outcome. The best cut-offs for predicting poor outcome were 1,880 mg/L in CSF protein concentration (sensitivity 70.8%, specificity 86.2%). After 2 weeks of treatment, CSF protein remained higher in the poor outcome group. High CSF protein concentration may prognosticate poor outcome in neonates with bacterial meningitis. PMID:26509880

  5. Karyotype complexity and prognosis in acute myeloid leukemia

    PubMed Central

    Stölzel, F; Mohr, B; Kramer, M; Oelschlägel, U; Bochtler, T; Berdel, W E; Kaufmann, M; Baldus, C D; Schäfer-Eckart, K; Stuhlmann, R; Einsele, H; Krause, S W; Serve, H; Hänel, M; Herbst, R; Neubauer, A; Sohlbach, K; Mayer, J; Middeke, J M; Platzbecker, U; Schaich, M; Krämer, A; Röllig, C; Schetelig, J; Bornhäuser, M; Ehninger, G

    2016-01-01

    A complex aberrant karyotype consisting of multiple unrelated cytogenetic abnormalities is associated with poor prognosis in patients with acute myeloid leukemia (AML). The European Leukemia Net classification and the UK Medical Research Council recommendation provide prognostic categories that differ in the definition of unbalanced aberrations as well as the number of single aberrations. The aim of this study on 3526 AML patients was to redefine and validate a cutoff for karyotype complexity in AML with regard to adverse prognosis. Our study demonstrated that (1) patients with a pure hyperdiploid karyotype have an adverse risk irrespective of the number of chromosomal gains, (2) patients with translocation t(9;11)(p21∼22;q23) have an intermediate risk independent of the number of additional aberrations, (3) patients with ⩾4 abnormalities have an adverse risk per se and (4) patients with three aberrations in the absence of abnormalities of strong influence (hyperdiploid karyotype, t(9;11)(p21∼22;q23), CBF-AML, unique adverse-risk aberrations) have borderline intermediate/adverse risk with a reduced overall survival compared with patients with a normal karyotype. PMID:26771812

  6. Evolution and prognosis of breast osteosarcoma: A case report

    PubMed Central

    GUO, WANFENG; CAO, YANG; TENG, GUANGJU; LIU, JIN; SU, JIANBIN

    2016-01-01

    Breast osteosarcoma is a rare malignancy of unknown etiology, with no standard adjuvant treatment at present. The prognosis of the disease is poor, and it has a high propensity for recurrence and metastasis. The current report presents the case of a 52-year-old woman, in whom adenomyoepithelioma gradually developed into breast osteosarcoma following three separate surgeries. The patient survived for 41 months from the initial lesion occurrence and resection in the left breast; during this time, she underwent surgery and chemotherapy (liposomal doxorubicin and cisplatin) for the treatment of disease recurrence and lung metastasis, along with molecular-targeted therapy (sunitinib). However, the patient eventually succumbed to respiratory failure due to progressive disease. The present case underwent a clear pathological transformation process, and may provide a basis for an improved understanding of the clinical characteristics and treatment of breast osteosarcoma. PMID:26870284

  7. Differences in Parent-Provider Concordance Regarding Prognosis and Goals of Care Among Children With Advanced Cancer

    PubMed Central

    Rosenberg, Abby R.; Orellana, Liliana; Kang, Tammy I.; Geyer, J. Russell; Feudtner, Chris; Dussel, Veronica; Wolfe, Joanne

    2014-01-01

    Purpose Concordance between parents of children with advanced cancer and health care providers has not been described. We aimed to describe parent-provider concordance regarding prognosis and goals of care, including differences by cancer type. Patients and Methods A total of 104 pediatric patients with recurrent or refractory cancer were enrolled at three large children's hospitals. On enrollment, their parents and providers were invited to complete a survey assessing perceived prognosis and goals of care. Patients' survival status was retrospectively abstracted from medical records. Concordance was assessed via discrepancies in perceived prognosis, κ statistics, and McNemar's test. Distribution of categorical variables and survival rates across cancer type were compared with Fisher's exact and log-rank tests, respectively. Results Data were available from 77 dyads (74% of enrolled). Parent-provider agreement regarding prognosis and goals of care was poor (κ, 0.12 to 0.30). Parents were more likely to report cure was likely (P < .001). The frequency of perceived likelihood of cure and the goal of cure varied by cancer type for both parents and providers (P < .001 to .004). Relatively optimistic responses were more common among parents and providers of patients with hematologic malignancies, although there were no differences in survival. Conclusion Parent-provider concordance regarding prognosis and goals in advanced pediatric cancer is generally poor. Perceptions of prognosis and goals of care vary by cancer type. Understanding these differences may inform parent-provider communication and decision making. PMID:25024073

  8. Survival Prediction Score: A Simple but Age-Dependent Method Predicting Prognosis in Patients Undergoing Palliative Radiotherapy

    PubMed Central

    Dalhaug, Astrid; Pawinski, Adam; Haukland, Ellinor

    2014-01-01

    Purpose. Validation of a Canadian three-tiered prognostic model (survival prediction score, SPS) in Norwegian cancer patients referred for palliative radiotherapy (PRT), and evaluation of age-dependent performance of the model. Patients and Methods. We analyzed all 579 PRT courses administered at a dedicated PRT facility between 20.06.07 and 31.12.2009. SPS was assigned as originally described, That is, by taking into consideration three variables: primary cancer type, site of metastases, and performance status. Results. Patients with poor prognosis (non-breast cancer, metastases other than bone, and Karnofsky performance status (KPS) ≤ 60) had median survival of 13 weeks. Those with intermediate prognosis (two of these parameters) survived for a median of 29 weeks, and patients with good prognosis for a median of 114 weeks, P < 0.001. While this model performed well in patients who were 60 years or older, it was less satisfactory in younger patients (no significant difference between the good and intermediate prognosis groups). Conclusion. SPS should mainly be used to predict survival of elderly cancer patients. However, even in this group accuracy is limited because the good prognosis group contained patients with short survival, while the poor prognosis group contained long-term survivors. Thus, improved models should be developed. PMID:25006508

  9. Role of IL-6 in the invasiveness and prognosis of glioma

    PubMed Central

    Shan, Yongzhi; He, Xin; Song, Wei; Han, Dong; Niu, Jianxing; Wang, Jianzhen

    2015-01-01

    IL-6 is a cytokine secreted by glioma cells and plays an important role in the tumor growth. However, the impact of IL-6 on the invasiveness and prognosis of glioma is still unclear. In this study, immunohistochemistry was performed to determine the expression of IL-6 in 86 glioma tissues, and ELISA to measure IL-6 in the serum and cerebrospinal fluid (CSF) of these patients. Results showed, as ccompared with normal controls, the IL-6 in the glioma, CSF and serumincreased remarkably, and increased with the elevation of glioma grade. In addition, IL-6 in the supernatant was also detectable in glioma cell lines U251, U87, A172 and T98G. Transwell invasion assay showed that the invasiveness of glioma U87 cells and U251 cells increased remarkably after exogenous IL-6 treatment. Survival analysis indicated higher IL-6 before surgery and significantly reduction in IL-6 after operation in the serum and CSF predicted a poor prognosis. Thus, we speculate that, the poor prognosis of glioma is related to the IL-6 autocrine in the glioma and the IL-6 induced tumor growth and invasion. IL-6 may serve as a therapeutic target for glioma patients and IL-6 in the CSF and serum of glioma may be used to predict the prognosis of these patients. PMID:26309566

  10. Comorbidities impacting on prognosis after lung transplant.

    PubMed

    Vaquero Barrios, José Manuel; Redel Montero, Javier; Santos Luna, Francisco

    2014-01-01

    The aim of this review is to give an overview of the clinical circumstances presenting before lung transplant that may have negative repercussions on the long and short-term prognosis of the transplant. Methods for screening and diagnosis of common comorbidities with negative impact on the prognosis of the transplant are proposed, both for pulmonary and extrapulmonary diseases, and measures aimed at correcting these factors are discussed. Coordination and information exchange between referral centers and transplant centers would allow these comorbidities to be detected and corrected, with the aim of minimizing the risks and improving the life expectancy of transplant receivers. PMID:24355755

  11. Comprehensive molecular portrait using next generation sequencing of resected intestinal-type gastric cancer patients dichotomized according to prognosis.

    PubMed

    Bria, E; Pilotto, S; Simbolo, M; Fassan, M; de Manzoni, G; Carbognin, L; Sperduti, I; Brunelli, M; Cataldo, I; Tomezzoli, A; Mafficini, A; Turri, G; Karachaliou, N; Rosell, R; Tortora, G; Scarpa, A

    2016-01-01

    In this study, we evaluated whether the presence of genetic alterations detected by next generation sequencing may define outcome in a prognostically-selected and histology-restricted population of resected gastric cancer (RGC). Intestinal type RGC samples from 34 patients, including 21 best and 13 worst prognostic performers, were studied. Mutations in 50 cancer-associated genes were evaluated. A significant difference between good and poor prognosis was found according to clinico-pathologic factors. The most commonly mutated genes in the whole population were PIK3CA (29.4%), KRAS (26.5%), TP53 (26.5%) MET (8.8%), SMAD4 (8.8%) and STK11 (8.8%). Multiple gene mutations were found in 14/21 (67%) patients with good prognosis, and 3/13 (23%) in the poor prognosis group. A single gene alteration was found in 5/21 (24%) good and 6/13 (46%) poor prognosis patients. No mutation was found in 2/21 (9.5%) and 4/13 (31%) of these groups, respectively. In the overall series, ß-catenin expression was the highest (82.4%), followed by E-Cadherin (76.5%) and FHIT (52.9%). The good prognosis group was characterized by a high mutation rate and microsatellite instability. Our proof-of-principle study demonstrates the feasibility of a molecular profiling approach with the aim to identify potentially druggable pathways and drive the development of customized therapies for RGC. PMID:26961069

  12. Comprehensive molecular portrait using next generation sequencing of resected intestinal-type gastric cancer patients dichotomized according to prognosis

    PubMed Central

    Bria, E.; Pilotto, S.; Simbolo, M.; Fassan, M.; de Manzoni, G.; Carbognin, L.; Sperduti, I.; Brunelli, M.; Cataldo, I.; Tomezzoli, A.; Mafficini, A.; Turri, G.; Karachaliou, N.; Rosell, R.; Tortora, G.; Scarpa, A.

    2016-01-01

    In this study, we evaluated whether the presence of genetic alterations detected by next generation sequencing may define outcome in a prognostically-selected and histology-restricted population of resected gastric cancer (RGC). Intestinal type RGC samples from 34 patients, including 21 best and 13 worst prognostic performers, were studied. Mutations in 50 cancer-associated genes were evaluated. A significant difference between good and poor prognosis was found according to clinico-pathologic factors. The most commonly mutated genes in the whole population were PIK3CA (29.4%), KRAS (26.5%), TP53 (26.5%) MET (8.8%), SMAD4 (8.8%) and STK11 (8.8%). Multiple gene mutations were found in 14/21 (67%) patients with good prognosis, and 3/13 (23%) in the poor prognosis group. A single gene alteration was found in 5/21 (24%) good and 6/13 (46%) poor prognosis patients. No mutation was found in 2/21 (9.5%) and 4/13 (31%) of these groups, respectively. In the overall series, ß-catenin expression was the highest (82.4%), followed by E-Cadherin (76.5%) and FHIT (52.9%). The good prognosis group was characterized by a high mutation rate and microsatellite instability. Our proof-of-principle study demonstrates the feasibility of a molecular profiling approach with the aim to identify potentially druggable pathways and drive the development of customized therapies for RGC. PMID:26961069

  13. Clinicopathological significance of gastric poorly differentiated medullary carcinoma.

    PubMed

    Hirai, Hideaki; Yoshizawa, Tadashi; Morohashi, Satoko; Haga, Toshihiro; Wu, Yunyan; Ota, Rie; Takatsuna, Masafumi; Akasaka, Harue; Hakamada, Kenichi; Kijima, Hiroshi

    2016-01-01

    Poorly differentiated gastric adenocarcinoma of solid type is known to show a clinicopathological diversity, but its morphological characteristics have rarely been investigated. In this study, we defined poorly differentiated medullary carcinoma indicating the following three characteristics: (i) more than 90% of the entire tumor were composed of poorly differentiated adenocarcinoma in a medullary growth, (ii) the tumor exhibited an expansive growth at the tumor margin, and (iii) special types such as an α-fetoprotein-producing carcinoma, neuroendocrine carcinoma, and carcinoma with lymphoid stroma were excluded. Based on the definition, we subclassified the poorly differentiated gastric adenocarcinoma of solid type into the two groups: medullary carcinoma and non-medullary carcinoma, and clinicopathologically analyzed 23 cases of medullary carcinomas and 38 cases of non-medullary carcinomas. The medullary carcinomas less frequently displayed lymphatic invasion, venous invasion, and lymph node metastasis, compared with the non-medullary carcinoma (P < 0.001, P = 0.002, and P < 0.001, respectively). The patients with medullary carcinomas significantly showed better disease-free survival (P = 0.017). This is the first study to demonstrate that poorly differentiated adenocarcinoma of solid type can be subclassified into tumors with low and high malignant potentials. Gastric poorly differentiated medullary carcinoma is considered to be a novel histological type predicting good patients' prognosis. PMID:27108877

  14. Forgotten Americans: The "Working Poor."

    ERIC Educational Resources Information Center

    Joe, Tom

    1984-01-01

    The working poor are employable people who have found low-paying jobs and barely scrape out a living. By removing many forms of federal aid, the Reagan administration has locked the working poor into poverty. In saving a few dollars today, we are penalizing the next generation. (CS)

  15. Association of Diabetes and Prognosis of Minor Stroke and Its Subtypes: A Prospective Observational Study

    PubMed Central

    Pan, Yuesong; Wang, Yongjun; Li, Hao; Gaisano, Herbert Y.; Wang, Yilong; He, Yan

    2016-01-01

    Background The association between diabetes mellitus (DM) and prognosis of minor stroke is unclear. The aim of this study is to investigate whether DM contributes to the prognosis of minor stroke or its specific subtype. Methods All minor ischemic stroke patients were derived from the China National Stroke Registry and classified into 5 subtypes according to the TOAST (Trial of Org 10172 in Acute Stroke Treatment) criteria. DM was defined as either self-reported physician diagnosis of diabetes or use of hypoglycemic medications during hospitalization or at discharge. Patients were followed up for 1 year for clinical outcomes of recurrent stroke, death and functional outcome. Poor functional outcomes were defined as a score of 2–6 for modified Rankin Score. Associations between DM and prognosis of minor stroke and its subtypes were analyzed by univariable and multivariable logistic regression. Results Of 4,548 patients with minor stroke, 1,230(27.0%) patients had DM, 1,038(22.8%) had poor outcomes and 570(13.0%) of 4,401 patients had recurrent stroke at 1 year. In multivariable analyses, DM were significantly associated with 1-year stroke recurrence (Odds Ratio [OR], 1.31; 95% confidence interval [CI]: 1.08–1.59) and poor outcome (OR, 1.51; 95%CI: 1.28–1.77). Among the subtypes of minor stroke, DM was only significantly associated with 1-year stroke recurrence (OR, 1.63; 95%CI: 1.07–2.50) and poor outcome (OR, 1.73; 95%CI: 1.22–2.45) in the small-artery occlusion subtype. Conclusions DM significantly increased the risk of stroke recurrence and poor outcome in the small-artery occlusion subtype, but not in other subtypes of minor stroke. PMID:27070309

  16. Holographic data processing methods for medical prognosis

    NASA Astrophysics Data System (ADS)

    Antonov, V. A.; Grosmann, M. H.; Kartavenko, V. I.; Larkin, A. I.; Trukhanov, K. A.

    2015-10-01

    The various methods of laser coherent photonic implementations of multiparametric classification are discussed in this paper. The holographic and optical data processing methods for medical application are considered. Inverse two-phase coding and analysis of light distribution in the correlation plane enables us to realize a number of algorithms: search for a precedent, Hamming distance measurement, Bayes probability algorithm, deterministic and ‘correspondence’ algorithms. The experimental holographic results for medicine prognosis are shown.

  17. Relationships Among Therapist Empathy and Authoritarianism and a Therapist's Prognosis

    ERIC Educational Resources Information Center

    Dubnicki, Carol

    1977-01-01

    Relationship between the therapist personality variables of empathy and authoritarianism and the prognosis that a therapist makes was investigated using 25 PhD psychologists as subjects. A positive relationship was found between therapist empathy and the prognosis variables dealing with perception of degree of disturbance and overall prognosis.…

  18. Seasonal variations of cancer incidence and prognosis

    PubMed Central

    Moan, Johan; Bruland, Øyvind; Juzeniene, Asta

    2010-01-01

    The overall death rates are highest in the winter season in many countries at high latitudes. In some but not all countries, this is also true for more specific diseases such as cancer, cardiovascular diseases and influenza. For internal cancers we find no consistent, significant seasonal variation, neither of incidence nor of death rates. On the other hand, we find a significant seasonal variation of cancer prognosis with season of diagnosis in Norway. Best prognosis is found for summer and autumn diagnosis; i.e., for the seasons of the best status of vitamin D in the population. There were no corresponding seasonal variations, neither of the rates of diagnosis, nor of the rates of death which could explain the variations of prognosis. The most likely reason for this variation is that the vitamin D status in Norway is significantly better in summer and autumn than in winter and spring. Earlier, seasonal variations have been explained by circannual variations of certain hormones, but the data are not consistent. PMID:21547098

  19. The Natural History and Prognosis of Primary Biliary Cirrhosis with Clinical Features of Autoimmune Hepatitis.

    PubMed

    Yang, Fan; Wang, Qixia; Wang, Zhaoyue; Miao, Qi; Xiao, Xiao; Tang, Ruqi; Chen, Xiaoyu; Bian, Zhaolian; Zhang, Haiyan; Yang, Yue; Sheng, Li; Fang, Jingyuan; Qiu, Dekai; Krawitt, Edward L; Gershwin, M Eric; Ma, Xiong

    2016-02-01

    Although a variant of primary biliary cirrhosis (PBC) characterized by features of autoimmune hepatitis (AIH) has been recognized for many years, few studies with ample numbers of patients have focused on its natural history. This study aimed to clarify the natural history, prognosis, and response to therapy in a cohort of patients with PBC with AIH features. We retrospectively analyzed 277 PBC patients without AIH features and 46 PBC patients with AIH features seen between September 2004 and April 2014. The 5-year adverse outcome-free survival of PBC patients with AIH features was 58% compared to 81% in PBC patients without AIH features. Multivariate analysis in the patients with AIH features indicated that total bilirubin ≥ 2.70× the upper limit of normal predicted a poor prognosis (p = 0.008, relative risk 8.39, 95% confidence interval (CI) 1.73, 40.73). Combination therapy with ursodeoxycholic acid (UDCA) and immunosuppression provided better short-term responses in PBC patients with AIH features, defined by multiple criteria. Higher aspartate aminotransferase (AST) level at accession suggested better prognosis for PBC patients with AIH features while worse prognosis for PBC patients without AIH features. PBC patients with AIH features differ from those without AIH features in terms of natural history, prognostic indicators, and response to therapy. PMID:26411425

  20. Signet-ring cell carcinoma of the stomach: Impact on prognosis and specific therapeutic challenge

    PubMed Central

    Pernot, Simon; Voron, Thibault; Perkins, Geraldine; Lagorce-Pages, Christine; Berger, Anne; Taieb, Julien

    2015-01-01

    While the incidence of gastric cancer has decreased worldwide in recent decades, the incidence of signet-ring cell carcinoma (SRCC) is rising. SRCC has a specific epidemiology and oncogenesis and has two forms: early gastric cancer, which can be resected endoscopically in some cases and which has a better outcome than non-SRCC, and advanced gastric cancer, which is generally thought to have a worse prognosis and lower chemosensitivity than non-SRCC. However, the prognosis of SRCC and its chemosensitivity with specific regimens are still controversial as SRCC is not specifically identified in most studies and its poor prognosis may be due to its more advanced stage. It therefore remains unclear if a specific therapeutic strategy is justified, as the benefit of perioperative chemotherapy and the value of taxane-based chemotherapy are unclear. In this review we analyze recent data on the epidemiology, oncogenesis, prognosis and specific therapeutic strategies in both early and advanced SRCC of the stomach and in hereditary diffuse gastric cancer. PMID:26523107

  1. Poor smokers, poor quitters, and cigarette tax regressivity.

    PubMed

    Remler, Dahlia K

    2004-02-01

    The traditional view that excise taxes are regressive has been challenged. I document the history of the term regressive tax, show that traditional definitions have always found cigarette taxes to be regressive, and illustrate the implications of the greater price responsiveness observed among the poor. I explain the different definitions of tax burden: accounting, welfare-based willingness to pay, and welfare-based time inconsistent. Progressivity (equity across income groups) is sensitive to the way in which tax burden is assessed. Analysis of horizontal equity (fairness within a given income group) shows that cigarette taxes heavily burden poor smokers who do not quit, no matter how tax burden is assessed. PMID:14759931

  2. Are Poor Chinese Text Comprehenders Also Poor in Written Composition?

    ERIC Educational Resources Information Center

    Guan, Connie Qun; Ye, Feifei; Meng, Wanjin; Leong, Che Kan

    2013-01-01

    We studied the performance in three genres of Chinese written composition (narration, exposition, and argumentation) of 158 grade 4, 5, and 6 poor Chinese text comprehenders compared with 156 good Chinese text comprehenders. We examined text comprehension and written composition relationship. Verbal working memory (verbal span working memory and…

  3. The management of poor performance

    PubMed Central

    Mayberry, John F

    2007-01-01

    Identification of poor performance is in an integral part of government policy. The suggested approach for the identification of such problems, advocated by the General Medical Council, is that of appraisal. However, traditionally, there has been a reluctance to deal with poor performers, as all doctors have made mistakes and are usually only too ready to forgive and be non‐critical of colleagues. The problems are widespread, and 6% of the senior hospital workforce in any 5‐year period may have problems. PMID:17308213

  4. Influencing factor on the prognosis of arthrocentesis

    PubMed Central

    Kim, Yoon Ho; Jeong, Tae Min; Pang, Kang Mi

    2014-01-01

    Objectives The purpose of this article is to evaluate factors influencing prognosis of arthrocentesis in patients with temporomandibular joint (TMJ) disorder. Materials and Methods The subjects included 145 patients treated with arthrocentesis at the Dental Center of Ajou University Hospital from 2011 to 2013 for the purpose of recovering mouth opening limitation (MOL) and pain relief. Prognosis of arthrocentesis was evaluated 1 month after the operation. Improvement on MOL was defined as an increase from below 30 mm (MOL ≤30 mm) to above 40 mm (MOL ≥40 mm), and pain relief was defined as when a group with TMJ pain with a visual analog scale (VAS) score of 4 or more (VAS ≥4) decreased to a score of 3 or more. The success of arthrocentesis was determined when either mouth opening improved or pain relief was fulfilled. To determine the factors influencing the success of arthrocentesis, the patients were classified by age, gender, diagnosis group (the anterior disc displacement without reduction group, the anterior disc displacement with reduction group, or other TMJ disorders group), time of onset and oral habits (clenching, bruxism) to investigate the correlations between these factors and prognosis. Results One hundred twenty out of 145 patients who underwent arthrocentesis (83.4%) were found to be successful. Among the influencing factors mentioned above, age, diagnosis and time of onset had no statistically significant correlation with the success of arthrocentesis. However, a group of patients in their fifties showed a lower success rate (ANOVA P=0.053) and the success rate of the group with oral habits was 71% (Pearson's chi-square test P=0.035). Conclusion From this study, we find that factors influencing the success of arthrocentesis include age and oral habits. We also conclude that arthrocentesis is effective in treating mouth opening symptoms and for pain relief. PMID:25247144

  5. Molecular Biology in Pediatric High-Grade Glioma: Impact on Prognosis and Treatment

    PubMed Central

    Rizzo, Daniela; Ruggiero, Antonio; Martini, Maurizio; Rizzo, Valentina; Maurizi, Palma; Riccardi, Riccardo

    2015-01-01

    High-grade gliomas are the main cause of death in children with brain tumours. Despite recent advances in cancer therapy, their prognosis remains poor and the treatment is still challenging. To date, surgery followed by radiotherapy and temozolomide is the standard therapy. However, increasing knowledge of glioma biology is starting to impact drug development towards targeted therapies. The identification of agents directed against molecular targets aims at going beyond the traditional therapeutic approach in order to develop a personalized therapy and improve the outcome of pediatric high-grade gliomas. In this paper, we critically review the literature regarding the genetic abnormalities implicated in the pathogenesis of pediatric malignant gliomas and the current development of molecularly targeted therapies. In particular, we analyse the impact of molecular biology on the prognosis and treatment of pediatric high-grade glioma, comparing it to that of adult gliomas. PMID:26448930

  6. Prospects for the Working Poor