Molecular analysis of tumor margins by MALDI mass spectrometry in renal carcinoma.

PubMed

Oppenheimer, Stacey R; Mi, Deming; Sanders, Melinda E; Caprioli, Richard M

2010-05-07

The rate of tumor recurrence post resection suggests that there are underlying molecular changes in nearby histologically normal tissue that go undetected by conventional diagnostic methods that utilize contrast agents and immunohistochemistry. MALDI MS is a molecular technology that has the specificity and sensitivity to monitor and identify molecular species indicative of these changes. The current study utilizes this technology to assess molecular distributions within a tumor and adjacent normal tissue in clear cell renal cell carcinoma biopsies. Results indicate that the histologically normal tissue adjacent to the tumor expresses many of the molecular characteristics of the tumor. Proteins of the mitochondrial electron transport system are examples of such distributions. This work demonstrates the utility of MALDI MS for the analysis of tumor tissue in the elucidation of aberrant molecular changes in the tumor microenvironment.

Comparison of telomere length and insulin-like growth factor-binding protein 7 promoter methylation between breast cancer tissues and adjacent normal tissues in Turkish women.

PubMed

Kaya, Zehra; Akkiprik, Mustafa; Karabulut, Sevgi; Peker, Irem; Gullu Amuran, Gokce; Ozmen, Tolga; Gulluoglu, Bahadır M; Kaya, Handan; Ozer, Ayse

2017-09-01

Both insulin-like growth factor-binding protein 7 (IGFBP7) and telomere length (TL) are associated with proliferation and senescence of human breast cancer. This study assessed the clinical significance of both TL and IGFBP7 methylation status in breast cancer tissues compared with adjacent normal tissues. We also investigated whether IGFBP7 methylation status could be affecting TL. Telomere length was measured by quantitative PCR to compare tumors with their adjacent normal tissues. The IGFBP7 promoter methylation status was evaluated by methylation-specific PCR and its expression levels were determined by western blotting. Telomeres were shorter in tumor tissues compared to controls (P<.0001). The mean TL was higher in breast cancer with invasive ductal carcinoma (IDC; n=72; P=.014) compared with other histological type (n=29), and TL in IDC with HER2 negative (n=53; P=.017) was higher than TL in IDC with HER2 positive (n=19). However, telomeres were shortened in advanced stages and growing tumors. IGFBP7 methylation was observed in 90% of tumor tissues and 59% of controls (P=.0002). Its frequency was significantly higher in IDC compared with invasive mixed carcinoma (IMC; P=.002) and it was not correlated either with protein expression or the other clinicopathological parameters. These results suggest that IGFBP7 promoter methylation and shorter TL in tumor compared with adjacent tissues may be predictive biomarkers for breast cancer. Telomere maintenance may be indicative of IDC and IDC with HER2 (-) of breast cancer. Further studies with larger number of cases are necessary to verify this association. © 2016 Wiley Periodicals, Inc.

Immunohistochemical quantification of the cobalamin transport protein, cell surface receptor and Ki-67 in naturally occurring canine and feline malignant tumors and in adjacent normal tissues

PubMed Central

Sysel, Annette M.; Valli, Victor E.; Bauer, Joseph A.

2015-01-01

Cancer cells have an obligate need for cobalamin (vitamin B12) to enable DNA synthesis necessary for cellular replication. This study quantified the immunohistochemical expression of the cobalamin transport protein (transcobalamin II; TCII), cell surface receptor (transcobalamin II-R; TCII-R) and proliferation protein (Ki-67) in naturally occurring canine and feline malignant tumors, and compared these results to expression in corresponding adjacent normal tissues. All malignant tumor tissues stained positively for TCII, TCII-R and Ki-67 proteins; expression varied both within and between tumor types. Expression of TCII, TCII-R and Ki-67 was significantly higher in malignant tumor tissues than in corresponding adjacent normal tissues in both species. There was a strong correlation between TCII and TCII-R expression, and a modest correlation between TCII-R and Ki-67 expression in both species; a modest association between TCII and Ki-67 expression was present in canine tissues only. These results demonstrate a quantifiable, synchronous up-regulation of TCII and TCII-R expression by proliferating canine and feline malignant tumors. The potential to utilize these proteins as biomarkers to identify neoplastic tissues, streamline therapeutic options, evaluate response to anti-tumor therapy and monitor for recurrent disease has important implications in the advancement of cancer management for both human and companion animal patients. PMID:25633912

Identification of Differentially Expressed IGFBP5-Related Genes in Breast Cancer Tumor Tissues Using cDNA Microarray Experiments.

PubMed

Akkiprik, Mustafa; Peker, İrem; Özmen, Tolga; Amuran, Gökçe Güllü; Güllüoğlu, Bahadır M; Kaya, Handan; Özer, Ayşe

2015-11-10

IGFBP5 is an important regulatory protein in breast cancer progression. We tried to identify differentially expressed genes (DEGs) between breast tumor tissues with IGFBP5 overexpression and their adjacent normal tissues. In this study, thirty-eight breast cancer and adjacent normal breast tissue samples were used to determine IGFBP5 expression by qPCR. cDNA microarrays were applied to the highest IGFBP5 overexpressed tumor samples compared to their adjacent normal breast tissue. Microarray analysis revealed that a total of 186 genes were differentially expressed in breast cancer compared with normal breast tissues. Of the 186 genes, 169 genes were downregulated and 17 genes were upregulated in the tumor samples. KEGG pathway analyses showed that protein digestion and absorption, focal adhesion, salivary secretion, drug metabolism-cytochrome P450, and phenylalanine metabolism pathways are involved. Among these DEGs, the prominent top two genes (MMP11 and COL1A1) which potentially correlated with IGFBP5 were selected for validation using real time RT-qPCR. Only COL1A1 expression showed a consistent upregulation with IGFBP5 expression and COL1A1 and MMP11 were significantly positively correlated. We concluded that the discovery of coordinately expressed genes related with IGFBP5 might contribute to understanding of the molecular mechanism of the function of IGFBP5 in breast cancer. Further functional studies on DEGs and association with IGFBP5 may identify novel biomarkers for clinical applications in breast cancer.

Quantitative Evaluation of Heavy Metals and Trace Elements in the Urinary Bladder: Comparison Between Cancerous, Adjacent Non-cancerous and Normal Cadaveric Tissue.

PubMed

Abdel-Gawad, Mahmoud; Elsobky, Emad; Shalaby, Mahmoud M; Abd-Elhameed, Mohamed; Abdel-Rahim, Mona; Ali-El-Dein, Bedeir

2016-12-01

The role of heavy metals and trace elements (HMTE) in the development of some cancers has been previously reported. Bladder carcinoma is a frequent malignancy of the urinary tract. The most common risk factors for bladder cancer are exposure to industrial carcinogens, cigarette smoking, gender, and possibly diet. The aim of this study was to evaluate HTME concentrations in the cancerous and adjacent non-cancerous tissues and compare them with those of normal cadaveric bladder. This prospective study included 102 paired samples of full-thickness cancer and adjacent non-cancerous bladder tissues of radical cystectomy (RC) specimens that were histologically proven as invasive bladder cancer (MIBC). We used 17 matched controls of non-malignant bladder tissue samples from cadavers. All samples were processed and evaluated for the concentration of 22 HMTE by using Inductively Coupled Plasma Optical Emission Spectrometry (ICP-OES). Outcome analysis was made by the Mann-Whitney U, chi-square, Kruskal-Wallis, and Wilcoxon signed ranks tests. When compared with cadaveric control or cancerous, the adjacent non-cancerous tissue had higher levels of six elements (arsenic, lead, selenium, strontium, zinc, and aluminum), and when compared with the control alone, it had a higher concentration of calcium, cadmium, chromium, potassium, magnesium, and nickel. The cancerous tissue had a higher concentration of cadmium, lead, chromium, calcium, potassium, phosphorous, magnesium, nickel, selenium, strontium, and zinc than cadaveric control. Boron level was higher in cadaveric control than cancerous and adjacent non-cancerous tissue. Cadmium level was higher in cancerous tissue with node-positive than node-negative cases. The high concentrations of cadmium, lead, chromium, nickel, and zinc, in the cancerous together with arsenic in the adjacent non-cancerous tissues of RC specimens suggest a pathogenic role of these elements in BC. However, further work-up is needed to support this conclusion by the application of these HMTE on BC cell lines.

Lipid Profiles of Canine Invasive Transitional Cell Carcinoma of the Urinary Bladder and Adjacent Normal Tissue by Desorption Electrospray Ionization Imaging Mass Spectrometry

PubMed Central

Dill, Allison L.; Ifa, Demian R.; Manicke, Nicholas E.; Costa, Anthony B.; Ramos-Vara, José A.; Knapp, Deborah W.; Cooks, R. Graham

2009-01-01

Desorption electrospray ionization (DESI) mass spectrometry (MS) was used in an imaging mode to interrogate the lipid profiles of thin tissue sections of canine spontaneous invasive transitional cell carcinoma (TCC) of the urinary bladder (a model of human invasive bladder cancer) as well as adjacent normal tissue from four different dogs. The glycerophospholipids and sphingolipids that appear as intense signals in both the negative ion and positive ion modes were identified by tandem mass spectrometry (MS/MS) product ion scans using collision-induced dissociation. Differences in the relative distributions of the lipid species were present between the tumor and adjacent normal tissue in both the negative and positive ion modes. DESI-MS images showing the spatial distributions of particular glycerophospholipids, sphinoglipids and free fatty acids in both the negative and positive ion modes were compared to serial tissue sections that were stained with hematoxylin and eosin (H&E). Increased absolute and relative intensities for at least five different glycerophospholipids and three free fatty acids in the negative ion mode and at least four different lipid species in the positive ion mode were seen in the tumor region of the samples in all four dogs. In addition, one sphingolipid species exhibited increased signal intensity in the positive ion mode in normal tissue relative to the diseased tissue. Principal component analysis (PCA) was also used to generate unsupervised statistical images from the negative ion mode data and these images are in excellent agreement with the DESI images obtained from the selected ions and also the H&E stained tissue PMID:19810710

Identifying DNA Methylation Features that Underlie Prostate Cancer Disparities

DTIC Science & Technology

2016-10-01

Report We will continue to recruit African American patients and bank their prostate tissue . We will continue dissecting tumor samples into tumor...in prostate tumors and adjacent normal tissue derived from both AA and EA individuals. We will determine if DNA methylation patterns in prostate... tissue (both cancerous and normal tissue ) differ between AA and EA individuals. We will also identify methylation features that differ between tumor

DNA Methylation Patterns in Normal Tissue Correlate more Strongly with Breast Cancer Status than Copy-Number Variants.

PubMed

Gao, Yang; Widschwendter, Martin; Teschendorff, Andrew E

2018-05-04

Normal tissue at risk of neoplastic transformation is characterized by somatic mutations, copy-number variation and DNA methylation changes. It is unclear however, which type of alteration may be more informative of cancer risk. We analyzed genome-wide DNA methylation and copy-number calls from the same DNA assay in a cohort of healthy breast samples and age-matched normal samples collected adjacent to breast cancer. Using statistical methods to adjust for cell type heterogeneity, we show that DNA methylation changes can discriminate normal-adjacent from normal samples better than somatic copy-number variants. We validate this important finding in an independent dataset. These results suggest that DNA methylation alterations in the normal cell of origin may offer better cancer risk prediction and early detection markers than copy-number changes. Copyright © 2018. Published by Elsevier B.V.

Low Iodine in the Follicular Lumen Caused by Cytoplasm Mis-localization of Sodium Iodide Symporter may Induce Nodular Goiter.

PubMed

Huang, Huibin; Shi, Yaxiong; Liang, Bo; Cai, Huiyao; Cai, Qingyan

2017-10-01

Iodine is a key ingredient in the synthesis of thyroid hormones and also a major factor in the regulation of thyroid function. A local reduction of iodine content in follicular lumen leads to overexpression of local thyroid-stimulating hormone receptor (TSHr), which in turn excessively stimulates the regional thyroid tissue, and result in the formation of nodular goiter. In this study, we investigated the relationship between iodine content and sodium iodide symporter (NIS) expression by using the clinical specimens from patients with nodular goiter and explored the pathogenesis triggered by iodine deficiency in nodular goiter. In total, 28 patients were clinically histopathologically confirmed to have nodular goiter and the corresponding adjacent normal thyroid specimens were harvested simultaneously. Western blot and immunohistochemistry were performed to assay NIS expression and localization in thyrocytes of both nodular goiter and adjacent normal thyroid tissues. NIS expression mediated by iodine in follicular lumen was confirmed by follicular model in vitro. Meanwhile, radioscan with iodine-131were conducted on both nodular goiter and adjacent normal thyroid. Our data showed that NIS expression in nodular goiter was significantly higher than that in adjacent normal tissues, which was associated with low iodine in the follicular lumen. Abnormal localization of NIS and lower amount of radioactive iodine-131 were also found in nodular goiter. Our data implied that low iodine in the follicular lumen caused by cytoplasm mis-localization of NIS may induce nodular goiter.

The MiAge Calculator: a DNA methylation-based mitotic age calculator of human tissue types.

PubMed

Youn, Ahrim; Wang, Shuang

2018-01-01

Cell division is important in human aging and cancer. The estimation of the number of cell divisions (mitotic age) of a given tissue type in individuals is of great interest as it allows not only the study of biological aging (using a new molecular aging target) but also the stratification of prospective cancer risk. Here, we introduce the MiAge Calculator, a mitotic age calculator based on a novel statistical framework, the MiAge model. MiAge is designed to quantitatively estimate mitotic age (total number of lifetime cell divisions) of a tissue using the stochastic replication errors accumulated in the epigenetic inheritance process during cell divisions. With the MiAge model, the MiAge Calculator was built using the training data of DNA methylation measures of 4,020 tumor and adjacent normal tissue samples from eight TCGA cancer types and was tested using the testing data of DNA methylation measures of 2,221 tumor and adjacent normal tissue samples of five other TCGA cancer types. We showed that within each of the thirteen cancer types studied, the estimated mitotic age is universally accelerated in tumor tissues compared to adjacent normal tissues. Across the thirteen cancer types, we showed that worse cancer survivals are associated with more accelerated mitotic age in tumor tissues. Importantly, we demonstrated the utility of mitotic age by showing that the integration of mitotic age and clinical information leads to improved survival prediction in six out of the thirteen cancer types studied. The MiAge Calculator is available at http://www.columbia.edu/∼sw2206/softwares.htm .

Genome-wide identification of RNA editing in hepatocellular carcinoma.

PubMed

Kang, Lin; Liu, Xiaoqiao; Gong, Zhoulin; Zheng, Hancheng; Wang, Jun; Li, Yingrui; Yang, Huanming; Hardwick, James; Dai, Hongyue; Poon, Ronnie T P; Lee, Nikki P; Mao, Mao; Peng, Zhiyu; Chen, Ronghua

2015-02-01

We did whole-transcriptome sequencing and whole-genome sequencing on nine pairs of Hepatocellular carcinoma (HCC) tumors and matched adjacent tissues to identify RNA editing events. We identified mean 26,982 editing sites with mean 89.5% canonical A→G edits in each sample using an improved bioinformatics pipeline. The editing rate was significantly higher in tumors than adjacent normal tissues. Comparing the difference between tumor and normal tissues of each patient, we found 7 non-synonymous tissue specific editing events including 4 tumor-specific edits and 3 normal-specific edits in the coding region, as well as 292 edits varying in editing degree. The significant expression changes of 150 genes associated with RNA editing were found in tumors, with 3 of the 4 most significant genes being cancer related. Our results show that editing might be related to higher gene expression. These findings indicate that RNA editing modification may play an important role in the development of HCC. Copyright © 2014 Elsevier Inc. All rights reserved.

Structural and quantitative expression analyses of HERV gene family in human tissues.

PubMed

Ahn, Kung; Kim, Heui-Soo

2009-08-31

Human endogenous retroviruses (HERVs) have been implicated in the pathogenesis of several human diseases as multi-copy members in the human genome. Their gene expression profiling could provide us with important insights into the pathogenic relationship between HERVs and cancer. In this study, we have evaluated the genomic structure and quantitatively determined the expression patterns in the env gene of a variety of HERV family members located on six specific loci by the RetroTector 10 program, as well as real-time RT-PCR amplification. The env gene transcripts evidenced significant differences in the human tumor/normal adjacent tissues (colon, liver, uterus, lung and testis). As compared to the adjacent normal tissues, high levels of expression were noted in testis tumor tissues for HERV-K, in liver and lung tumor tissues for HERV-R, in liver, lung, and testis tumor tissues for HERV-H, and in colon and liver tumor tissues for HERV-P. These data warrant further studies with larger groups of patients to develop biomarkers for specific human cancers.

A randomized, placebo-controlled, preoperative trial of allopurinol in subjects with colorectal adenoma.

PubMed

Puntoni, Matteo; Branchi, Daniela; Argusti, Alessandra; Zanardi, Silvia; Crosta, Cristiano; Meroni, Emanuele; Munizzi, Francesco; Michetti, Paolo; Coccia, Gianni; De Roberto, Giuseppe; Bandelloni, Roberto; Turbino, Laura; Minetti, Egle; Mori, Marco; Salvi, Sandra; Boccardo, Simona; Gatteschi, Beatrice; Benelli, Roberto; Sonzogni, Angelica; DeCensi, Andrea

2013-02-01

Inflammation and oxidative stress play a crucial role in the development of colorectal cancer (CRC) and interference with these mechanisms represents a strategy in CRC chemoprevention. Allopurinol, a safe molecular scavenger largely used as antigout agent, has been shown to increase survival of patients with advanced CRC and to reduce CRC incidence in long-term gout users in epidemiologic studies. We conducted a randomized, double-blind, placebo-controlled preoperative trial in subjects with colorectal adenomatous polyps to assess the activity of allopurinol on biomarkers of colorectal carcinogenesis. After complete colonoscopy and biopsy of the index polyp, 73 subjects with colorectal adenomas were assigned to either placebo or one of two doses of allopurinol (100 mg or 300 mg) and treated for four weeks before polyp removal. Change of Ki-67 labeling index in adenomatous tissue was the primary endpoint. Secondary endpoints were the immunohistochemical (IHC) expression of NF-κB, β-catenin, topoisomerase-II-α, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) in adenomatous polyps and normal adjacent colonic tissue. Compared with placebo, Ki-67 levels were not significantly modulated by allopurinol, whereas β-catenin and NF-κB expression levels decreased significantly in adenomatous tissue, with a mean change from baseline of -10.6%, 95% confidence interval (CI), -20.5 to -0.7, and -8.1%, 95% CI, -22.7 to 6.5, respectively. NF-κB also decreased significantly in normal adjacent tissue (-16.4%; 95% CI, -29.0 to -3.8). No dose-response relationship was noted, except for NF-κB expression in normal tissue. Allopurinol can inhibit biomarkers of oxidative activation in colon adenomatous polyps and normal adjacent tissue. Further studies should define its potential chemopreventive activity.

Characterizing the heterogeneity of triple-negative breast cancers using microdissected normal ductal epithelium and RNA-sequencing

PubMed Central

Radovich, Milan; Clare, Susan E.; Atale, Rutuja; Pardo, Ivanesa; Hancock, Bradley A.; Solzak, Jeffrey P.; Kassem, Nawal; Mathieson, Theresa; Storniolo, Anna Maria V.; Rufenbarger, Connie; Lillemoe, Heather A.; Blosser, Rachel J.; Choi, Mi Ran; Sauder, Candice A.; Doxey, Diane; Henry, Jill E.; Hilligoss, Eric E.; Sakarya, Onur; Hyland, Fiona C.; Hickenbotham, Matthew; Zhu, Jin; Glasscock, Jarret; Badve, Sunil; Ivan, Mircea; Liu, Yunlong; Sledge, George W.; Schneider, Bryan P.

2014-01-01

Triple-negative breast cancers (TNBCs) are a heterogeneous set of tumors defined by an absence of actionable therapeutic targets (ER−,PR−,HER2−). Microdissected normal ductal epithelium from healthy volunteers represents a novel comparator to reveal insights into TNBC heterogeneity and to inform drug development. Using RNA-sequencing data from our institution and The Cancer Genome Atlas (TCGA) we compared the transcriptomes of 94 TNBCs, 20 microdissected normal breast tissues from healthy volunteers from the Susan G. Komen for the Cure Tissue Bank, and 10 histologically normal tissues adjacent to tumor. Pathway analysis comparing TNBCs to optimized normal controls of microdissected normal epithelium versus classic controls composed of adjacent normal tissue revealed distinct molecular signatures. Differential gene expression of TNBC compared with normal comparators demonstrated important findings for TNBC-specific clinical trials testing targeted agents; lack of over-expression for negative studies and over-expression in studies with drug activity. Next, by comparing each individual TNBC to the set of microdissected normals, we demonstrate that TNBC heterogeneity is attributable to transcriptional chaos, is associated with non-silent DNA mutational load, and explains transcriptional heterogeneity in addition to known molecular subtypes. Finally, chaos analysis identified 146 core genes dysregulated in >90% of TNBCs revealing an over-expressed central network. In conclusion, Use of microdissected normal ductal epithelium from healthy volunteers enables an optimized approach for studying TNBC and uncovers biological heterogeneity mediated by transcriptional chaos. PMID:24292813

Characterizing the heterogeneity of triple-negative breast cancers using microdissected normal ductal epithelium and RNA-sequencing.

PubMed

Radovich, Milan; Clare, Susan E; Atale, Rutuja; Pardo, Ivanesa; Hancock, Bradley A; Solzak, Jeffrey P; Kassem, Nawal; Mathieson, Theresa; Storniolo, Anna Maria V; Rufenbarger, Connie; Lillemoe, Heather A; Blosser, Rachel J; Choi, Mi Ran; Sauder, Candice A; Doxey, Diane; Henry, Jill E; Hilligoss, Eric E; Sakarya, Onur; Hyland, Fiona C; Hickenbotham, Matthew; Zhu, Jin; Glasscock, Jarret; Badve, Sunil; Ivan, Mircea; Liu, Yunlong; Sledge, George W; Schneider, Bryan P

2014-01-01

Triple-negative breast cancers (TNBCs) are a heterogeneous set of tumors defined by an absence of actionable therapeutic targets (ER, PR, and HER-2). Microdissected normal ductal epithelium from healthy volunteers represents a novel comparator to reveal insights into TNBC heterogeneity and to inform drug development. Using RNA-sequencing data from our institution and The Cancer Genome Atlas (TCGA) we compared the transcriptomes of 94 TNBCs, 20 microdissected normal breast tissues from healthy volunteers from the Susan G. Komen for the Cure Tissue Bank, and 10 histologically normal tissues adjacent to tumor. Pathway analysis comparing TNBCs to optimized normal controls of microdissected normal epithelium versus classic controls composed of adjacent normal tissue revealed distinct molecular signatures. Differential gene expression of TNBC compared with normal comparators demonstrated important findings for TNBC-specific clinical trials testing targeted agents; lack of over-expression for negative studies and over-expression in studies with drug activity. Next, by comparing each individual TNBC to the set of microdissected normals, we demonstrate that TNBC heterogeneity is attributable to transcriptional chaos, is associated with non-silent DNA mutational load, and explains transcriptional heterogeneity in addition to known molecular subtypes. Finally, chaos analysis identified 146 core genes dysregulated in >90 % of TNBCs revealing an over-expressed central network. In conclusion, use of microdissected normal ductal epithelium from healthy volunteers enables an optimized approach for studying TNBC and uncovers biological heterogeneity mediated by transcriptional chaos.

Distribution of erlotinib in rash and normal skin in cancer patients receiving erlotinib visualized by matrix assisted laser desorption/ionization mass spectrometry imaging.

PubMed

Nishimura, Meiko; Hayashi, Mitsuhiro; Mizutani, Yu; Takenaka, Kei; Imamura, Yoshinori; Chayahara, Naoko; Toyoda, Masanori; Kiyota, Naomi; Mukohara, Toru; Aikawa, Hiroaki; Fujiwara, Yasuhiro; Hamada, Akinobu; Minami, Hironobu

2018-04-06

The development of skin rashes is the most common adverse event observed in cancer patients treated with epidermal growth factor receptor-tyrosine kinase inhibitors such as erlotinib. However, the pharmacological evidence has not been fully revealed. Erlotinib distribution in the rashes was more heterogeneous than that in the normal skin, and the rashes contained statistically higher concentrations of erlotinib than adjacent normal skin in the superficial skin layer (229 ± 192 vs. 120 ± 103 ions/mm 2 ; P = 0.009 in paired t -test). LC-MS/MS confirmed that the concentration of erlotinib in the skin rashes was higher than that in normal skin in the superficial skin layer (1946 ± 1258 vs. 1174 ± 662 ng/cm 3 ; P = 0.028 in paired t -test). The results of MALDI-MSI and LC-MS/MS were well correlated (coefficient of correlation 0.879, P < 0.0001). Focal distribution of erlotinib in the skin tissue was visualized using non-labeled MALDI-MSI. Erlotinib concentration in the superficial layer of the skin rashes was higher than that in the adjacent normal skin. We examined patients with advanced pancreatic cancer who developed skin rashes after treatment with erlotinib and gemcitabine. We biopsied both the rash and adjacent normal skin tissues, and visualized and compared the distribution of erlotinib within the skin using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI). The tissue concentration of erlotinib was also measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) with laser microdissection.

Distribution of erlotinib in rash and normal skin in cancer patients receiving erlotinib visualized by matrix assisted laser desorption/ionization mass spectrometry imaging

PubMed Central

Mizutani, Yu; Takenaka, Kei; Imamura, Yoshinori; Chayahara, Naoko; Toyoda, Masanori; Kiyota, Naomi; Mukohara, Toru; Aikawa, Hiroaki; Fujiwara, Yasuhiro; Hamada, Akinobu; Minami, Hironobu

2018-01-01

Background The development of skin rashes is the most common adverse event observed in cancer patients treated with epidermal growth factor receptor-tyrosine kinase inhibitors such as erlotinib. However, the pharmacological evidence has not been fully revealed. Results Erlotinib distribution in the rashes was more heterogeneous than that in the normal skin, and the rashes contained statistically higher concentrations of erlotinib than adjacent normal skin in the superficial skin layer (229 ± 192 vs. 120 ± 103 ions/mm2; P = 0.009 in paired t-test). LC-MS/MS confirmed that the concentration of erlotinib in the skin rashes was higher than that in normal skin in the superficial skin layer (1946 ± 1258 vs. 1174 ± 662 ng/cm3; P = 0.028 in paired t-test). The results of MALDI-MSI and LC-MS/MS were well correlated (coefficient of correlation 0.879, P < 0.0001). Conclusions Focal distribution of erlotinib in the skin tissue was visualized using non-labeled MALDI-MSI. Erlotinib concentration in the superficial layer of the skin rashes was higher than that in the adjacent normal skin. Methods We examined patients with advanced pancreatic cancer who developed skin rashes after treatment with erlotinib and gemcitabine. We biopsied both the rash and adjacent normal skin tissues, and visualized and compared the distribution of erlotinib within the skin using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI). The tissue concentration of erlotinib was also measured by liquid chromatography-tandem mass spectrometry (LC–MS/MS) with laser microdissection. PMID:29719624

Markers of fibrosis and epithelial to mesenchymal transition demonstrate field cancerization in histologically normal tissue adjacent to breast tumors

PubMed Central

Trujillo, Kristina A.; Heaphy, Christopher M.; Mai, Minh; Vargas, Keith M.; Jones, Anna C.; Vo, Phung; Butler, Kimberly S.; Joste, Nancy E.; Bisoffi, Marco; Griffith, Jeffrey K

2011-01-01

Previous studies have shown that a field of genetically altered but histologically normal tissue extends 1 cm or more from the margins of human breast tumors. The extent, composition and biological significance of this field are only partially understood, but the molecular alterations in affected cells could provide mechanisms for limitless replicative capacity, genomic instability and a microenvironment that supports tumor initiation and progression. We demonstrate by microarray, qRT-PCR and immunohistochemistry a signature of differential gene expression that discriminates between patient-matched, tumor-adjacent histologically normal breast tissues located 1 cm and 5 cm from the margins of breast adenocarcinomas (TAHN-1 and TAHN-5, respectively). The signature includes genes involved in extracellular matrix remodeling, wound healing, fibrosis and epithelial to mesenchymal transition (EMT). Myofibroblasts, which are mediators of wound healing and fibrosis, and intra-lobular fibroblasts expressing MMP2, SPARC, TGF-β3, which are inducers of EMT, were both prevalent in TAHN-1 tissues, sparse in TAHN-5 tissues, and absent in normal tissues from reduction mammoplasty. Accordingly, EMT markers S100A4 and vimentin were elevated in both luminal and myoepithelial cells, and EMT markers α-smooth muscle actin and SNAIL were elevated in luminal epithelial cells of TAHN-1 tissues. These results identify cellular processes that are differentially activated between TAHN-1 and TAHN-5 breast tissues, implicate myofibroblasts as likely mediators of these processes, provide evidence that EMT is occurring in histologically normal tissues within the affected field and identify candidate biomarkers to investigate whether or how field cancerization contributes to the development of primary or recurrent breast tumors. PMID:21105047

Overexpression of NEK3 is associated with poor prognosis in patients with gastric cancer.

PubMed

Cao, Yongfeng; Song, Jiaye; Chen, Jia; Xiao, Jinzhang; Ni, Jingyi; Wu, Changping

2018-01-01

The NIMA-related kinase 3 (NEK3) plays an important role in cell migration, cell proliferation, and cell viability. Recently, NEK3 was reported to enhance the malignancy of breast cancer. However, its role in gastric cancer has not been completely characterized. In this study, we explored the prognostic significance of NEK3 in human gastric cancer. Reverse transcription-polymerase chain reaction and western blot were performed to detect the NEK3 mRNA and protein expression in 6 paired fresh human gastric cancer tissues and surrounding normal tissues. NEK3 levels in gastric cancer and its adjacent normal samples of 168 cases were detected by immunohistochemistry, and the relationships between the NEK3 level and various clinicopathological features were analyzed. NEK3 mRNA and protein were significantly overexpressed in gastric cancer tissues, compared with adjacent normal tissues. Immunohistochemistry staining assay showed the percentage of high NEK3 expression in gastric cancer samples was higher than that in adjacent normal samples. NEK3 overexpression was significantly correlated with pT stage, pathologic TNM stage, lymph node metastasis, and poor prognosis of gastric cancer. Cox multivariate regression analyses suggested that NEK3 was an independent prognostic factor for survival of patients with gastric cancer. The data demonstrate that NEK3 is overexpressed in gastric cancer, which promotes the malignancy of gastric cancer. NEK3 may be as a prognostic biomarker and a potential therapeutic target for gastric cancer. Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.

Promoter hypermethylation and downregulation of the FAS gene may be involved in colorectal carcinogenesis

PubMed Central

MANOOCHEHRI, MEHDI; BORHANI, NASIM; KARBASI, ASHRAF; KOOCHAKI, AMENEH; KAZEMI, BAHRAM

2016-01-01

Aberrant DNA methylation has been investigated in carcinogenesis and as biomarker for the early detection of colorectal cancer (CRC). The present study aimed to define the methylation status in the regulatory elements of two proapoptotic genes, Fas cell surface death receptor (FAS) and BCL2-associated X protein (BAX). DNA methylation analysis was performed in tumor and adjacent normal tissue using HpaII/MspI restriction digestion and methylation-specific polymerase chain reaction (PCR). The results observed downregulation of the FAS and BAX genes in the CRC tissues compared with the adjacent normal samples. Furthermore, demethylation using 5-aza-2′-deoxycytidine treatment followed by reverse-transcription quantitative PCR were performed on the HT-29 cell line to measure BAX and FAS mRNA expression following demethylation. The 5-aza-2′-deoxycytidine treatment resulted in significant FAS gene upregulation in the HT-29 cell line, but no significant difference in BAX expression. Furthermore, analysis of CpG islands in the FAS gene promoter revealed that the FAS promoter was significantly hypermethylated in 53.3% of tumor tissues compared with adjacent normal samples. Taken together, the results indicate that decreased expression of the FAS gene due to hypermethylation of its promoter may lead to apoptotic resistance, and acts as an important step during colorectal carcinogenesis. PMID:27347139

Promoter hypermethylation and downregulation of the FAS gene may be involved in colorectal carcinogenesis.

PubMed

Manoochehri, Mehdi; Borhani, Nasim; Karbasi, Ashraf; Koochaki, Ameneh; Kazemi, Bahram

2016-07-01

Aberrant DNA methylation has been investigated in carcinogenesis and as biomarker for the early detection of colorectal cancer (CRC). The present study aimed to define the methylation status in the regulatory elements of two proapoptotic genes, Fas cell surface death receptor (FAS) and BCL2-associated X protein (BAX). DNA methylation analysis was performed in tumor and adjacent normal tissue using Hpa II/ Msp I restriction digestion and methylation-specific polymerase chain reaction (PCR). The results observed downregulation of the FAS and BAX genes in the CRC tissues compared with the adjacent normal samples. Furthermore, demethylation using 5-aza-2'-deoxycytidine treatment followed by reverse-transcription quantitative PCR were performed on the HT-29 cell line to measure BAX and FAS mRNA expression following demethylation. The 5-aza-2'-deoxycytidine treatment resulted in significant FAS gene upregulation in the HT-29 cell line, but no significant difference in BAX expression. Furthermore, analysis of CpG islands in the FAS gene promoter revealed that the FAS promoter was significantly hypermethylated in 53.3% of tumor tissues compared with adjacent normal samples. Taken together, the results indicate that decreased expression of the FAS gene due to hypermethylation of its promoter may lead to apoptotic resistance, and acts as an important step during colorectal carcinogenesis.

Various clinical application of phase contrast X-ray

NASA Astrophysics Data System (ADS)

Oh, Chilhwan; Park, Sangyong; Ha, Seunghan; Park, Gyuman; Lee, Gunwoo; Lee, Onseok; Je, Jungho

2008-02-01

In biomedical application study using phase contrast X-ray, both sample thickness or density and absorption difference are very important factors in aspects of contrast enhancement. We present experimental evidence that synchrotron hard X-ray are suitable for radiological imaging of biological samples down to the cellular level. We investigated the potential of refractive index radiology using un-monochromatized synchrotron hard X-rays for the imaging of cell and tissue in various diseases. Material had been adopted various medical field, such as apoE knockout mouse in cardiologic field, specimen from renal and prostatic carcinoma patient in urology, basal cell epithelioma in dermatology, brain tissue from autosy sample of pakinson's disease, artificially induced artilrtis tissue from rabbits and extracted tooth from patients of crack tooth syndrome. Formalin and paraffin fixed tissue blocks were cut in 3 mm thickness for the X-ray radiographic imaging. From adjacent areas, 4 μm thickness sections were also prepared for hematoxylin-eosin staining. Radiographic images of dissected tissues were obtained using the hard X-rays from the 7B2 beamline of the Pohang Light Source (PLS). The technique used for the study was the phase contrast images were compared with the optical microscopic images of corresponding histological slides. Radiographic images of various diseased tissues showed clear histological details of organelles in normal tissues. Most of cancerous lesions were well differentiated from adjacent normal tissues and detailed histological features of each tumor were clearly identified. Also normal microstructures were identifiable by the phase contrast imaging. Tissue in cancer or other disease showed clearly different findings from those of surrounding normal tissue. For the first time we successfully demonstrated that synchrotron hard X-rays can be used for radiological imaging of relatively thick tissue samples with great histological details.

Cancer testis antigen OY-TES-1 expression and serum immunogenicity in colorectal cancer: its relationship to clinicopathological parameters.

PubMed

Luo, Bin; Yun, Xiang; Fan, Rong; Lin, Yong-Da; He, Shu-Jia; Zhang, Qing-Mei; Mo, Fa-Rong; Chen, Fang; Xiao, Shao-Wen; Xie, Xiao-Xun

2013-01-01

Cancer testis (CT) antigens are attractive targets for cancer immunotherapy because their expression is restricted in normal germ line tissues but frequently detected in variety of tumors. OY-TES-1 is identified as a member of CT antigens. Current knowledge about OY-TES-1 expression in colorectal cancer (CRC) is solely based on mRNA analysis. None of previous researches has studied OY-TES-1 at protein level. In this study, OY-TES-1 polyclonal antibody was generated. The expression of OY-TES-1 mRNA and protein was detected by RT-PCR and immunohistochemistry in 60 CRC and paired adjacent non-tumor tissues, 24 colorectal adenoma and 3 normal colon tissues, respectively. Sera from 73 CRC patients were also tested for OY-TES-1 antibody by ELISA. Our results showed that the frequency of OY-TES-1 mRNA expression was statistically higher in CRC (73.3%, 44/60) than that in adjacent non-tumor tissue (55.0%, 33/60) and colorectal adenoma (45.8%, 11/24). For the first time, OY-TES-1 protein expression was found in (43.3%, 26/60) of CRC tissues, but absent in any of adjacent non-tumor and colorectal adenoma tissues. No OY-TES-1 expression was found in normal colon by either RT-PCR or immunohistochemistry. Furthermore, OY-TES-1 protein expression was correlated with tumor invasion stage (P=0.004) and histological grade (P=0.040). Anti-OY-TES-1 antibody was detected in (9.6%, 7/73) of CRC patients' sera but not in 76 healthy donors. This finding demonstrates that OY-TES-1 is frequently expressed in CRC and is able to induce humoral immune response spontaneously in CRC patients, suggesting that it might be a promising immunotherapy target for CRC.

Immunohistochemical detection of a hypoxia marker in spontaneous canine tumours.

PubMed Central

Cline, J. M.; Thrall, D. E.; Page, R. L.; Franko, A. J.; Raleigh, J. A.

1990-01-01

An immunoperoxidase technique has been used to detect the in vivo binding of a 2-nitroimidazole hypoxia marker in histochemical sections of a variety of excised canine tumours. The binding occurred 10-12 cell diameters away from tumour blood vessels, consistent with the expected location of hypoxic cells in tissues in which oxygen concentration gradients are established by diffusion. Hypoxic fractions ranging from 4 to 13% have been estimated on the basis of morphometric analysis of multiple tumour sections. The binding of the marker was restricted to the cytoplasm of the cells. The marker appeared in regions adjacent to necrosis but also in regions free of necrosis. As in earlier autoradiography studies, binding was occasionally observed in cells adjacent to tumour blood vessels. Generally, binding to normal tissues was not observed. However, binding to smooth muscle cells surrounding arterioles in some sections of normal tissue and tumour tissue was observed. Images Figure 1 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 PMID:1701659

Promoter methylation assay of SASH1 gene in hepatocellular carcinoma.

PubMed

Peng, Liu; Wei, He; Liren, Li

2014-01-01

To analyse the relationship between the expression of SASH1 and its methylation level in human hepatocellular carcinoma. Expression levels of SASH1 were examined with real-time PCR (RT-PCR) in tissues and cells, and methylation analysis was performed with MassArray. The expression levels of SASH1 were strongly reduced in liver cancer tissues compared with adjacent normal tissues. Quantitative methylation analysis by MassArray revealed different CpG sites in SASH1 promoter shared similar methylation pattern between liver cancer tissues and adjacent normal tissues and the CpG sites of significant difference in methylation level were found as follows: CpG_3, CpG_17, CpG_21.22, CpG_25, CpG_26.27, CpG_28, CpG_34.35.36 and CpG_51.52. Moreover, 5-aza-2'-deoxycytidine treatment of Hep-G2 cell line caused significant elevation of SASH1 mRNA. Based on these data, we propose that increase of DNA methylation degree in the promoter region of SASH1 gene, particularly CpG_26.27 sites, possibly repressed SASH1 expression in liver cancer.

miR-7 Increases Cisplatin Sensitivity of Gastric Cancer Cells Through Suppressing mTOR

PubMed Central

Lian, Yan-Jun; Dai, Xiang; Wang, Yuan-Jie

2017-01-01

MicroRNAs have been reported to play an important role in diverse biological processes and cancer progression. MicroRNA-7 has been observed to be downregulated in human gastric cancer tissues, but the function of microRNA-7 in gastric cancer has not been well investigated. In this study, we demonstrate that the expression of microRNA-7 was significantly downregulated in 30 pairs of human gastric cancer tissues compared to adjacent normal tissues. Enforced expression of microRNA-7 inhibited cell proliferation and migration abilities of gastric cancer cells, BGC823 and SGC7901. Furthermore, microRNA-7 targeted mTOR in gastric cancer cells. In human clinical specimens, mTOR was higher expressed in gastric cancer tissues compared with adjacent normal tissues. More interestingly, microRNA-7 also sensitizes gastric cancer cells to cisplatin (CDDP) by targeting mTOR. Collectively, our results demonstrate that microRNA-7 is a tumor suppressor microRNA and indicate its potential application for the treatment of human gastric cancer in future. PMID:28693382

A study on quantitative analysis of field size and dose by using gating system in 4D conformal radiation treatment

NASA Astrophysics Data System (ADS)

Ji, Youn-Sang; Dong, Kyung-Rae; Kim, Chang-Bok; Chung, Woon-Kwan; Cho, Jae-Hwan; Lee, Hae-Kag

2012-10-01

This study evaluated the gating-based 4-D conformal radiation therapy (4D-CT) treatment planning by a comparison with the common 3-D conformal radiation therapy (3D-CT) treatment planning and examined the change in treatment field size and dose to the tumors and adjacent normal tissues because an unnecessary dose is also included in the 3-D treatment planning for the radiation treatment of tumors in the chest and abdomen. The 3D-CT and gating-based 4D-CT images were obtained from patients who had undergone radiation treatment for chest and abdomen tumors in the oncology department. After establishing a treatment plan, the CT treatment and planning system were used to measure the change in field size for analysis. A dose volume histogram (DVH) was used to calculate the appropriate dose to planning target volume (PTV) tumors and adjacent normal tissue. The difference in the treatment volume of the chest was 0.6 and 0.83 cm on the X- and Y-axis, respectively, for the gross tumor volume (GTV). Accordingly, the values in the 4D-CT treatment planning were smaller and the dose was more concentrated by 2.7% and 0.9% on the GTV and clinical target volume (CTV), respectively. The normal tissues in the surrounding normal tissues were reduced by 3.0%, 7.2%, 0.4%, 1.7%, 2.6% and 0.2% in the bronchus, chest wall, esophagus, heart, lung and spinal cord, respectively. The difference in the treatment volume of the abdomen was 0.72 cm on the X-axis and 0.51 cm on the Y-axis for the GTV; and 1.06 cm on the X-axis and 1.85 cm on the Y-axis for the PTV. Therefore, the values in the 4D-CT treatment planning were smaller. The dose was concentrated by 6.8% and 4.3% on the GTV and PTV, respectively, whereas the adjacent normal tissues in the cord, Lt. kidney, Rt. kidney, small bowels and whole liver were reduced by 3.2%, 4.2%, 1.5%, 6.2% and 12.7%, respectively. The treatment field size was smaller in volume in the case of the 4D-CT treatment planning. In the DVH, the 4D-CT treatment planning showed a higher dose concentration on the part to be treated than the 3D-CT treatment planning with a lower dose to the adjacent normal tissues. Overall, the gating-based 4D-CT treatment planning is believed to be more helpful than the 3D-CT treatment planning.

Dubinett - Targeted Sequencing 2012 — EDRN Public Portal

Cancer.gov

we propose to use targeted massively parallel DNA sequencing to identify somatic alterations within mutational hotspots in matched sets of primary lung tumors, premalignant lesions, and adjacent,histologically normal lung tissue.

Cyclooxygenase-2 expression is related to nuclear grade in ductal carcinoma in situ and is increased in its normal adjacent epithelium

NASA Technical Reports Server (NTRS)

Shim, Veronica; Gauthier, Mona L.; Sudilovsky, Daniel; Mantei, Kristin; Chew, Karen L.; Moore, Dan H.; Cha, Imok; Tlsty, Thea D.; Esserman, Laura J.

2003-01-01

Cyclooxygenase-2 (COX-2) is emerging as an important cancer biomarker and is now an experimental target for solid tumor treatment.However, no study has exclusively focused on COX-2 expression in early lesions such as ductal carcinoma in situ (DCIS). We examined COX-2 expression by immunohistochemistry in 46 cases of women undergoing surgical resection for DCIS. We found that COX-2 expression was detected in 85% of all DCIS specimens, with increased COX-2 staining correlating with higher nuclear grade. Strikingly, COX-2 staining intensity in the normal adjacent epithelium was stronger than in the DCIS lesion itself. Our observations demonstrate that COX-2 is up-regulated in the normal adjacent epithelium and supports the hypothesis that the surrounding epithelial tissue is part of the disease process in DCIS.

Defining Genomic Changes in Triple-Negative Breast Cancer in Women of African Descent

DTIC Science & Technology

2012-06-01

African and African - American breast cancer cases. Gene Expression Array Studies The 31 triple negative Kijabe samples were... American Adjacent Normal Breast Tissue PI: Pegram & Baumbach Defining Genomic Changes in Triple Negative Breast Cancer in Women of African ...Tissues from African - American and East African Patients with Triple Negative Breast

Differential Expression of Cytochrome P450 Enzymes in Normal and Tumor Tissues from Childhood Rhabdomyosarcoma

PubMed Central

Molina-Ortiz, Dora; Camacho-Carranza, Rafael; González-Zamora, José Francisco; Shalkow-Kalincovstein, Jaime; Cárdenas-Cardós, Rocío; Ností-Palacios, Rosario; Vences-Mejía, Araceli

2014-01-01

Intratumoral expression of genes encoding Cytochrome P450 enzymes (CYP) might play a critical role not only in cancer development but also in the metabolism of anticancer drugs. The purpose of this study was to compare the mRNA expression patterns of seven representative CYPs in paired tumor and normal tissue of child patients with rabdomyosarcoma (RMS). Using real time quantitative RT-PCR, the gene expression pattern of CYP1A1, CYP1A2, CYP1B1, CYP2E1, CYP2W1, CYP3A4, and CYP3A5 were analyzed in tumor and adjacent non-tumor tissues from 13 child RMS patients. Protein concentration of CYPs was determined using Western blot. The expression levels were tested for correlation with the clinical and pathological data of the patients. Our data showed that the expression levels of CYP1A1 and CYP1A2 were negligible. Elevated expression of CYP1B1 mRNA and protein was detected in most RMS tumors and adjacent normal tissues. Most cancerous samples exhibit higher levels of both CYP3A4 and CYP3A5 compared with normal tissue samples. Expression of CYP2E1 mRNA was found to be significantly higher in tumor tissue, however no relation was found with protein levels. CYP2W1 mRNA and/or protein are mainly expressed in tumors. In conclusion, we defined the CYP gene expression profile in tumor and paired normal tissue of child patients with RMS. The overexpression of CYP2W1, CYP3A4 and CYP3A5 in tumor tissues suggests that they may be involved in RMS chemoresistance; furthermore, they may be exploited for the localized activation of anticancer prodrugs. PMID:24699256

Laser ablation of human atherosclerotic plaque without adjacent tissue injury

NASA Technical Reports Server (NTRS)

Grundfest, W. S.; Litvack, F.; Forrester, J. S.; Goldenberg, T.; Swan, H. J. C.

1985-01-01

Seventy samples of human cadaver atherosclerotic aorta were irradiated in vitro using a 308 nm xenon chloride excimer laser. Energy per pulse, pulse duration and frequency were varied. For comparison, 60 segments were also irradiated with an argon ion and an Nd:YAG laser operated in the continuous mode. Tissue was fixed in formalin, sectioned and examined microscopically. The Nd:YAG and argon ion-irradiated tissue exhibited a central crater with irregular edges and concentric zones of thermal and blast injury. In contrast, the excimer laser-irradiated tissue had narrow deep incisions with minimal or no thermal injury. These preliminary experiments indicate that the excimer laser vaporizes tissue in a manner different from that of the continuous wave Nd:YAG or argon ion laser. The sharp incision margins and minimal damage to adjacent normal tissue suggest that the excimer laser is more desirable for general surgical and intravascular uses than are the conventionally used medical lasers.

Detection of reactive oxygen metabolites in malignant and adjacent normal tissues of patients with lung cancer.

PubMed

Okur, Hacer Kuzu; Yuksel, Meral; Lacin, Tunc; Baysungur, Volkan; Okur, Erdal

2013-01-17

Different types of reactive oxygen metabolites (ROMs) are known to be involved in carcinogenesis. Several studies have emphasized the formation of ROMs in ischemic tissues and in cases of inflammation. The increased amounts of ROMs in tumor tissues can either be because of their causative effects or because they are produced by the tumor itself. Our study aimed to investigate and compare the levels of ROMs in tumor tissue and adjacent lung parenchyma obtained from patients with lung cancer. Fifteen patients (all male, mean age 63.6 ± 9 years) with non-small cell lung cancer were enrolled in the study. All patients were smokers. Of the patients with lung cancer, twelve had epidermoid carcinoma and three had adenocarcinoma. During anatomical resection of the lung, tumor tissue and macroscopically adjacent healthy lung parenchyma (control) that was 5 cm away from the tumor were obtained. The tissues were freshly frozen and stored at -20°C. The generation of ROMs was monitored using luminol- and lucigenin-enhanced chemiluminescence (CL) techniques. Both luminol (specific for (.)OH, H(2)O(2), and HOCl(-)) and lucigenin (selective for O(2)(.)(-)) CL measurements were significantly higher in tumor tissues than in control tissues (P <0.001). Luminol and lucigenin CL measurements were 1.93 ± 0.71 and 2.5 ± 0.84 times brighter, respectively, in tumor tissues than in the adjacent parenchyma (P = 0.07). In patients with lung cancer, all ROM levels were increased in tumor tissues when compared with the adjacent lung tissue. Because the increase in lucigenin concentration, which is due to tissue ischemia, is higher than the increase in luminol, which is directly related to the presence and severity of inflammation, ischemia may be more important than inflammation for tumor development in patients with lung cancer.

The components of somatostatin and ghrelin systems are altered in neuroendocrine lung carcinoids and associated to clinical-histological features.

PubMed

Herrera-Martínez, Aura D; Gahete, Manuel D; Sánchez-Sánchez, Rafael; Salas, Rosa Ortega; Serrano-Blanch, Raquel; Salvatierra, Ángel; Hofland, Leo J; Luque, Raúl M; Gálvez-Moreno, María A; Castaño, Justo P

2017-07-01

Lung carcinoids (LCs) are rare tumors that comprise 1-5% of lung malignancies but represent 20-30% of neuroendocrine tumors. Their incidence is progressively increasing and a better characterization of these tumors is required. Alterations in somatostatin (SST)/cortistatin (CORT) and ghrelin systems have been associated to development/progression of various endocrine-related cancers, wherein they may become useful diagnostic, prognostic and therapeutic biomarkers. We aimed to evaluate the expression levels of ghrelin and SST/CORT system components in LCs, as well as to explore their putative relationship with histological/clinical characteristics. An observational retrospective study was performed; 75 LC patients with clinical/histological characteristics were included. Samples from 46 patients were processed to isolate mRNA from tumor and adjacent non-tumor region, and the expression levels of SST/CORT and ghrelin systems components, determined by quantitative-PCR, were compared to those of 7 normal lung tissues. Patient cohort was characterized by mean age 53±15 years, 48% males, 34% with tobacco exposure; 71.4/28.6% typical/atypical carcinoids, 21.7% incidental tumors, 4.3% functioning tumors, 17.7% with metastasis. SST/CORT and ghrelin system components were expressed at variable levels in a high proportion of tumors, as well as in adjacent non-tumor tissues, while a lower proportion of normal lung samples also expressed these molecules. A gradation was observed from normal non-neoplastic lung tissues, non-tumor adjacent tissue and LCs, being SST, sst4, sst5, GHS-R1a and GHS-R1b overexpressed in tumor tissue compared to normal tissue. Importantly, several SST/CORT and ghrelin system components displayed significant correlations with relevant clinical parameters, such as necrosis, peritumoral and vascular invasion, or metastasis. Altogether, these data reveal a prominent, widespread expression of key SST/CORT/ghrelin system components in LCs, where they display clinical-histological correlations, which could provide novel, valuable markers for NET patient management. Copyright © 2017 Elsevier B.V. All rights reserved.

A subset of high Gleason grade prostate carcinomas contain a large burden of prostate cancer syndecan-1 positive stromal cells.

PubMed

Sharpe, Benjamin; Alghezi, Dhafer A; Cattermole, Claire; Beresford, Mark; Bowen, Rebecca; Mitchard, John; Chalmers, Andrew D

2017-05-01

There is a pressing need to identify prognostic and predictive biomarkers for prostate cancer to aid treatment decisions in both early and advanced disease settings. Syndecan-1, a heparan sulfate proteoglycan, has been previously identified as a potential prognostic biomarker by multiple studies at the tissue and serum level. However, other studies have questioned its utility. Anti-Syndecan-1 immunohistochemistry was carried out on 157 prostate tissue samples (including cancerous, adjacent normal tissue, and non-diseased prostate) from three independent cohorts of patients. A population of Syndecan-1 positive stromal cells was identified and the number and morphological parameters of these cells quantified. The identity of the Syndecan-1-positive stromal cells was assessed by multiplex immunofluorescence using a range of common cell lineage markers. Finally, the burden of Syndecan-1 positive stromal cells was tested for association with clinical parameters. We identified a previously unreported cell type which is marked by Syndecan-1 expression and is found in the stroma of prostate tumors and adjacent normal tissue but not in non-diseased prostate. We call these cells Prostate Cancer Syndecan-1 Positive (PCSP) cells. Immunofluorescence analysis revealed that the PCSP cell population did not co-stain with markers of common prostate epithelial, stromal, or immune cell populations. However, morphological analysis revealed that PCSP cells are often elongated and displayed prominent lamellipodia, suggesting they are an unidentified migratory cell population. Analysis of clinical parameters showed that PCSP cells were found with a frequency of 20-35% of all tumors evaluated, but were not present in non-diseased normal tissue. Interestingly, a subset of primary Gleason 5 prostate tumors had a high burden of PCSP cells. The current study identifies PCSP cells as a novel, potentially migratory cell type, which is marked by Syndecan-1 expression and is found in the stroma of prostate carcinomas, adjacent normal tissue, but not in non-diseased prostate. A subset of poor prognosis high Gleason grade 5 tumors had a particularly high PCSP cell burden, suggesting an association between this unidentified cell type and tumor aggressiveness. © 2017 Wiley Periodicals, Inc.

Karyometry of the colonic mucosa.

PubMed

Alberts, David S; Einspahr, Janine G; Krouse, Robert S; Prasad, Anil; Ranger-Moore, James; Hamilton, Peter; Ismail, Ayaaz; Lance, Peter; Goldschmid, Steven; Hess, Lisa M; Yozwiak, Michael; Bartels, Hubert G; Bartels, Peter H

2007-12-01

The study summarizes results of karyometric measurements in epithelial cells of the colorectal mucosa to document evidence of a field effect of preneoplastic development among patients with colorectal adenocarcinoma or adenoma. Karyometric analyses were done on high-resolution images of histologic sections from 48 patients with colorectal adenocarcinomas and 44 patients with adenomas and on images from matching normal-appearing mucosa directly adjacent to such lesions, at a 1-cm and 10-cm distance from the lesions or from the rectal mucosa of adenoma patients, as well as from 24 healthy normal controls with no family history of colonic disease. The nuclei recorded in the histologically normal-appearing mucosa of patients with either colorectal adenoma or adenocarcinoma exhibited differences in karyometric features in comparison with nuclei recorded in rectal mucosa from patients who were free of a colonic lesion. These differences were expressed to the same extent in tissue adjacent to the lesions and in normal-appearing tissue as distant as the rectum. The nuclear chromatin pattern may serve as an integrating biomarker for a preneoplastic development. The field effect might provide an end point in chemopreventive intervention trials.

Decreased expression of dual specificity phosphatase 22 in colorectal cancer and its potential prognostic relevance for stage IV CRC patients.

PubMed

Yu, Dan; Li, Zhenli; Gan, Meifu; Zhang, Hanyun; Yin, Xiaoyang; Tang, Shunli; Wan, Ledong; Tian, Yiping; Zhang, Shuai; Zhu, Yimin; Lai, Maode; Zhang, Dandan

2015-11-01

Dual specificity phosphatase 22 (DUSP22) is a novel dual specificity phosphatase that has been demonstrated to be a cancer suppressor gene associated with numerous biological and pathological processes. However, little is known of DUSP22 expression profiling in colorectal cancer and its prognostic value. Our study aims to investigate the role of DUSP22 expression in the prognosis of colorectal cancer. We detected the mRNA expression in 92 paired primary colorectal cancer tissues and the corresponding adjacent normal tissues by using QuantiGenePlex assay. The Friedman test was used to determine the statistical difference of gene expression. Kaplan-Meier survival analysis was performed. Mann-Whitney test and Kruskal-Wallis test were used to conduct data analyses to determine the prognostic value. Statistical significance was set at P < 0.05. In 74 of 92 cases, DUSP22 mRNA was reduced in primary colorectal cancer tissues, compared to the adjacent normal tissues. The mRNA levels of DUSP22 were significantly lower in colorectal cancer tissues than in adjacent normal tissues (0.0290 vs. 0.0658; P < 0.001). Low expression of DUSP22 correlated significantly with large tumor size (P = 0.013). No association was observed between DUSP22 mRNA expression and differentiation, histopathological type, tumor invasion, lymph node metastases, metastases, TNM stage, and Duke's phase (all P > 0.05). Kaplan-Meier analysis indicated that DUSP22 expression had no significant relationship with overall survival in all patients (P > 0.05). Interestingly, low expression level of DUSP22 in stage IV patients had a poor survival measures with a marginal P value (P = 0.07). Reduced DUSP22 expression was found in colorectal cancer specimens. Low expression level of DUSP22 in stage IV patients had a poor survival outcome. Further study is required for the investigation of the role of DUSP22 in colorectal cancer.

Cancer testis antigen OY-TES-1 expression and serum immunogenicity in colorectal cancer: its relationship to clinicopathological parameters

PubMed Central

Luo, Bin; Yun, Xiang; Fan, Rong; Lin, Yong-Da; He, Shu-Jia; Zhang, Qing-Mei; Mo, Fa-Rong; Chen, Fang; Xiao, Shao-Wen; Xie, Xiao-Xun

2013-01-01

Cancer testis (CT) antigens are attractive targets for cancer immunotherapy because their expression is restricted in normal germ line tissues but frequently detected in variety of tumors. OY-TES-1 is identified as a member of CT antigens. Current knowledge about OY-TES-1 expression in colorectal cancer (CRC) is solely based on mRNA analysis. None of previous researches has studied OY-TES-1 at protein level. In this study, OY-TES-1 polyclonal antibody was generated. The expression of OY-TES-1 mRNA and protein was detected by RT-PCR and immunohistochemistry in 60 CRC and paired adjacent non-tumor tissues, 24 colorectal adenoma and 3 normal colon tissues, respectively. Sera from 73 CRC patients were also tested for OY-TES-1 antibody by ELISA. Our results showed that the frequency of OY-TES-1 mRNA expression was statistically higher in CRC (73.3%, 44/60) than that in adjacent non-tumor tissue (55.0%, 33/60) and colorectal adenoma (45.8%, 11/24). For the first time, OY-TES-1 protein expression was found in (43.3%, 26/60) of CRC tissues, but absent in any of adjacent non-tumor and colorectal adenoma tissues. No OY-TES-1 expression was found in normal colon by either RT-PCR or immunohistochemistry. Furthermore, OY-TES-1 protein expression was correlated with tumor invasion stage (P=0.004) and histological grade (P=0.040). Anti-OY-TES-1 antibody was detected in (9.6%, 7/73) of CRC patients’ sera but not in 76 healthy donors. This finding demonstrates that OY-TES-1 is frequently expressed in CRC and is able to induce humoral immune response spontaneously in CRC patients, suggesting that it might be a promising immunotherapy target for CRC. PMID:24294369

Proteomic profiling of fetal esophageal epithelium, esophageal cancer, and tumor-adjacent esophageal epithelium and immunohistochemical characterization of a representative differential protein, PRX6

PubMed Central

Guo, Jun-Hui; Xing, Guo-Lan; Fang, Xin-Hui; Wu, Hui-Fang; Zhang, Bo; Yu, Jin-Zhong; Fan, Zong-Min; Wang, Li-Dong

2017-01-01

AIM To understand the molecular mechanism of esophageal cancer development and provide molecular markers for screening high-risk populations and early diagnosis. METHODS Two-dimensional electrophoresis combined with mass spectrometry were adopted to screen differentially expressed proteins in nine cases of fetal esophageal epithelium, eight cases of esophageal cancer, and eight cases of tumor-adjacent normal esophageal epithelium collected from fetuses of different gestational age, or esophageal cancer patients from a high-risk area of esophageal cancer in China. Immunohistochemistry (avidin-biotin-horseradish peroxidase complex method) was used to detect the expression of peroxiredoxin (PRX)6 in 91 cases of esophageal cancer, tumor-adjacent normal esophageal tissue, basal cell hyperplasia, dysplasia, and carcinoma in situ, as well as 65 cases of esophageal epithelium from fetuses at a gestational age of 3-9 mo. RESULTS After peptide mass fingerprint analysis and search of protein databases, 21 differential proteins were identified; some of which represent a protein isoform. Varying degrees of expression of PRX6 protein, which was localized mainly in the cytoplasm, were detected in adult and fetal normal esophageal tissues, precancerous lesions, and esophageal cancer. With the progression of esophageal lesions, PRX6 protein expression showed a declining trend (P < 0.05). In fetal epithelium from fetuses at gestational age 3-6 mo, PRX6 protein expression showed a declining trend with age (P < 0.05). PRX6 protein expression was significantly higher in well-differentiated esophageal cancer tissues than in poorly differentiated esophageal cancer tissues (P < 0.05). CONCLUSION Development and progression of esophageal cancer result from interactions of genetic changes (accumulation or superposition). PRX6 protein is associated with fetal esophageal development and cancer differentiation. PMID:28293090

Proteomic profiling of fetal esophageal epithelium, esophageal cancer, and tumor-adjacent esophageal epithelium and immunohistochemical characterization of a representative differential protein, PRX6.

PubMed

Guo, Jun-Hui; Xing, Guo-Lan; Fang, Xin-Hui; Wu, Hui-Fang; Zhang, Bo; Yu, Jin-Zhong; Fan, Zong-Min; Wang, Li-Dong

2017-02-28

To understand the molecular mechanism of esophageal cancer development and provide molecular markers for screening high-risk populations and early diagnosis. Two-dimensional electrophoresis combined with mass spectrometry were adopted to screen differentially expressed proteins in nine cases of fetal esophageal epithelium, eight cases of esophageal cancer, and eight cases of tumor-adjacent normal esophageal epithelium collected from fetuses of different gestational age, or esophageal cancer patients from a high-risk area of esophageal cancer in China. Immunohistochemistry (avidin-biotin-horseradish peroxidase complex method) was used to detect the expression of peroxiredoxin (PRX)6 in 91 cases of esophageal cancer, tumor-adjacent normal esophageal tissue, basal cell hyperplasia, dysplasia, and carcinoma in situ , as well as 65 cases of esophageal epithelium from fetuses at a gestational age of 3-9 mo. After peptide mass fingerprint analysis and search of protein databases, 21 differential proteins were identified; some of which represent a protein isoform. Varying degrees of expression of PRX6 protein, which was localized mainly in the cytoplasm, were detected in adult and fetal normal esophageal tissues, precancerous lesions, and esophageal cancer. With the progression of esophageal lesions, PRX6 protein expression showed a declining trend ( P < 0.05). In fetal epithelium from fetuses at gestational age 3-6 mo, PRX6 protein expression showed a declining trend with age ( P < 0.05). PRX6 protein expression was significantly higher in well-differentiated esophageal cancer tissues than in poorly differentiated esophageal cancer tissues ( P < 0.05). Development and progression of esophageal cancer result from interactions of genetic changes (accumulation or superposition). PRX6 protein is associated with fetal esophageal development and cancer differentiation.

Activation of RAS family genes in urothelial carcinoma.

PubMed

Boulalas, I; Zaravinos, A; Karyotis, I; Delakas, D; Spandidos, D A

2009-05-01

Bladder cancer is the fifth most common malignancy in men in Western society. We determined RAS codon 12 and 13 point mutations and evaluated mRNA expression levels in transitional cell carcinoma cases. Samples from 30 human bladder cancers and 30 normal tissues were analyzed by polymerase chain reaction/restriction fragment length polymorphism and direct sequencing to determine the occurrence of mutations in codons 12 and 13 of RAS family genes. Moreover, we used real-time reverse transcriptase-polymerase chain reaction to evaluate the expression profile of RAS genes in bladder cancer specimens compared to that in adjacent normal tissues. Overall H-RAS mutations in codon 12 were observed in 9 tumor samples (30%). Two of the 9 patients (22%) had invasive bladder cancer and 7 (77%) had noninvasive bladder cancer. One H-RAS mutation (11%) was homozygous and the remaining 89% were heterozygous. All samples were WT for K and N-RAS oncogenes. Moreover, 23 of 30 samples (77%) showed over expression in at least 1 RAS family gene compared to adjacent normal tissue. K and N-RAS had the highest levels of over expression in bladder cancer specimens (50%), whereas 27% of transitional cell carcinomas demonstrated H-RAS over expression relative to paired normal tissues. Our results underline the importance of H-RAS activation in human bladder cancer by codon 12 mutations. Moreover, they provide evidence that increased expression of all 3 RAS genes is a common event in bladder cancer that is associated with disease development.

Aldosterone-stimulating somatic gene mutations are common in normal adrenal glands

PubMed Central

Nishimoto, Koshiro; Tomlins, Scott A.; Kuick, Rork; Cani, Andi K.; Giordano, Thomas J.; Hovelson, Daniel H.; Liu, Chia-Jen; Sanjanwala, Aalok R.; Edwards, Michael A.; Gomez-Sanchez, Celso E.; Nanba, Kazutaka; Rainey, William E.

2015-01-01

Primary aldosteronism (PA) represents the most common cause of secondary hypertension, but little is known regarding its adrenal cellular origins. Recently, aldosterone-producing cell clusters (APCCs) with high expression of aldosterone synthase (CYP11B2) were found in both normal and PA adrenal tissue. PA-causing aldosterone-producing adenomas (APAs) harbor mutations in genes encoding ion channels/pumps that alter intracellular calcium homeostasis and cause renin-independent aldosterone production through increased CYP11B2 expression. Herein, we hypothesized that APCCs have APA-related aldosterone-stimulating somatic gene mutations. APCCs were studied in 42 normal adrenals from kidney donors. To clarify APCC molecular characteristics, we used microarrays to compare the APCC transcriptome with conventional adrenocortical zones [zona glomerulosa (ZG), zona fasciculata, and zona reticularis]. The APCC transcriptome was most similar to ZG but with an enhanced capacity to produce aldosterone. To determine if APCCs harbored APA-related mutations, we performed targeted next generation sequencing of DNA from 23 APCCs and adjacent normal adrenal tissue isolated from both formalin-fixed, paraffin-embedded, and frozen tissues. Known aldosterone driver mutations were identified in 8 of 23 (35%) APCCs, including mutations in calcium channel, voltage-dependent, L-type, α1D-subunit (CACNA1D; 6 of 23 APCCs) and ATPase, Na+/K+ transporting, α1-polypeptide (ATP1A1; 2 of 23 APCCs), which were not observed in the adjacent normal adrenal tissue. Overall, we show three major findings: (i) APCCs are common in normal adrenals, (ii) APCCs harbor somatic mutations known to cause excess aldosterone production, and (iii) the mutation spectrum of aldosterone-driving mutations is different in APCCs from that seen in APA. These results provide molecular support for APCC as a precursor of PA. PMID:26240369

Genomic Changes in Normal Breast Tissue in Women at Normal Risk or at High Risk for Breast Cancer

PubMed Central

Danforth, David N.

2016-01-01

Sporadic breast cancer develops through the accumulation of molecular abnormalities in normal breast tissue, resulting from exposure to estrogens and other carcinogens beginning at adolescence and continuing throughout life. These molecular changes may take a variety of forms, including numerical and structural chromosomal abnormalities, epigenetic changes, and gene expression alterations. To characterize these abnormalities, a review of the literature has been conducted to define the molecular changes in each of the above major genomic categories in normal breast tissue considered to be either at normal risk or at high risk for sporadic breast cancer. This review indicates that normal risk breast tissues (such as reduction mammoplasty) contain evidence of early breast carcinogenesis including loss of heterozygosity, DNA methylation of tumor suppressor and other genes, and telomere shortening. In normal tissues at high risk for breast cancer (such as normal breast tissue adjacent to breast cancer or the contralateral breast), these changes persist, and are increased and accompanied by aneuploidy, increased genomic instability, a wide range of gene expression differences, development of large cancerized fields, and increased proliferation. These changes are consistent with early and long-standing exposure to carcinogens, especially estrogens. A model for the breast carcinogenic pathway in normal risk and high-risk breast tissues is proposed. These findings should clarify our understanding of breast carcinogenesis in normal breast tissue and promote development of improved methods for risk assessment and breast cancer prevention in women. PMID:27559297

Confocal fluorescence microscopy to evaluate changes in adipocytes in the tumor microenvironment associated with invasive ductal carcinoma and ductal carcinoma in situ.

PubMed

Dobbs, Jessica L; Shin, Dongsuk; Krishnamurthy, Savitri; Kuerer, Henry; Yang, Wei; Richards-Kortum, Rebecca

2016-09-01

Adipose tissue is a dynamic organ that provides endocrine, inflammatory and angiogenic factors, which can assist breast carcinoma cells with invasion and metastasis. Previous studies have shown that adipocytes adjacent to carcinoma, known as cancer-associated adipocytes, undergo extensive changes that correspond to an "activated phenotype," such as reduced size relative to adipocytes in non-neoplastic breast tissue. Optical imaging provides a tool that can be used to characterize adipocyte morphology and other features of the tumor microenvironment. In this study, we used confocal fluorescence microscopy to acquire images of freshly excised breast tissue stained topically with proflavine. We developed a computerized algorithm to identify and quantitatively measure phenotypic properties of adipocytes located adjacent to and far from normal collagen, ductal carcinoma in situ and invasive ductal carcinoma. Adipocytes were measured in confocal fluorescence images of fresh breast tissue collected from 22 patients. Results show that adipocytes adjacent to neoplastic tissue margins have significantly smaller area compared to adipocytes far from the margins of neoplastic lesions and compared to adipocytes adjacent to non-neoplastic collagenous stroma. These findings suggest that confocal microscopic images can be utilized to evaluate phenotypic properties of adipocytes in breast stroma which may be useful in defining alterations in microenvironment that may aid in the development and progression of neoplastic lesions. © 2016 UICC.

Demonstration of Iodide Transport Defect but Normal Iodide Organification in Nonfunctioning Nodules of Human Thyroid Glands

PubMed Central

Field, James B.; Larsen, P. Reed; Yamashita, Kamejiro; Mashiter, Keith; Dekker, Andrew

1973-01-01

Benign and malignant nodules in human thyroid glands, which did not concentrate iodide in vivo, were also unable to accumulate iodide in vitro. The mean thyroid-to-medium ratio (T/M) in seven benign nodules was 0.8±0.2 compared with 7±2 in adjacent normal thyroid tissue. In four malignant thyroid nodules, the mean T/M was 0.5±0.1 compared with 11±4 in adjacent normal thyroid. Despite the inability of such nodules to concentrate iodide, iodide organification was present but was only one-half to one-third as active as in surrounding normal thyroid. Thyroid-stimulating hormone (TSH) increased iodide organification equally in both benign nodules and normal thyroid although it had no effect in three of the four malignant lesions. The reduction in organification is probably related to the absence of iodide transport, since incubation of normal thyroid slices with perchlorate caused similar diminution in iodide incorporation but no change in the response to TSH. Monoiodotyrosine (MIT) and di-iodotyrosine (DIT) accounted for most of the organic iodide in both the nodules and normal tissue. The MIT/DIT ratio was similar in normal and nodule tissue. The normal tissue contained much more inorganic iodide than the nodules, consistent with the absence of the iodide trap in the latter tissue. The thyroxine content of normal thyroid was 149±17 μg/g wet wt and 18±4 μg/g wet wt in the nodules. The transport defect in the nodules was not associated with any reduction in total, Na+-K+- or Mg++-activated ATPase activities or the concentration of ATP. Basal adenylate cyclase was higher in nodules than normal tissue. Although there was no difference between benign and malignant nodules, the response of adenylate cyclase to TSH was greater in the benign lesions. These studies demonstrate that nonfunctioning thyroid nodules, both benign and malignant, have a specific defect in iodide transport that accounts for their failure to accumulate radioactive iodide in vivo. In benign nodules, iodide organification was increased by TSH while no such effect was found in three of four malignant lesions, suggesting additional biochemical defects in thyroid carcinomas. PMID:4353998

MicroRNA-211 expression is down-regulated and associated with poor prognosis in human glioma.

PubMed

Zhang, Jun; Lv, Jianguang; Zhang, Feng; Che, Hongmin; Liao, Qiwei; Huang, Wobin; Li, Shaopeng; Li, Yuqian

2017-07-01

Accumulating evidence has supported the role of microRNAs in the initiation and development of malignant tumors. MicroRNA-211 (miR-211), which was reported to involve in diverse physiological activities in several cancers, was investigated for its expression in human glioma and adjacent normal brain tissues, as well as its correlation with patient prognosis. Glioma tissues and adjacent normal brain tissues were obtained from 82 patients who underwent surgical resection, and quantitative real-time polymerase chain reaction was performed to assess the expression level of miR-211. Here, we found that miR-211 was significantly decreased in glioma tissues compared with adjacent normal brain tissues (glioma, 3.52 ± 0.14 vs. normal, 4.96 ± 0.17, p < 0.001), and inversely associated with ascending WHO classification (grade III-IV, 3.16 ± 0.21 vs. grade I-II, 4.22 ± 0.26, p < 0.001). Then, the correlation of miR-211 with clinicopathological factors was investigated by Pearson's Chi square test, indicating that miR-211 might be a potential biomarker to predict the malignant status of glioma. Further, Kaplan-Meier curves with log-rank analysis were carried out to determine the relationship between miR-211 expression level and the overall survival rate of glioma patients. Our data showed that there was a close correlation between down-regulated miR-211 and shorter survival time in 82 patients (p = 0.026). Finally, the multivariate Cox regression analysis indicated that WHO grade (HR = 2.437, 95% CI 1.251-4.966, p = 0.007), KPS (HR = 2.215, 95% CI 1.168-4.259, p = 0.016), and miR-211 expression level (HR = 3.614, 95% CI 2.152-6.748, p < 0.001) were considered as independent risk factors for glioma prognosis. These results suggested that lower miR-211 expression might be a marker for poor prognosis of glioma patients.

Systematic bias in genomic classification due to contaminating non-neoplastic tissue in breast tumor samples.

PubMed

Elloumi, Fathi; Hu, Zhiyuan; Li, Yan; Parker, Joel S; Gulley, Margaret L; Amos, Keith D; Troester, Melissa A

2011-06-30

Genomic tests are available to predict breast cancer recurrence and to guide clinical decision making. These predictors provide recurrence risk scores along with a measure of uncertainty, usually a confidence interval. The confidence interval conveys random error and not systematic bias. Standard tumor sampling methods make this problematic, as it is common to have a substantial proportion (typically 30-50%) of a tumor sample comprised of histologically benign tissue. This "normal" tissue could represent a source of non-random error or systematic bias in genomic classification. To assess the performance characteristics of genomic classification to systematic error from normal contamination, we collected 55 tumor samples and paired tumor-adjacent normal tissue. Using genomic signatures from the tumor and paired normal, we evaluated how increasing normal contamination altered recurrence risk scores for various genomic predictors. Simulations of normal tissue contamination caused misclassification of tumors in all predictors evaluated, but different breast cancer predictors showed different types of vulnerability to normal tissue bias. While two predictors had unpredictable direction of bias (either higher or lower risk of relapse resulted from normal contamination), one signature showed predictable direction of normal tissue effects. Due to this predictable direction of effect, this signature (the PAM50) was adjusted for normal tissue contamination and these corrections improved sensitivity and negative predictive value. For all three assays quality control standards and/or appropriate bias adjustment strategies can be used to improve assay reliability. Normal tissue sampled concurrently with tumor is an important source of bias in breast genomic predictors. All genomic predictors show some sensitivity to normal tissue contamination and ideal strategies for mitigating this bias vary depending upon the particular genes and computational methods used in the predictor.

Measurement of glutathione S-transferase and its class-pi in plasma and tissue biopsies obtained after laparoscopy and endoscopy from subjects with esophagus and gastric cancer.

PubMed

Mohammadzadeh, G S; Nasseri Moghadam, S; Rasaee, M J; Zaree, A B; Mahmoodzadeh, H; Allameh, A

2003-06-01

To develop an indirect enzyme-linked immunosorbent assay (ELISA) for measuring class-pi glutathione S-transferase (GST) in plasma, and tissue biopsies obtained from upper gastrointestinal cancer (UGI Ca) patients. GST activity and GST-pi concentration were detected in normal human squamous esophageal epithelium, normal gastric cardia and their corresponding malignant tumor biopsies. Plasma GST was significantly higher (p < 0.05) in UGI Ca patients as compared to those obtained from normal individuals. Plasma GST-pi concentration in normal subjects was 6.6 +/- 1.9 ng/mg protein, whereas it was higher in UGI Ca patients (esophageal, 10.0 +/- 1.8; gastric, 10.7 +/- 1.7 ng/mL, p

DNA methylation in lung tissues of mouse offspring exposed in utero to polycyclic aromatic hydrocarbons.

PubMed

Fish, Trevor J; Benninghoff, Abby D

2017-11-01

Polycyclic aromatic hydrocarbons (PAHs) comprise an important class of environmental pollutants that are known to cause lung cancer in animals and are suspected lung carcinogens in humans. Moreover, evidence from cell-based studies points to PAHs as modulators of the epigenome. The objective of this work was to assess patterns of genome-wide DNA methylation in lung tissues of adult offspring initiated in utero with the transplacental PAH carcinogens dibenzo [def,p]chrysene (DBC) or benzo [a]pyrene (BaP). Genome-wide methylation patterns for normal (not exposed), normal adjacent and lung tumor tissues obtained from adult offspring were determined using methylated DNA immunoprecipitation (MeDIP) with the NimbleGen mouse DNA methylation CpG island array. Lung tumor incidence in 45-week old mice initiated with BaP was 32%, much lower than that of the DBC-exposed offspring at 96%. Also, male offspring appeared more susceptible to BaP as compared to females. Distinct patterns of DNA methylation were associated with non-exposed, normal adjacent and adenocarcinoma lung tissues, as determined by principal components, hierarchical clustering and gene ontology analyses. From these methylation profiles, a set of genes of interest was identified that includes potential important targets for epigenetic modification during the process of lung tumorigenesis in animals exposed to environmental PAHs. Copyright © 2017 Elsevier Ltd. All rights reserved.

Differential expression of colon cancer associated transcript1 (CCAT1) along the colonic adenoma-carcinoma sequence.

PubMed

Alaiyan, Bilal; Ilyayev, Nadia; Stojadinovic, Alexander; Izadjoo, Mina; Roistacher, Marina; Pavlov, Vera; Tzivin, Victoria; Halle, David; Pan, Honguang; Trink, Barry; Gure, Ali O; Nissan, Aviram

2013-04-17

The transition from normal epithelium to adenoma and, to invasive carcinoma in the human colon is associated with acquired molecular events taking 5-10 years for malignant transformation. We discovered CCAT1, a non-coding RNA over-expressed in colon cancer (CC), but not in normal tissues, thereby making it a potential disease-specific biomarker. We aimed to define and validate CCAT1 as a CC-specific biomarker, and to study CCAT1 expression across the adenoma-carcinoma sequence of CC tumorigenesis. Tissue samples were obtained from patients undergoing resection for colonic adenoma(s) or carcinoma. Normal colonic tissue (n = 10), adenomatous polyps (n = 18), primary tumor tissue (n = 22), normal mucosa adjacent to primary tumor (n = 16), and lymph node(s) (n = 20), liver (n = 8), and peritoneal metastases (n = 19) were studied. RNA was extracted from all tissue samples, and CCAT1 expression was analyzed using quantitative real time-PCR (qRT-PCR) with confirmatory in-situ hybridization (ISH). Borderline expression of CCAT1 was identified in normal tissue obtained from patients with benign conditions [mean Relative Quantity (RQ) = 5.9]. Significant relative CCAT1 up-regulation was observed in adenomatous polyps (RQ = 178.6 ± 157.0; p = 0.0012); primary tumor tissue (RQ = 64.9 ± 56.9; p = 0.0048); normal mucosa adjacent to primary tumor (RQ = 17.7 ± 21.5; p = 0.09); lymph node, liver and peritoneal metastases (RQ = 11,414.5 ± 12,672.9; 119.2 ± 138.9; 816.3 ± 2,736.1; p = 0.0001, respectively). qRT-PCR results were confirmed by ISH, demonstrating significant correlation between CCAT1 up-regulation measured using these two methods. CCAT1 is up-regulated across the colon adenoma-carcinoma sequence. This up-regulation is evident in pre-malignant conditions and through all disease stages, including advanced metastatic disease suggesting a role in both tumorigenesis and the metastatic process.

Expression of cyclooxygenase-1 and cyclooxygenase-2, syndecan-1 and connective tissue growth factor in benign and malignant breast tissue from premenopausal women.

PubMed

Fahlén, M; Zhang, H; Löfgren, L; Masironi, B; von Schoultz, E; von Schoultz, B; Sahlin, L

2017-05-01

Stromal factors have been identified as important for tumorigenesis and metastases of breast cancer. From 49 premenopausal women, samples were collected from benign or malignant tumors and the seemingly normal tissue adjacent to the tumor. The factors studied, with real-time polymerase chain reaction (PCR) and immunohistochemistry, were cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2), syndecan-1 (S-1) and connective tissue growth factor (CTGF). COX-1 and S-1 mRNA levels were higher in the malignant tumors than in normal and benign tissues. The COX-2 mRNA level was lower in the malignant tumor than in the normal tissue, while CTGF mRNA did not differ between the groups. COX-1 immunostaining was higher in stroma from malignant tumors than in benign tissues, whereas COX-2 immunostaining was higher in the malignant tissue. Glandular S-1 immunostaining was lower in malignant tumors compared to benign and normal tissues, and the opposite was found in stroma. Conclusively, mRNA levels of COX-1 and COX-2 were oppositely regulated, with COX-1 being increased in the malignant tumor while COX-2 was decreased. S-1 protein localization switched from glandular to stromal cells in malignant tissues. Thus, these markers are, in premenopausal women, localized and regulated differently in normal/benign breast tissue as compared to the malignant tumor.

Near-infrared (NIR) fluorescence imaging of head and neck squamous cell carcinoma for fluorescence-guided surgery (Conference Presentation)

NASA Astrophysics Data System (ADS)

Moore, Lindsay; Warram, Jason M.; de Boer, Esther; Carroll, William R.; Morlandt, Anthony; Withrow, Kirk P.; Rosenthal, Eben L.

2016-03-01

During fluorescence-guided surgery, a cancer-specific optical probe is injected and visualized using a compatible device intraoperatively to provide visual contrast between diseased and normal tissues to maximize resection of cancer and minimize the resection of precious adjacent normal tissues. Six patients with squamous cell carcinomas of the head and neck region (oral cavity (n=4) or cutaneous (n=2)) were injected with an EGFR-targeting antibody (Cetuximab) conjugated to a near-infrared (NIR) fluorescent dye (IRDye800) 3, 4, or 7 days prior to surgical resection of the cancer. Each patient's tumor was then imaged using a commercially available, open-field NIR fluorescence imaging device each day prior to surgery, intraoperatively, and post-operatively. The mean fluorescence intensity (MFI) of the tumor was calculated for each specimen at each imaging time point. Adjacent normal tissue served as an internal anatomic control for each patient to establish a patient-matched "background" fluorescence. Resected tissues were also imaged using a closed-field NIR imaging device. Tumor to background ratios (TBRs) were calculated for each patient using both devices. Fluorescence histology was correlated with traditional pathology assessment to verify the specificity of antibody-dye conjugate binding. Peak TBRs using the open-field device ranged from 2.2 to 11.3, with an average TBR of 4.9. Peak TBRs were achieved between days 1 and 4. This study demonstrated that a commercially available NIR imaging device suited for intraoperative and clinical use can successfully be used with a fluorescently-labeled dye to delineate between diseased and normal tissue in this single cohort human study, illuminated the potential for its use in fluoresence-guided surgery.

Expression profile of circular RNAs in human gastric cancer tissues

PubMed Central

Huang, You-Sheng; Jie, Na; Zou, Ke-Jian; Weng, Yang

2017-01-01

Circular RNAs (circRNAs) represent a newly identified class of non-coding RNA molecules, which interfere with gene transcription by adsorbing microRNAs (miRNAs). CircRNAs serve important roles in disease development and have the potential to serve as a novel class of biomarkers for clinical diagnosis. However, the role of circRNAs in the occurrence and development of gastric cancer (GC) remains unclear. In the present study, the expression profiles of circRNAs were compared between GC and adjacent normal tissues using a circRNA microarray, following which quantitative polymerase chain reaction (qPCR) was used to confirm the results of the circRNA microarray. Compared with the adjacent, normal mucosal tissues, 16 circRNAs were upregulated and 84 circRNAs were downregulated in GC. A total of 10 circRNAs were selected for validation in three pairs of GC and adjacent noncancerous tissues. The qPCR results were consistent with the findings of the microarray-based expression analysis. Of the circRNAs studied, only circRNA-0026 (hsa_circ_0000026) exhibited significantly different expression in GC (2.8-fold, P=0.001). Furthermore, online Database for Annotation, Visualization and Integrated Discovery annotation was used to predict circRNA-targeted miRNA-gene interactions. The analysis revealed that circRNA-0026 may regulate RNA transcription, RNA metabolism, gene expression, gene silencing and other biological functions in GC. In conclusion, differential expression of circRNAs may be associated with GC tumorigenesis, and circRNA-0026 is a promising biomarker for GC diagnosis and targeted therapy. PMID:28737829

Relationship between transmembrane serine protease expression and prognosis of esophageal squamous cell carcinoma.

PubMed

Liu, G T; Shen, C; Ren, X H; Yang, L; Yu, Y M; Xiu, Y X; Li, R H; Jiang, L; Zhang, C L; Li, Y W

2017-01-01

Esophageal squamous cell carcinoma is the most common type of esophageal cancer in Eastern Europe and Asia, being the 6th most common cause of cancer deaths worldwide. The aim of this study was to analyze the expression of transmembrane serine protein in esophageal squamous cell carcinoma, and to correlate it with the clinical biological features of esophageal cancer. The expression of transmembrane protease serine 4 (TMPRSS4) mRNA and protein in carcinoma tissues and corresponding adjacent tissues and non-tumorous esophageal tissues was determined using PCR (qRT-PCR). The results show that both TMPRSS4 mRNA and protein expression were remarkably lower in adjacent normal tissues than in tumorous tissues. TMPRSS4 protein expression in esophageal carcinoma was correlated with patient demographic characteristics, tumor type, high TNM stages and overall survival (OS). Based on the experimental results, we conclude that TMPRSS4 is closely related to the occurrence, development and metastasis of esophageal squamous cell carcinoma.

Wound repair in Pocillopora

USGS Publications Warehouse

Rodríguez-Villalobos, Jenny Carolina; Work, Thierry M.; Calderon-Aguileraa, Luis Eduardo

2016-01-01

Corals routinely lose tissue due to causes ranging from predation to disease. Tissue healing and regeneration are fundamental to the normal functioning of corals, yet we know little about this process. We described the microscopic morphology of wound repair in Pocillopora damicornis. Tissue was removed by airbrushing fragments from three healthy colonies, and these were monitored daily at the gross and microscopic level for 40 days. Grossly, corals healed by Day 30, but repigmentation was not evident at the end of the study (40 d). On histology, from Day 8 onwards, tissues at the lesion site were microscopically indistinguishable from adjacent normal tissues with evidence of zooxanthellae in gastrodermis. Inflammation was not evident. P. damicornis manifested a unique mode of regeneration involving projections of cell-covered mesoglea from the surface body wall that anastomosed to form gastrovascular canals.

The overexpression of Rabl3 is associated with pathogenesis and clinicopathologic variables in hepatocellular carcinoma.

PubMed

Pan, Yuhang; Liu, Zhiyong; Feng, Zhiying; Hui, Dayang; Huang, Xiangqi; Tong, Dayue; Jin, Yi

2017-04-01

Overexpression of Rabl3 is associated with some malignancies. However, their relationship with hepatocellular carcinoma remains unclear. In this study, the expression of Rabl3 in hepatocellular carcinoma cell lines, and four pairs of matched hepatocellular carcinoma tissues and their adjacent normal hepatic tissues were detected by quantitative reverse transcription polymerase chain reaction and western blot. In addition, the protein expression of Rabl3 was examined in 162 cases of hepatocellular carcinoma by immunohistochemistry. Rabl3 in hepatocellular carcinoma cell lines was elevated at both messenger RNA and protein levels, and the Rabl3 protein was significantly upregulated by upto 3.3-fold in hepatocellular carcinoma compared with the paired normal hepatic tissues. Immunohistochemical analysis revealed that overexpressions of Rabl3 were 80.2% in hepatocellular carcinoma. Rabl3 is expressed at significantly higher rates in hepatocellular carcinoma compared with adjacent normal hepatic tissue (p < 0.01). Statistical analysis suggested the upregulation of Rabl3 was significantly associated with lymph node metastasis, tumor thrombus of the portal vein, and advanced clinical stage (p < 0.05). Furthermore, we found that overexpression of Rabl3 in hepatocellular carcinoma cells could significantly enhance cell proliferation and growth ability. Conversely, silencing Rabl3 by small hairpin RNA interference caused an inhibition of cell proliferation and growth. Our studies suggest that the Rabl3 is a valuable marker of hepatocellular carcinoma progression and that the overexpression of Rabl3 plays an important role in the development and pathogenesis of hepatocellular carcinoma.

Down-regulation of BAX gene during carcinogenesis and acquisition of resistance to 5-FU in colorectal cancer.

PubMed

Manoochehri, Mehdi; Karbasi, Ashraf; Bandehpour, Mojgan; Kazemi, Bahram

2014-04-01

Carcinogenesis and resistance to chemotherapy could be as results of expression variations in apoptosis regulating genes. Changes in the expression of apoptosis interfering genes may contribute to colorectal carcinogenesis and resistance to 5-Flourouracil (5-FU) during treatment schedule period. The present study aimed to evaluate the expression of pro-apoptotic and anti-apoptotic genes in colorectal cancer tumor tissues, normal adjacent tissues, and tumor colorectal cancer cell line during acquiring resistance to 5-FU in HT-29 based on Bolus treatment protocol. The normal and tumor tissues were obtained from hospital after surgery and total RNA was extracted for expression analysis. The HT-29 colorectal cancer cell line was cultured and exposed with 5-FU in three stages based on Bolus protocol. The MTT assay and Real Time PCR were carried out to determine the sensitivity to the drug and expression of desired genes, respectively. The obtained data showed that Proapoptotic genes, BAX and BID, were down-regulated in resistant derivate cells compared to wild type HT-29 cells. On the other hand Antiapoptotic genes, CIAP1 and XIAP, showed upregulation in resistant cells compared to wild type ones. Furthermore, BAX and FAS genes showed down-regulation in tumor samples in comparison to normal adjacent tissues. In conclusion, the results of our study suggest that BAX down-regulation could contribute as an important factor during both colorectal carcinogenesis and cell resistance to 5-FU.

Overexpression of Rabl3 and Cullin7 is associated with pathogenesis and poor prognosis in hepatocellular carcinoma.

PubMed

An, Jun; Liu, Zhiyong; Liang, Qiong; Pan, Yuhang; Li, Haifeng; Wang, Ruizhi; Jin, Yi

2017-09-01

The expression of Rabl3 and Cullin7 is relevant to the carcinogenesis of certain cancers. However, the relationship of this expression with hepatocellular carcinoma remains unclear. To study the protein expression of Rabl3 and Cullin7 and to evaluate their role in hepatocarcinogenesis, in 162 cases of hepatocellular carcinoma, we used immunohistochemistry to investigate the expression of Rabl3 and Cullin7 in both the cancer tissues and the normal hepatic tissues around the hepatocellular carcinoma. The results demonstrated that the rates of positive Rabl3 and Cullin7 expression were 80.2% and 69.1%, respectively, in hepatocellular carcinoma tissues. However, the rates of positive Rabl3 and Cullin7 expression were 31.5% and 29.0%, respectively, in adjacent normal hepatic tissues. Rabl3 and Cullin7 were expressed at significantly higher rates in hepatocellular carcinoma compared with adjacent normal hepatic tissues (P<.01). The rates of positive Rabl3 and Cullin7 expression were higher in the hepatocellular carcinoma tissues of patients with lymph node metastasis, tumor thrombi in the portal vein and an advanced clinical stage (P<.05). A positive correlation between the expression of Rabl3 and the expression of Cullin7 (r=0.27, P<.001) was also observed in our hepatocellular carcinoma cohort. Moreover, patients with positive expression for both Rabl3 and Cullin7 had a remarkably shorter survival time compared with patients with negative expression for both proteins (P<.05). Therefore, the expression of the Rabl3 and Cullin7 proteins may play an important role in the pathogenesis and progression of hepatocellular carcinoma and could be used as a prognostic indicator in patients with hepatocellular carcinoma. Copyright © 2017 Elsevier Inc. All rights reserved.

Microfluidic extraction and microarray detection of biomarkers from cancer tissue slides

NASA Astrophysics Data System (ADS)

Nguyen, H. T.; Dupont, L. N.; Jean, A. M.; Géhin, T.; Chevolot, Y.; Laurenceau, E.; Gijs, M. A. M.

2018-03-01

We report here a new microfluidic method allowing for the quantification of human epidermal growth factor receptor 2 (HER2) expression levels from formalin-fixed breast cancer tissues. After partial extraction of proteins from the tissue slide, the extract is routed to an antibody (Ab) microarray for HER2 titration by fluorescence. Then the HER2-expressing cell area is evaluated by immunofluorescence (IF) staining of the tissue slide and used to normalize the fluorescent HER2 signal measured from the Ab microarray. The number of HER2 gene copies measured by fluorescence in situ hybridization (FISH) on an adjacent tissue slide is concordant with the normalized HER2 expression signal. This work is the first study implementing biomarker extraction and detection from cancer tissue slides using microfluidics in combination with a microarray system, paving the way for further developments towards multiplex and precise quantification of cancer biomarkers.

MicroRNA-145 Inhibits Cell Migration and Invasion and Regulates Epithelial-Mesenchymal Transition (EMT) by Targeting Connective Tissue Growth Factor (CTGF) in Esophageal Squamous Cell Carcinoma.

PubMed

Han, Qiang; Zhang, Hua-Yong; Zhong, Bei-Long; Wang, Xiao-Jing; Zhang, Bing; Chen, Hua

2016-10-23

BACKGROUND This study investigated the mechanism of miR-145 in targeting connective tissue growth factor (CTGF), which affects the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of ESCC cells. MATERIAL AND METHODS A total of 50 ESCC tissues and their corresponding normal adjacent esophageal tissue samples were collected. Then, miR-145 expression in both ESCC clinical specimens and cell lines was detected using quantitative real-time PCR. CTGF protein was detected using immunohistochemistry. Dual luciferase reporter gene assay was employed to assess the effect of miR-145 on the 3'UTR luciferase activity of CTGF. Eca109 cells were transfected with miR-145 mimics and CTGF siRNA, respectively, and changes in cellular proliferation, migration, and invasion were detected via MTT assay, wound-healing assay, and Transwell assay, respectively. Western blotting assay was used to detect the expression of marker genes related to EMT. RESULTS MiR-145 was significantly down-regulated in ESCC tissues and cell lines compared with normal tissues and cell lines (P<0.05). We found significantly more positively expressed CTGF protein in ESCC tissues was than in normal adjacent esophageal tissues (P<0.01). Dual luciferase reporter gene assay showed that miR-145 can specifically bind with the 3'UTR of CTGF and significantly inhibit the luciferase activity by 55% (P<0.01). Up-regulation of miR-145 or down-regulation of CTGF can suppress the proliferation, migration, invasion, and EMT process of ESCC cells. CONCLUSIONS MiR-145 was significantly down-regulated in ESCC tissues and cell lines, while the protein expression of CTGF exhibited the opposite trend. MiR-145 inhibited the proliferation, migration, invasiveness, and the EMT process of ESCC cells through targeted regulation of CTGF expression.

Prostate cancer region prediction using MALDI mass spectra

NASA Astrophysics Data System (ADS)

Vadlamudi, Ayyappa; Chuang, Shao-Hui; Sun, Xiaoyan; Cazares, Lisa; Nyalwidhe, Julius; Troyer, Dean; Semmes, O. John; Li, Jiang; McKenzie, Frederic D.

2010-03-01

For the early detection of prostate cancer, the analysis of the Prostate-specific antigen (PSA) in serum is currently the most popular approach. However, previous studies show that 15% of men have prostate cancer even their PSA concentrations are low. MALDI Mass Spectrometry (MS) proves to be a better technology to discover molecular tools for early cancer detection. The molecular tools or peptides are termed as biomarkers. Using MALDI MS data from prostate tissue samples, prostate cancer biomarkers can be identified by searching for molecular or molecular combination that can differentiate cancer tissue regions from normal ones. Cancer tissue regions are usually identified by pathologists after examining H&E stained histological microscopy images. Unfortunately, histopathological examination is currently done on an adjacent slice because the H&E staining process will change tissue's protein structure and it will derogate MALDI analysis if the same tissue is used, while the MALDI imaging process will destroy the tissue slice so that it is no longer available for histopathological exam. For this reason, only the most confident cancer region resulting from the histopathological examination on an adjacent slice will be used to guide the biomarker identification. It is obvious that a better cancer boundary delimitation on the MALDI imaging slice would be beneficial. In this paper, we proposed methods to predict the true cancer boundary, using the MALDI MS data, from the most confident cancer region given by pathologists on an adjacent slice.

MiR-32 promotes gastric carcinoma tumorigenesis by targeting Kruppel-like factor 4

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

Yan, Chao; Yu, Jianchun, E-mail: yu_jchpumch@163.com; Liu, Yuqin

Gastric cancer (GC) is a prevalent malignant cancer worldwide and is highly lethal because of its fast growth. Currently, the clinical therapy options for GC remain limited. MiR-32 has been reported as an oncogenic microRNA in many cancers, but its role in GC is unclear. Here, we found that miR-32 was overexpressed in GC tissues compared with adjacent normal tissue, and miR-32 was higher in GC patients' plasma compared with healthy individuals. Furthermore, we have identified miR-32 to be oncogenic, by promoting gastric cell proliferation, migration and invasion. We also identified Kruppel-like factor 4 (KLF4) as a direct target ofmore » miR-32. Knockdown of KLF4 promoted proliferation, migration and invasion of GC cells. We conclude that miR-32 promotes GC cell proliferation, migration and invasion by targeting KLF4, suggesting that the miR-32-KLF4 pathway may be useful in clinical diagnosis and therapeutics. - Highlights: • miR-32 was overexpression in GC tissues than adjacent normal tissue. • miR-32 was higher in GC patients' plasma compared with healthy people. • miR-32 promotes GC cell proliferation, migration and invasion by targeting KLF4.« less

Quantitative proteomic analysis of microdissected oral epithelium for cancer biomarker discovery.

PubMed

Xiao, Hua; Langerman, Alexander; Zhang, Yan; Khalid, Omar; Hu, Shen; Cao, Cheng-Xi; Lingen, Mark W; Wong, David T W

2015-11-01

Specific biomarkers are urgently needed for the detection and progression of oral cancer. The objective of this study was to discover cancer biomarkers from oral epithelium through utilizing high throughput quantitative proteomics approaches. Morphologically malignant, epithelial dysplasia, and adjacent normal epithelial tissues were laser capture microdissected (LCM) from 19 patients and used for proteomics analysis. Total proteins from each group were extracted, digested and then labelled with corresponding isobaric tags for relative and absolute quantitation (iTRAQ). Labelled peptides from each sample were combined and analyzed by liquid chromatography-mass spectrometry (LC-MS/MS) for protein identification and quantification. In total, 500 proteins were identified and 425 of them were quantified. When compared with adjacent normal oral epithelium, 17 and 15 proteins were consistently up-regulated or down-regulated in malignant and epithelial dysplasia, respectively. Half of these candidate biomarkers were discovered for oral cancer for the first time. Cornulin was initially confirmed in tissue protein extracts and was further validated in tissue microarray. Its presence in the saliva of oral cancer patients was also explored. Myoglobin and S100A8 were pre-validated by tissue microarray. These data demonstrated that the proteomic biomarkers discovered through this strategy are potential targets for oral cancer detection and salivary diagnostics. Copyright © 2015 Elsevier Ltd. All rights reserved.

Correlation between the methylation of APC gene promoter and colon cancer.

PubMed

Li, Bing-Qiang; Liu, Peng-Peng; Zhang, Cai-Hua

2017-08-01

The present study was planned to explore the correlation between the methylation of APC (adenomatous polyposis coli) and colon carcinogenesis. Colon cancer tissues and tumor-adjacent normal tissues of 60 colon cancer patients (who received surgical operation in our hospital from January 2012 to December 2014) were collected. SW1116 cells in human colon cancer tissues were selected for culturing. 5-aza-2c-deoxycytidine (5-aza-dC) was utilized as an inhibitor of the methylation for APC gene. Methylation specific PCR (MSP) was utilized for detection of APC methylation in SW1116 cells. The MTT and Transwell assays were performed to detect the effect of the methylation of APC gene on the proliferation and invasive abilities of SW1116 cells. The correlation between the methylation of APC gene and pathological parameters of colon cancer patients was analyzed. MSP results revealed that 41 cases (68.33%) showed methylation of APC gene in colon cancer tissues. No methylation of APC gene was found in tumor-adjacent normal tissues. 5-aza-dC was able to inhibit the methylation of APC gene in SW1116 cells. APC gene methylation was correlated with tumor size, differentiation degree, lymph node metastasis and Dukes staging. In conclusion, the levels of the methylation of APC in colon cancer tissues and SW1116 cells are relatively high. The methylation of APC promoted the proliferation and invasion abilities of SW1116 cells. Furthermore, methylation is correlated with a variety of clinicopathological features of colon cancer patients.

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

Liu, Xing; Xu, Yanli; Meng, Qian

Colorectal cancer (CRC) is one of the most common types of malignant tumor worldwide. Currently, although many researchers have been devoting themselves in CRC studies, the process of locating biomarkers for CRC early diagnosis and prognostic is still very slow. Using a centrifugal proteomic reactor-based proteomic analysis of minute amount of colonic biopsies by enteroscopy sampling, 2620 protein groups were quantified between cancer mucosa and adjacent normal colorectal mucosa. Of which, 403 protein groups were differentially expressed with statistic significance between cancer and normal tissues, including 195 up-regulated and 208 down-regulated proteins in cancer tissues. Three proteins (SOD3, PRELP andmore » NGAL) were selected for further Western blot validation. And the resulting Western blot experimental results were consistent with the quantitative proteomic data. SOD3 and PRELP are down-regulated in CRC mucosa comparing to adjacent normal tissue, while NGAL is up-regulated in CRC mucosa. In conclusion, the centrifugal proteomic reactor-based label-free quantitative proteomic approach provides a highly sensitive and powerful tool for analyzing minute protein sample from tiny colorectal biopsies, which may facilitate CRC biomarkers discovery for diagnoses and prognoses. -- Highlights: •Minute amount of colonic biopsies by endoscopy is suitable for proteomic analysis. •Centrifugal proteomic reactor can be used for processing tiny clinic biopsy sample. •SOD3 and PRELP are down-regulated in CRC, while NGAL is up-regulated in CRC.« less

Changes in cell proliferation and morphology in the large intestine of normal and DMH-treated rats following colostomy.

PubMed

Barkla, D H; Tutton, P J

1987-04-01

Colostomies were formed in the midcolon of normal and DMH-treated rats. Changes in cell proliferation in the mucosa adjacent to the colostomy and in the defunctioned distal segment were measured at seven, 14, 30, and 72 days using a stathmokinetic technique. Animals were given intraperitoneal injections of vinblastine and sacrificed three hours later; counts of mitotic and nonmitotic cells were made in tissue sections, and three-hour accumulated mitotic indexes were estimated. The results show that, except at seven days in DMH-treated rats, cell proliferation was unchanged in the colon proximal to the colostomy. Morphologic evidence of hyperplasia was seen in some animals at seven and 14 days. The defunctioned segment showed rapid atrophy of both mucosa and muscularis and a gradual but progressive decrease in cell proliferation. The morphology of the mucosa adjacent to the suture line in both functioning and defunctioned segments in normal and DMH-treated rats was abnormal in many animals. Abnormalities that were seen included collections of dysplastic epithelial cells in the submucosa, focal adenomatous changes, and intramural carcinoma formation. Aggregates of lymphoid tissue often were associated with carcinomas.

Tissue spray ionization mass spectrometry for rapid recognition of human lung squamous cell carcinoma

NASA Astrophysics Data System (ADS)

Wei, Yiping; Chen, Liru; Zhou, Wei; Chingin, Konstantin; Ouyang, Yongzhong; Zhu, Tenggao; Wen, Hua; Ding, Jianhua; Xu, Jianjun; Chen, Huanwen

2015-05-01

Tissue spray ionization mass spectrometry (TSI-MS) directly on small tissue samples has been shown to provide highly specific molecular information. In this study, we apply this method to the analysis of 38 pairs of human lung squamous cell carcinoma tissue (cancer) and adjacent normal lung tissue (normal). The main components of pulmonary surfactants, dipalmitoyl phosphatidylcholine (DPPC, m/z 757.47), phosphatidylcholine (POPC, m/z 782.52), oleoyl phosphatidylcholine (DOPC, m/z 808.49), and arachidonic acid stearoyl phosphatidylcholine (SAPC, m/z 832.43), were identified using high-resolution tandem mass spectrometry. Monte Carlo sampling partial least squares linear discriminant analysis (PLS-LDA) was used to distinguish full-mass-range mass spectra of cancer samples from the mass spectra of normal tissues. With 5 principal components and 30 - 40 Monte Carlo samplings, the accuracy of cancer identification in matched tissue samples reached 94.42%. Classification of a tissue sample required less than 1 min, which is much faster than the analysis of frozen sections. The rapid, in situ diagnosis with minimal sample consumption provided by TSI-MS is advantageous for surgeons. TSI-MS allows them to make more informed decisions during surgery.

Epigenetic alterations are involved in the overexpression of glutathione S-transferase π-1 in human colorectal cancers.

PubMed

Zhang, Rui; Kang, Kyoung Ah; Piao, Mei Jing; Kim, Ki Cheon; Zheng, Jian; Yao, Cheng Wen; Cha, Ji Won; Maeng, Young Hee; Chang, Weon Young; Moon, Pyong-Gon; Baek, Moon-Chang; Hyun, Jin Won

2014-09-01

Glutathione S-transferase π-1 (GSTP-1) is a member of the glutathione S-transferase enzyme superfamily, which catalyzes the conjugation of electrophiles to glutathione during the process of detoxification. In this study, the epigenetic alterations of GSTP-1 expression in human colorectal cancers and the underlying mechanisms were investigated. In 10 colon cancer patients, proteomic analysis revealed that expression of GSTP-1 protein was higher in tumor tissues than in paired adjacent normal tissues. Likewise, in 7 of 10 colon cancer patients, GSTP-1 protein expression was more than 1.5-fold higher in tumor tissues than in adjacent normal tissues, as determined by western blotting. Immunohistochemical data confirmed that GSTP-1 protein was expressed at higher levels in colon cancer tissues compared to normal mucosa. GSTP-1 enzyme activity was closely correlated with GSTP-1 protein expression in colon cancer patients. Consistent with this, GSTP-1 mRNA, protein and activity levels were higher in the colorectal cancer cell lines Caco-2, HCT-116, HT-29, SNU-407 and SNU-1033 compared to the normal colon cell line FHC. Methylation-specific PCR results indicated that the high levels of GSTP-1 in human colorectal cancer cell lines were likely due to the lower degree of promoter methylation in colon cancer cell lines compared to the normal colon cell line, consistent with findings in colon cancer patients. Moreover, the levels of specific activator-protein complexes and histone marks were higher in human colorectal cancer cells compared to the normal human colon cell line, whereas the repressor protein complexes exhibited the opposite pattern. Furthermore, chromatin immunoprecipitation assays demonstrated that expression levels of the transcription factors AP-1 and SP-1 were correlated with the upregulation of GSTP-1 expression in colorectal cancer cells. Finally, knockdown of GSTP-1 promoted the sensitivity of SNU-407 cells to the anticancer agent 5-fluorouracil. These data indicate that GSTP-1 may serve as a clinically useful biomarker of colon cancer and a target for anti-colon cancer drugs.

A Molecular Framework for Understanding DCIS

DTIC Science & Technology

2016-10-01

frozen patient biopsies, these have been annotated by our pathologist and prepared to be taken on for sequencing. The tissue includes DCIS, IDC...stroma adjacent to DCIS/IDC and normal tissue . We have initiated the RNA sequencing from these samples and also the DNA sequencing 15. SUBJECT TERMS DCIS...before they reach 55. Utilizing a unique bank of frozen mammary biopsies, containing samples with DCIS alone, and a combination of DCIS and IDC, we aim

Preliminary observations on differences in the Raman spectra of cancerous and noncancerous cells and connective tissue of human skin

NASA Astrophysics Data System (ADS)

Short, Michael A.; Lui, Harvey; McLean, David I.; Zeng, Haishan; Alajlan, Abdulmajeed; Chen, Michael X.

2005-04-01

A less invasive method of reliably detecting skin cancers is required. Raman spectroscopy is just one of several spectroscopic methods that look promising, but are not yet sufficiently reliable. More information is needed on how and why the Raman spectra of cancerous skin tissue is different from its normal counterpart. We have used confocal micro-Raman spectroscopy with a spatial resolution of about a micron to obtain spectra of unstained thin sections of human skin. We found that there were clear differences in the Raman spectra between cancerous and non-cancerous tissue both in cells and in the connective tissue. The DNA contribution to the spectra was generally stronger in malignant cells than normal ones. In regions of the dermis far away from the tumor one obtains the usual collagen spectra of normal skin, but adjacent to the tumor the spectra no longer appeared to be those of native collagen.

A histopathological study of bulbar conjunctival flaps occurring in 2 contact lens wearers.

PubMed

Markoulli, Maria; Francis, Ian C; Yong, Jim; Jalbert, Isabelle; Carnt, Nicole; Cole, Nerida; Papas, Eric

2011-09-01

To study the histopathology of paralimbal bulbar conjunctival flaps occurring secondary to soft contact lens wear. Slit-lamp biomicroscopy using sodium fluorescein, cobalt blue light, and a Wratten filter was used to observe the presence, location, and dimensions of bulbar conjunctival flaps presenting in a cohort of contact lens wearers. Two subjects who exhibited such flaps agreed to undergo conjunctival biopsy. Tissue samples, obtained from the region of the flap, and an adjacent unaffected area were processed by standard histopathological methods. In the first subject, analysis of the flap tissue showed even collagen distribution and overall normal histology. The flap of the second subject displayed a mild focal increase in collagen and mild degeneration of collagen, but no increase in elastic tissue. Conjunctival epithelium was normal in both cases. In these 2 subjects, conjunctival flap tissue either was normal or showed only minimal abnormality. There is insufficient evidence for significant pathological change on the time scale of this study.

Hyperspectral Stimulated Raman Scattering Microscopy Unravels Aberrant Accumulation of Saturated Fat in Human Liver Cancer.

PubMed

Yan, Shuai; Cui, Sishan; Ke, Kun; Zhao, Bixing; Liu, Xiaolong; Yue, Shuhua; Wang, Ping

2018-06-05

Lipid metabolism is dysregulated in human cancers. The analytical tools that could identify and quantitatively map metabolites in unprocessed human tissues with submicrometer resolution are highly desired. Here, we implemented analytical hyperspectral stimulated Raman scattering microscopy to map the lipid metabolites in situ in normal and cancerous liver tissues from 24 patients. In contrast to the conventional wisdom that unsaturated lipid accumulation enhances tumor cell survival and proliferation, we unexpectedly visualized substantial amount of saturated fat accumulated in cancerous liver tissues, which was not seen in majority of their adjacent normal tissues. Further analysis by mass spectrometry confirmed significant high levels of glyceryl tripalmitate specifically in cancerous liver. These findings suggest that the aberrantly accumulated saturated fat may have great potential to be a metabolic biomarker for liver cancer.

Prognostic Value of FBXO39 and ETS-1 but not BMI-1 in Iranian Colorectal Cancer Patients

PubMed

Motalebzadeh, Jamshid; Shabani, Samira; Rezayati, Saeedeh; Shakournia, Narges; Mirzaei, Rezvan; Mahjoubi, Bahar; Hoseini, Kamal; Mahjoubi, Frouzandeh

2018-05-26

Background: Colorectal cancer (CRC) is one of the most prevalent cancers worldwide. Despite recent progress in diagnosis and treatment, it remains a major health problem and further studies are needed. We here investigated expression profiles of the FBXO39, ETS-1 and BMI-1 genes in CRCs to validate any possible diagnostic/prognostic significance. Material and Methods: Thirty six patients with locally advanced CRC admitted to Hazrate-Rasoul Hospital-Tehran were enrolled. Initially the expression pattern of FBXO39, ETS-1 and BMI-1 genes were determined using RT-PCR in CRC tumor and adjacent normal tissues then real-time RT-PCR was employed to quantify BMI-1 gene expression. Results: FBXO39 expression was restricted to tumor tissues. Interestingly, expression of this gene was detected in all stage-0 tumor samples. There was a significant relation between FBXO39 gene expression and lymph node involvement. The ETS-1 gene was expressed in 66% of all tumor tissues with p-value=0.03 for increase as compared to the adjacent normal samples. In addition, there was a significant relation between ETS-1 gene expression and tumor size and lymph node involvement. RT-PCR demonstrated BMI-1 gene expression in both tumor and normal tissues and quantification by real-time RT-PCR showed no association between BMI-1 levels and CRC clinicopathological features. Conclusion: Expression of FBXO39 and ETS-1 with lymph node involvement may be considered as an alarm for the occurrence of CRC metastasis, and therfore have prognostic value while BMI-1 appears without importance. Creative Commons Attribution License

Altered mitochondrial genome content signals worse pathology and prognosis in prostate cancer.

PubMed

Kalsbeek, Anton M F; Chan, Eva K F; Grogan, Judith; Petersen, Desiree C; Jaratlerdsiri, Weerachai; Gupta, Ruta; Lyons, Ruth J; Haynes, Anne-Maree; Horvath, Lisa G; Kench, James G; Stricker, Phillip D; Hayes, Vanessa M

2018-01-01

Mitochondrial genome (mtDNA) content is depleted in many cancers. In prostate cancer, there is intra-glandular as well as inter-patient mtDNA copy number variation. In this study, we determine if mtDNA content can be used as a predictor for prostate cancer staging and outcomes. Fresh prostate cancer biopsies from 115 patients were obtained at time of surgery. All cores underwent pathological review, followed by isolation of cancer and normal tissue. DNA was extracted and qPCR performed to quantify the total amount of mtDNA as a ratio to genomic DNA. Differences in mtDNA content were compared for prostate cancer pathology features and disease outcomes. We showed a significantly reduced mtDNA content in prostate cancer compared with normal adjacent prostate tissue (mean difference 1.73-fold, P-value <0.001). Prostate cancer with increased mtDNA content showed unfavorable pathologic characteristics including, higher disease stage (PT2 vs PT3 P-value = 0.018), extracapsular extension (P-value = 0.02) and a trend toward an increased Gleason score (P-value = 0.064). No significant association was observed between changes in mtDNA content and biochemical recurrence (median follow up of 107 months). Contrary to other cancer types, prostate cancer tissue shows no universally depleted mtDNA content. Rather, the change in mtDNA content is highly variable, mirroring known prostate cancer genome heterogeneity. Patients with high mtDNA content have an unfavorable pathology, while a high mtDNA content in normal adjacent prostate tissue is associated with worse prognosis. © 2017 Wiley Periodicals, Inc.

Functional insulin receptors are overexpressed in thyroid tumors: is this an early event in thyroid tumorigenesis?

PubMed

Frittitta, L; Sciacca, L; Catalfamo, R; Ippolito, A; Gangemi, P; Pezzino, V; Filetti, S; Vigneri, R

1999-01-15

Insulin receptor (IR), a member of the receptor tyrosine kinase family, is expressed in normal thyroid cells and affects thyroid cell proliferation and differentiation. The authors measured IR content in benign and malignant thyroid tumors by three independent methods: a specific radioimmunoassay, 125I-insulin binding studies, and immunohistochemistry. The results obtained were compared with the IR content in paired, adjacent, normal thyroid tissue. To assess IR function in thyroid carcinoma cells, glucose uptake responsiveness to insulin was also studied in a human transformed thyroid cell line (B-CPAP) and in follicular carcinoma cells in primary culture. In 9 toxic adenomas, the average IR content was similar to that observed in the 9 paired normal thyroid tissue specimens from the same patients (2.2+/-0.3 vs. 2.1+/-0.3). In 13 benign nonfunctioning, or "cold," adenomas, the average IR content was significantly higher (P < 0.001) than in paired normal tissue specimens (4.3+/-0.5 vs. 1.8+/-0.1). In 12 papillary and 10 follicular carcinomas, IR content was significantly higher (P < 0.001) than in the adjacent normal thyroid tissue (4.0+/-0.4 vs. 1.6+/-0.2 and 5.6+/-1.0 vs. 1.8+/-0.2, respectively). The finding of a higher IR content in benign "cold" adenomas and in thyroid carcinomas was confirmed by both binding and immunostaining studies. The current studies indicate that 1) IR content is elevated in most follicular and papillary differentiated thyroid carcinomas, and 2) IR content is also elevated in most benign follicular adenomas ("cold" nodules) but not in highly differentiated, hyperfunctioning follicular adenomas ("hot" nodules), which very rarely become malignant. This observation suggests that increased IR expression is not restricted to the thyroid malignant phenotype but is already present in the premalignant "cold" adenomas. It may contribute, therefore, to thyroid tumorigenesis and/or represent an early event that gives a selective growth advantage to transformed thyroid cells.

Expression of cytoskeleton regulatory protein Mena in human hepatocellular carcinoma and its prognostic significance.

PubMed

Hu, Kunpeng; Wang, Jiani; Yao, Zhicheng; Liu, Bo; Lin, Yuan; Liu, Lei; Xu, Lihua

2014-05-01

The molecular mechanisms of the development and progression of hepatocellular carcinoma (HCC) are poorly understood. The main objective of this study was to analyze the expression of Enabled [mammalian Ena (Mena)] protein and its clinical significance in human HCC. The Mena expression was examined at mRNA and protein levels by real-time quantitative polymerase chain reaction and Western blotting analysis in ten paired HCC tissues and the adjacent normal tissues. The expression of Mena protein in 81 specimens of HCC tissues was determined by immunohistochemistry. Associations of Mena expression with the clinicopathological features were analyzed, and prognosis of HCC patients was evaluated. The result shows the expression of Mena mRNA and protein was higher in HCC than in the adjacent normal tissues in ten paired samples. Mena was mainly accumulated in the cytoplasm of tumor cells and over-expressed in 40.74% (33/81) patients by immunohistochemical staining. Over-expression of Mena was significantly associated with poor cellular differentiation (P = 0.025), advanced tumor stage (P = 0.003) and worse disease-free survival (DFS, P < 0.001). In addition, Mena is an independent prognostic factor for DFS in multivariate analysis (HR 2.309, 95% CI 1.104-4.828; P = 0.026). Mena is up-regulated in HCC and associated with tumor differentiation and clinical stage. Mena may be an independent prognostic marker for DFS of HCC patients.

Data-Independent Acquisition-Based Quantitative Proteomic Analysis Reveals Potential Biomarkers of Kidney Cancer.

PubMed

Song, Yimeng; Zhong, Lijun; Zhou, Juntuo; Lu, Min; Xing, Tianying; Ma, Lulin; Shen, Jing

2017-12-01

Renal cell carcinoma (RCC) is a malignant and metastatic cancer with 95% mortality, and clear cell RCC (ccRCC) is the most observed among the five major subtypes of RCC. Specific biomarkers that can distinguish cancer tissues from adjacent normal tissues should be developed to diagnose this disease in early stages and conduct a reliable prognostic evaluation. Data-independent acquisition (DIA) strategy has been widely employed in proteomic analysis because of various advantages, including enhanced protein coverage and reliable data acquisition. In this study, a DIA workflow is constructed on a quadrupole-Orbitrap LC-MS platform to reveal dysregulated proteins between ccRCC and adjacent normal tissues. More than 4000 proteins are identified, 436 of these proteins are dysregulated in ccRCC tissues. Bioinformatic analysis reveals that multiple pathways and Gene Ontology items are strongly associated with ccRCC. The expression levels of L-lactate dehydrogenase A chain, annexin A4, nicotinamide N-methyltransferase, and perilipin-2 examined through RT-qPCR, Western blot, and immunohistochemistry confirm the validity of the proteomic analysis results. The proposed DIA workflow yields optimum time efficiency and data reliability and provides a good choice for proteomic analysis in biological and clinical studies, and these dysregulated proteins might be potential biomarkers for ccRCC diagnosis. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Aberrant gene expression in mucosa adjacent to tumor reveals a molecular crosstalk in colon cancer

PubMed Central

2014-01-01

Background A colorectal tumor is not an isolated entity growing in a restricted location of the body. The patient’s gut environment constitutes the framework where the tumor evolves and this relationship promotes and includes a complex and tight correlation of the tumor with inflammation, blood vessels formation, nutrition, and gut microbiome composition. The tumor influence in the environment could both promote an anti-tumor or a pro-tumor response. Methods A set of 98 paired adjacent mucosa and tumor tissues from colorectal cancer (CRC) patients and 50 colon mucosa from healthy donors (246 samples in total) were included in this work. RNA extracted from each sample was hybridized in Affymetrix chips Human Genome U219. Functional relationships between genes were inferred by means of systems biology using both transcriptional regulation networks (ARACNe algorithm) and protein-protein interaction networks (BIANA software). Results Here we report a transcriptomic analysis revealing a number of genes activated in adjacent mucosa from CRC patients, not activated in mucosa from healthy donors. A functional analysis of these genes suggested that this active reaction of the adjacent mucosa was related to the presence of the tumor. Transcriptional and protein-interaction networks were used to further elucidate this response of normal gut in front of the tumor, revealing a crosstalk between proteins secreted by the tumor and receptors activated in the adjacent colon tissue; and vice versa. Remarkably, Slit family of proteins activated ROBO receptors in tumor whereas tumor-secreted proteins transduced a cellular signal finally activating AP-1 in adjacent tissue. Conclusions The systems-level approach provides new insights into the micro-ecology of colorectal tumorogenesis. Disrupting this intricate molecular network of cell-cell communication and pro-inflammatory microenvironment could be a therapeutic target in CRC patients. PMID:24597571

Expression and significance of CD44s, CD44v6, and nm23 mRNA in human cancer.

PubMed

Liu, Yong-Jun; Yan, Pei-Song; Li, Jun; Jia, Jing-Fen

2005-11-14

To investigate the relationship between the expression levels of nm23 mRNA, CD44s, and CD44v6, and oncogenesis, development and metastasis of human gastric adenocarcinoma, colorectal adenocarcinoma, intraductal carcinoma of breast, and lung cancer. Using tissue microarray by immuhistochemical (IHC) staining and in situ hybridization (ISH), we examined the expression levels of nm23 mRNA, CD44s, and CD44v6 in 62 specimens of human gastric adenocarcinoma and 62 specimens of colorectal adenocarcinoma; the expression of CD44s and CD44v6 in 120 specimens of intraductal carcinoma of breast and 20 specimens of normal breast tissue; the expression of nm23 mRNA in 72 specimens of human lung cancer and 23 specimens of normal tissue adjacent to cancer. The expression of nm23 mRNA in the tissues of gastric and colorectal adenocarcinoma was not significantly different from that in the normal tissues adjacent to cancer (P>0.05), and was not associated with the invasion of tumor and the pathology grade of adenocarcinoma (P>0.05). However, the expression of nm23 mRNA was correlated negatively to the lymph node metastasis of gastric and colorectal adenocarcinoma (r = -0.49, P<0.01; r = -4.93, P<0.01). The expression of CD44s in the tissues of gastric and colorectal adenocarcinoma was significantly different from that in the normal tissues adjacent to cancer (P<0.05; P<0.01). CD44v6 was expressed in the tissues of gastric and colorectal adenocarcinoma only, the expression of CD44v6 was significantly associated with the lymph node metastasis, invasion and pathological grade of the tumor (r = 0.47, P<0.01; r = 5.04, P<0.01). CD44s and CD44v6 were expressed in intraductal carcinoma of breast, the expression of CD44s and CD44v6 was significantly associated with lymph node metastases and invasion (P<0.01). However, neither of them was expressed in the normal breast tissue. In addition, the expression of CD44v6 was closely related to the degree of cell differentiation of intraductal carcinoma of breast (c2 = 5.68, P<0.05). The expressional level of nm23 mRNA was closely related to the degree of cell differentiation (P<0.05) and lymph node metastasis (P<0.01), but the expression of nm23 gene was not related to sex, age, and type of histological classification (P>0.05). Patients with overexpression of CD44s and CD44v6 and low expression of nm23 mRNA have a higher lymph node metastatic rate and invasion. In addition, overexpression of CD44v6 is closely related to the degree of cell differentiation. Detection of the three genes is able to provide a reliable index to evaluate the invasion and metastasis of tumor cells.

MUC4 (sialomucin complex) expression in salivary gland tumors and squamous cell carcinoma of the upper aerodigestive tract.

PubMed

Weed, D T; Gomez-Fernandez, C; Bonfante, E; Lee, T D; Pacheco, J; Carvajal, M E; Goodwin, W J; Carraway, K L

2001-02-01

This study investigates MUC4 expression in normal squamous epithelia and squamous cell carcinoma (SCC) of the upper aerodigestive tract (UADT), and in salivary gland neoplasms. MUC4 antigens in tumor and adjacent normal tissue are localized by immunocytochemical studies. Fresh frozen tissues from surgical resection specimens are further analyzed by Western blot. MUC4 is identified by immunocytochemical staining throughout the normal UADT mucosa, in 34 of 40 primary UADT SCC, and in 11 of 12 metastatic cervical lymph nodes. A trend toward decreased MUC4 staining in moderately and poorly differentiated tumors is noted. Immunoblots show MUC4 in 4 of 5 SCC analyzed. Immunocytochemical staining of MUC4 in 13 major and minor salivary gland neoplasms reveal variable staining of normal and neoplastic tissue. MUC4 is demonstrated in immunoblots of normal parotid tissue and in the single parotid malignancy analyzed, but is not demonstrated in one minor salivary gland malignancy. These findings characterize normal UADT mucosal and salivary MUC4 expression, and MUC4 expression in SCC of the UADT and in salivary gland tumors. Correlation of MUC4 expression with clinical outcomes may establish MUC4 as a potential molecular prognostic marker for these tumors.

Aberrant expression of stress-induced phosphoprotein 1 in colorectal cancer and its clinicopathologic significance.

PubMed

Zhang, Zhimei; Ren, Hui; Yang, Liang; Zhang, Xinhua; Liang, Wei; Wu, Hui; Huang, Leilei; Kang, Jihui; Xu, Jianbo; Zhai, Ertao; Cai, Shirong; He, Yulong

2018-06-04

Stress-Inducible Phosphoprotein1 (STIP1) is an adaptor protein that bridges HSP70 and HSP90 folding and a secretory protein that regulates malignant tumor progression. The aim of the present study was to demonstrate the clinicopathological significance and prognostic role of STIP1 in colorectal cancer (CRC). We used data from The Cancer Genome Atlas (TCGA) to analyze STIP1 expression in CRC and utilized 8 pairs of fresh-frozen tissue samples to investigate STIP1 expression in CRC tissues and adjacent normal tissues using quantitative real-time polymerase chain reaction (qRT-PCR) and western blot assays. We also used immunohistochemical staining to detect STIP1 expression in 144 formalin-fixed, paraffin-embedded (FFPE) CRC tissue samples and determine the clinical significance of STIP1 expression in CRC. The results of bioinformatics analysis, qRT-PCR, and western blot showed that STIP1 expression was higher in CRC tissues than in adjacent normal tissues. High STIP1 expression was significantly correlated with advanced T stage (P=.01), N stage (P=.001), M stage (P﹤0.001), and TNM stage (P﹤0.001). Moreover, Kaplan-Meier analyses indicated that higher STIP1 expression predicted a worse prognosis in patients with CRC, and Cox regression analysis revealed that STIP1 was an independent prognostic factor for overall survival and disease-free survival in patients with CRC. In conclusion, our results suggest that STIP1 acts as an oncogene in CRC and can therefore serve as a biomarker for the prognosis of patients with CRC. Copyright © 2018. Published by Elsevier Inc.

Defining Genomic Changes in Triple-Negative Breast Cancer in Women of African Descent

DTIC Science & Technology

2012-06-01

Triple negative breast cancer • Ethnic disparities • Breast cancer amongst African Americans and Africans • Gene expression profiling • Array... negative cases seen in both African and African - American breast cancer cases. Gene Expression Array Studies The 31 triple negative Kijabe... African - American Adjacent Normal Breast Tissue PI: Pegram &

Clinicopathological observations of colorectal serrated lesions associated with invasive carcinoma and high-grade intraepithelial neoplasm

PubMed Central

XU, SHENG; WANG, LUPING; YANG, GUANGZHI; LI, LIN; WANG, JIN; XU, CHUNWEI; GE, CHANG

2013-01-01

The aim of this study was to investigate the clinicopathological characteristics of colorectal serrated lesions associated with invasive carcinoma and high-grade intraepithelial neoplasm (HIN), as well as to determine the immunohistochemical expression of MutL homolog 1 (MLH1), MutS homolog 2 (MSH2), K-ras and O6-methylguanine-DNA methyltransferase (MGMT). A total of 5,347 cases diagnosed with colorectal polyp or adenoma were included in this study from October 2002 to September 2009. A total of 16 cases of colorectal serrated lesions associated with invasive carcinoma/HIN were screened. These comprised seven cases of traditional serrated adenoma (TSA) associated with invasive carcinoma and HIN, six cases of sessile serrated adenoma (SSA) associated with invasive carcinoma/HIN and three cases of hyperplastic polyp (HP) associated with invasive carcinoma/HIN. TSA associated with invasive carcinoma/HIN predominantly occurred in the rectum with a clearly serrated structure and ectopic crypts. High-grade dysplasia was observed in filiform TSA, which was more prone to carcinogenesis. SSA associated with invasive carcinoma/HIN mainly occurred in the ileocecal junction, with the SSA serrated glands closely located adjacent to the muscularis mucosa and the basal crypt expanded with inverted T- or L-shaped branches. HPs were observed in three cases in the cancer-adjacent tissues with invasive carcinoma, while a HP-SSA/TSA-carcinoma sequence was found in two cases. Immunohistochemistry showed that MGMT expression was significantly different in the serrated lesion tissues compared with that in cancer tissues (P=0.022), control cancer tissues (P=0.002) and normal colorectal epithelial tissues (P=0.003). TSA and SSA may progress to cancer or directly develop into invasive adenocarcinoma. Filiform TSA easily develops into HIN, followed by infiltration. HP may arise from the cancer-adjacent tissues of the invasive carcinoma, which are closely adjacent to the cancer tissues. Further research is needed to investigate the potential direct involvement of HP in carcinogenesis. PMID:24223631

Proliferative activity of denture-induced fibrous inflammatory hyperplasia analyzed by proliferating cell nuclear antigen labeling index.

PubMed

Coelho, C M; Zucoloto, S

1999-01-01

Denture-induced fibrous inflammatory hyperplasia (FIH) occurs around the borders of an ill-fitting denture. There has been no report in the literature concerning epithelial proliferative activity in FIH. The purpose of this study was to observe the labeling of proliferating cell nuclear antigen (PCNA) and evaluate its clinicopathologic results. The labeling index (LI) was assessed by using the PCNA, a nuclear protein synthesized mainly in the G1-S stages of the cell cycle that could be detected immunohistochemically by the monoclonal antibody PC10. The PCNA LI was assessed in FIH specimens, in clinically normal specimens 1 cm from the FIH margin (adjacent group), and in clinically normal specimens located at least 2 cm from the adjacent group; the last were considered the control group. The mean PCNA LI values in the basal, parabasal, and overall epithelial layers were similar in FIH and in the adjacent group and were significantly higher than in the control group. These data support the importance of the surgical treatment of FIH with wide excision (about 1 cm) since the clinically normal tissue around the lesion could be histologically altered.

Identification and pathway analysis of microRNAs with no previous involvement in breast cancer.

PubMed

Romero-Cordoba, Sandra; Rodriguez-Cuevas, Sergio; Rebollar-Vega, Rosa; Quintanar-Jurado, Valeria; Maffuz-Aziz, Antonio; Jimenez-Sanchez, Gerardo; Bautista-Piña, Veronica; Arellano-Llamas, Rocio; Hidalgo-Miranda, Alfredo

2012-01-01

microRNA expression signatures can differentiate normal and breast cancer tissues and can define specific clinico-pathological phenotypes in breast tumors. In order to further evaluate the microRNA expression profile in breast cancer, we analyzed the expression of 667 microRNAs in 29 tumors and 21 adjacent normal tissues using TaqMan Low-density arrays. 130 miRNAs showed significant differential expression (adjusted P value = 0.05, Fold Change = 2) in breast tumors compared to the normal adjacent tissue. Importantly, the role of 43 of these microRNAs has not been previously reported in breast cancer, including several evolutionary conserved microRNA*, showing similar expression rates to that of their corresponding leading strand. The expression of 14 microRNAs was replicated in an independent set of 55 tumors. Bioinformatic analysis of mRNA targets of the altered miRNAs, identified oncogenes like ERBB2, YY1, several MAP kinases, and known tumor-suppressors like FOXA1 and SMAD4. Pathway analysis identified that some biological process which are important in breast carcinogenesis are affected by the altered microRNA expression, including signaling through MAP kinases and TP53 pathways, as well as biological processes like cell death and communication, focal adhesion and ERBB2-ERBB3 signaling. Our data identified the altered expression of several microRNAs whose aberrant expression might have an important impact on cancer-related cellular pathways and whose role in breast cancer has not been previously described.

Assessing the potential for AAV vector genotoxicity in a murine model

PubMed Central

Li, Hojun; Malani, Nirav; Hamilton, Shari R.; Schlachterman, Alexander; Bussadori, Giulio; Edmonson, Shyrie E.; Shah, Rachel; Arruda, Valder R.; Mingozzi, Federico; Fraser Wright, J.; Bushman, Frederic D.

2011-01-01

Gene transfer using adeno-associated virus (AAV) vectors has great potential for treating human disease. Recently, questions have arisen about the safety of AAV vectors, specifically, whether integration of vector DNA in transduced cell genomes promotes tumor formation. This study addresses these questions with high-dose liver-directed AAV-mediated gene transfer in the adult mouse as a model (80 AAV-injected mice and 52 controls). After 18 months of follow-up, AAV-injected mice did not show a significantly higher rate of hepatocellular carcinoma compared with controls. Tumors in mice treated with AAV vectors did not have significantly different amounts of vector DNA compared with adjacent normal tissue. A novel high-throughput method for identifying AAV vector integration sites was developed and used to clone 1029 integrants. Integration patterns in tumor tissue and adjacent normal tissue were similar to each other, showing preferences for active genes, cytosine-phosphate-guanosine islands, and guanosine/cysteine-rich regions. Gene expression data showed that genes near integration sites did not show significant changes in expression patterns compared with genes more distal to integration sites. No integration events were identified as causing increased oncogene expression. Thus, we did not find evidence that AAV vectors cause insertional activation of oncogenes and subsequent tumor formation. PMID:21106988

The influence of the microenvironment on the malignant phenotype

NASA Technical Reports Server (NTRS)

Park, C. C.; Bissell, M. J.; Barcellos-Hoff, M. H.

2000-01-01

Normal tissue homeostasis is maintained by dynamic interactions between epithelial cells and their microenvironment. As tissue becomes cancerous, there are reciprocal interactions between neoplastic cells, adjacent normal cells such as stroma and endothelium, and their microenvironments. The current dominant paradigm wherein multiple genetic lesions provide both the impetus for, and the Achilles heel of, cancer might be inadequate to understand cancer as a disease process. In the following brief review, we will use selected examples to illustrate the influence of the microenvironment in the evolution of the malignant phenotype. We will also discuss recent studies that suggest novel therapeutic interventions might be derived from focusing on microenvironment and tumor cells interactions.

A Role for the NF-kb/Rel Transcription Factors in Human Breast Cancer

DTIC Science & Technology

1998-07-01

binding proteins present in a series of nuclear extracts from cell lines and from breast tumor tissues as well as normal mammary epithelium. Finally, we...RelA is nuclear in several examples. Our recent data on nuclear extracts of breast tumors shows that there is a significant increase in NF-KB binding...Figure 2 in the appendix). Additionally, immunoblotting of nuclear extracts versus adjacent tissue controls showed that NF-KB p50, p52 and c-Rel were

MicroRNA Expression Profiling to Identify and Validate Reference Genes for the Relative Quantification of microRNA in Rectal Cancer.

PubMed

Eriksen, Anne Haahr Mellergaard; Andersen, Rikke Fredslund; Pallisgaard, Niels; Sørensen, Flemming Brandt; Jakobsen, Anders; Hansen, Torben Frøstrup

2016-01-01

MicroRNAs (miRNAs) play important roles in regulating biological processes at the post-transcriptional level. Deregulation of miRNAs has been observed in cancer, and miRNAs are being investigated as potential biomarkers regarding diagnosis, prognosis and prediction in cancer management. Real-time quantitative polymerase chain reaction (RT-qPCR) is commonly used, when measuring miRNA expression. Appropriate normalisation of RT-qPCR data is important to ensure reliable results. The aim of the present study was to identify stably expressed miRNAs applicable as normaliser candidates in future studies of miRNA expression in rectal cancer. We performed high-throughput miRNA profiling (OpenArray®) on ten pairs of laser micro-dissected rectal cancer tissue and adjacent stroma. A global mean expression normalisation strategy was applied to identify the most stably expressed miRNAs for subsequent validation. In the first validation experiment, a panel of miRNAs were analysed on 25 pairs of micro dissected rectal cancer tissue and adjacent stroma. Subsequently, the same miRNAs were analysed in 28 pairs of rectal cancer tissue and normal rectal mucosa. From the miRNA profiling experiment, miR-645, miR-193a-5p, miR-27a and let-7g were identified as stably expressed, both in malignant and stromal tissue. In addition, NormFinder confirmed high expression stability for the four miRNAs. In the RT-qPCR based validation experiments, no significant difference between tumour and stroma/normal rectal mucosa was detected for the mean of the normaliser candidates miR-27a, miR-193a-5p and let-7g (first validation P = 0.801, second validation P = 0.321). MiR-645 was excluded from the data analysis, because it was undetected in 35 of 50 samples (first validation) and in 24 of 56 samples (second validation), respectively. Significant difference in expression level of RNU6B was observed between tumour and adjacent stromal (first validation), and between tumour and normal rectal mucosa (second validation). We recommend the mean expression of miR-27a, miR-193a-5p and let-7g as normalisation factor, when performing miRNA expression analyses by RT-qPCR on rectal cancer tissue.

Diagnosing basal cell carcinoma in vivo by near-infrared Raman spectroscopy: a Principal Components Analysis discrimination algorithm

NASA Astrophysics Data System (ADS)

Silveira, Landulfo, Jr.; Silveira, Fabrício L.; Bodanese, Benito; Pacheco, Marcos Tadeu T.; Zângaro, Renato A.

2012-02-01

This work demonstrated the discrimination among basal cell carcinoma (BCC) and normal human skin in vivo using near-infrared Raman spectroscopy. Spectra were obtained in the suspected lesion prior resectional surgery. After tissue withdrawn, biopsy fragments were submitted to histopathology. Spectra were also obtained in the adjacent, clinically normal skin. Raman spectra were measured using a Raman spectrometer (830 nm) with a fiber Raman probe. By comparing the mean spectra of BCC with the normal skin, it has been found important differences in the 800-1000 cm-1 and 1250-1350 cm-1 (vibrations of C-C and amide III, respectively, from lipids and proteins). A discrimination algorithm based on Principal Components Analysis and Mahalanobis distance (PCA/MD) could discriminate the spectra of both tissues with high sensitivity and specificity.

Effects of holmium:YAG laser on equine articular cartilage and subchondral bone adjacent to traumatic lesions

NASA Astrophysics Data System (ADS)

Collier, Michael A.; Haugland, L. Mark; Bellamy, Janine; Johnson, Lanny L.; Rohrer, Michael D.; Walls, Robert C.; Bartels, Kenneth E.

1994-09-01

The effects of Ho:YAG laser energy on articular cartilage and subchondral bone adjacent to traumatically created cartilage lesions in a continuous weight-bearing model were investigated. The 2.1 micrometers wavelength was delivered in hand-controlled contact and near-contact hard tissue arthroscopic surgery in a saline medium. Bilateral arthroscopy was performed on normal antebrachiocarpal and intercarpal joints of four adult horses. One-hundred twenty traumatic lesions were created on three weight-bearing articular surfaces with a knife, curette, or a motorized burr. Depths of the lesions were partial and full thickness. Configurations of the lesions were lacerations, scrapes, and craters. Left limbs were used as controls. Right limb lesions were treated with various intensities of laser energy. Animals were sacrificed at intervals of 1, 3, and 8 weeks. Gross microscopic anatomy was documented, and tissue sections were subjected to blind review by a pathologist. Mankin grading for cellularity and proteoglycan content was used to qualitatively evaluate cartilage response. Cartilage adjacent to all lesions exposed to laser energy had better cellularity and proteoglycan content than corresponding controls by Mankin grading.

SHCBP1 is over-expressed in breast cancer and is important in the proliferation and apoptosis of the human malignant breast cancer cell line.

PubMed

Feng, Wen; Li, Hong-Chang; Xu, Ke; Chen, Ya-Feng; Pan, Li-Yun; Mei, Yi; Cai, Han; Jiang, Yi-Ming; Chen, Teng; Feng, Dian-Xu

2016-08-01

SHC SH2-binding protein 1, a member of Src homolog and collagen homolog (Shc) family, has been recently identified in different contexts in unbiased screening assays. It has been reported to be over-expressed in several malignant cancers. Immunohistochemistry of SHCBP1 on 128 breast cancer tissues and adjacent normal tissues were used to evaluate the prognostic significance of SHCBP1. Survival analyses were performed by Kaplan-Meier method. CRISPR/CAS9 method was used to knockout SHCBP1 expression. CRISPR/CAS9 technology was used to knockout SHCBP1 in 2 breast cancer cell lines. MTT assay, BrdU assay, colony formation assay, cell cycle assay and apoptosis analysis in MCF-7 and MDA-MB-231 cell lines were carried out to evaluate the effects of SHCBP1 on breast cancer in vitro. Immunohistochemical analysis revealed SHCBP1 was significantly up-regulated in breast cancer tissues compared with adjacent normal tissues (82 of 128, 64%). Over-expressed SHCBP1 was correlated with advanced clinical stage and poorer survival. Ablation of SHCBP1 inhibited the proliferation in vitro. SHCBP1 knockout increased cyclin-dependent kinase inhibitor p21, and decreased the Cyclin B1 and CDK1. Our study suggests SHCBP1 is dysregulated expressed in breast cancer and plays a critical role in cancer progression, which can be a potential prognosis predictor of breast cancer. Copyright © 2016. Published by Elsevier B.V.

Increased expression of tumor necrosis factor-α is associated with advanced colorectal cancer stages.

PubMed

Al Obeed, Omar A; Alkhayal, Khayal A; Al Sheikh, Abdulmalik; Zubaidi, Ahmad M; Vaali-Mohammed, Mansoor-Ali; Boushey, Robin; Mckerrow, James H; Abdulla, Maha-Hamadien

2014-12-28

To detect the expression of tumor necrosis factor-α (TNF-α) in colorectal cancer (CRC) cells among Saudi patients, and correlate its expression with clinical stages of cancer. Archival tissue specimens were collected from 30 patients with CRC who had undergone surgical intervention at King Khalid University Hospital. Patient demographic information, including age and gender, tumor sites, and histological type of CRC, was recorded. To measure TNF-α mRNA expression in CRC, total RNA was extracted from tumor formalin-fixed, paraffin-embedded, and adjacent normal tissues. Reverse transcription and reverse transcription polymerase chain reaction were performed. Colorectal tissue microarrays were constructed to investigate the protein expression of TNF-α by immunohistochemistry. The relative expression of TNF-α mRNA in colorectal cancer was significantly higher than that seen in adjacent normal colorectal tissue. High TNF-α gene expression was associated with Stage III and IV neoplasms when compared with earlier tumor stages (P = 0.004). Eighty-three percent of patients (25/30) showed strong TNF-α positive staining, while only 10% (n = 3/30) of patients showed weak staining, and 7% (n = 2/30) were negative. We showed the presence of elevated TNF-α gene expression in cancer cells, which strongly correlated with advanced stages of tumor. High levels of TNF-α expression could be an independent diagnostic indicator of colorectal cancer, and targeting TNF-α might be a promising prognostic tool by assessment of the clinical stages of CRC.

Increased expression of tumor necrosis factor-α is associated with advanced colorectal cancer stages

PubMed Central

Al Obeed, Omar A; Alkhayal, Khayal A; Al Sheikh, Abdulmalik; Zubaidi, Ahmad M; Vaali-Mohammed, Mansoor-Ali; Boushey, Robin; Mckerrow, James H; Abdulla, Maha-Hamadien

2014-01-01

AIM: To detect the expression of tumor necrosis factor-α (TNF-α) in colorectal cancer (CRC) cells among Saudi patients, and correlate its expression with clinical stages of cancer. METHODS: Archival tissue specimens were collected from 30 patients with CRC who had undergone surgical intervention at King Khalid University Hospital. Patient demographic information, including age and gender, tumor sites, and histological type of CRC, was recorded. To measure TNF-α mRNA expression in CRC, total RNA was extracted from tumor formalin-fixed, paraffin-embedded, and adjacent normal tissues. Reverse transcription and reverse transcription polymerase chain reaction were performed. Colorectal tissue microarrays were constructed to investigate the protein expression of TNF-α by immunohistochemistry. RESULTS: The relative expression of TNF-α mRNA in colorectal cancer was significantly higher than that seen in adjacent normal colorectal tissue. High TNF-α gene expression was associated with Stage III and IV neoplasms when compared with earlier tumor stages (P = 0.004). Eighty-three percent of patients (25/30) showed strong TNF-α positive staining, while only 10% (n = 3/30) of patients showed weak staining, and 7% (n = 2/30) were negative. We showed the presence of elevated TNF-α gene expression in cancer cells, which strongly correlated with advanced stages of tumor. CONCLUSION: High levels of TNF-α expression could be an independent diagnostic indicator of colorectal cancer, and targeting TNF-α might be a promising prognostic tool by assessment of the clinical stages of CRC. PMID:25561807

[Roles of Y box-binding protein 1 in SK-BR-3 breast cancer proliferation].

PubMed

Shi, Jianhong; Lü, Xinrui; Wang, Bing; Daudan, Lin; Yanan, Wang; Yuhui, Bu; Zhenfeng, Ma

2014-09-30

To explore the roles of Y box-binding protein 1 (YB-1) in breast cancer cell proliferation. Twenty cases of surgical removal of breast cancer tissue (diagnosed with invasive ductal carcinoma, stage II, by postoperative paraffin pathology) and normal breast tissues adjacent to carcinoma were collected during June 2013 to August 2013.Quantitative real-time PCR (qRT-PCR) was performed to detect the YB1 mRNA levels. Cultured mammary epithelial cells (HBL-100) and breast cancer cells (MCF7, MDA-MB-231 & SK-BR-3 cells) were harvested and qRT-PCR was performed to detect the YB1 mRNA levels.SK-BR-3 cells were stimulated with various concentrations of PDGF-BB and YB1 expression levels were detected by qRT-PCR. Down-regulation or over-expression of YB1 by si-YB1 or Ad-GFP-YB1 was detected in SK-BR-3 cells. And MTS cell proliferation assay kit was used to detect cell proliferation. YB1 mRNA levels were significantly higher in breast cancer tissues and MDA-MB-231 and SK-BR-3 breast cancer cell lines than that in adjacent normal breast tissues and HBL-100 mammary epithelial cells respectively (P < 0.05).YB1 expression levels increased in PDGF-BB stimulated SK-BR-3 cells in a dose-dependent manner. A down-regulation of endogenous YB1 decreases and an over-expression of exogenous YB1 promotes the proliferation activity in SK-BR-3 cells.

Bisphenol A Concentrates Preferentially in Human Uterine Leiomyoma and Induces Proliferation in Rat Myometrium.

PubMed

Othman, Essam R; Al-Adly, Dina M M; Elgamal, Dalia A; Ghandour, Nagwa; El-Sharkawy, Sawsan

2016-04-01

To measure tissue levels of bisphenol A (BPA) in uterine leiomyoma (ULM), adjacent myometrium (Myo-F), and normal myometrium (Myo-N). Also, we tested the effect of BPA treatment on rat myometrium. Uterine leiomyomas and Myo-F tissues were isolated from hysterectomy specimens done to treat symptomatic ULMs (N = 30). Normal myometrium is isolated from hysterectomies done on ULM-free uteri for other benign indications (N = 25). Bisphenol A was measured in 1 g of tissue using solid-phase extraction and high-performance liquid chromatography, with fluorescence detectors. Experimentally, adult female rats were fed BPA orally at a dose of 50 mg/kg/d for 90 days. Animals were killed, and their myometrial thickness and proliferating cell nuclear antigen (PCNA) immunostaining were evaluated. Tissue concentration of BPA in each of ULM (12.3 ± 2.8 µg/g) and Myo-F (10.1 ± 0.2 µg/g) was significantly higher than that of Myo-N (0.58 ± 0.2 µg/g). There was no statistically significant difference in BPA level between ULM and Myo-F within submucous or interstitial/subserous fibroid groups. Compared to control rats, BPA-treated animals showed significantly higher myometrial thickness (168.67 ± 5.7 µm and 281.6 ± 20.32 µm, respectively, P = .003) and increased myometrial PCNA immunoscores (1.5 ± 0.37 and 10.38 ± 0.67, respectively, P ≤ .001). Bisphenol A concentrates in human ULM tissue and its adjacent Myo-F compared to Myo-N. No significant difference is detected in BPA content of ULM tissue of different subtypes. Bisphenol A increases thickness and induces cellular proliferation in rat myometrium. Taken together, our results support a role of BPA in ULM development/growth. © The Author(s) 2015.

Normal breast tissue DNA methylation differences at regulatory elements are associated with the cancer risk factor age.

PubMed

Johnson, Kevin C; Houseman, E Andres; King, Jessica E; Christensen, Brock C

2017-07-10

The underlying biological mechanisms through which epidemiologically defined breast cancer risk factors contribute to disease risk remain poorly understood. Identification of the molecular changes associated with cancer risk factors in normal tissues may aid in determining the earliest events of carcinogenesis and informing cancer prevention strategies. Here we investigated the impact cancer risk factors have on the normal breast epigenome by analyzing DNA methylation genome-wide (Infinium 450 K array) in cancer-free women from the Susan G. Komen Tissue Bank (n = 100). We tested the relation of established breast cancer risk factors, age, body mass index, parity, and family history of disease, with DNA methylation adjusting for potential variation in cell-type proportions. We identified 787 cytosine-guanine dinucleotide (CpG) sites that demonstrated significant associations (Q value <0.01) with subject age. Notably, DNA methylation was not strongly associated with the other evaluated breast cancer risk factors. Age-related DNA methylation changes are primarily increases in methylation enriched at breast epithelial cell enhancer regions (P = 7.1E-20), and binding sites of chromatin remodelers (MYC and CTCF). We validated the age-related associations in two independent populations, using normal breast tissue samples (n = 18) and samples of normal tissue adjacent to tumor tissue (n = 97). The genomic regions classified as age-related were more likely to be regions altered in both pre-invasive (n = 40, P = 3.0E-03) and invasive breast tumors (n = 731, P = 1.1E-13). DNA methylation changes with age occur at regulatory regions, and are further exacerbated in cancer, suggesting that age influences breast cancer risk in part through its contribution to epigenetic dysregulation in normal breast tissue.

The clinical and prognostic value of polo-like kinase 1 in lung squamous cell carcinoma patients: immunohistochemical analysis

PubMed Central

Li, Hefei; Sun, Zhenqing; Guo, Qiang; Shi, Hongyun; Jia, Youchao

2017-01-01

Polo-like kinase 1 (PLK1) has been suggested to serve as an oncogene in most human cancers. The aim of our study is to present more evidence about the clinical and prognostic value of PLK1 in lung squamous cell carcinoma patients. The status of PLK1 was observed in lung adenocarcinoma, lung squamous cell carcinoma, and normal lung tissues through analyzing microarray dataset (GEO accession numbers: GSE1213 and GSE 3627). PLK1 mRNA and protein expressions were detected in lung squamous cell carcinoma and normal lung tissues by using quantitative real-time PCR (qRT-PCR) and immunohistochemistry. In our results, the levels of PLK1 in lung squamous cell carcinoma tissues were higher than that in lung adenocarcinoma tissues. Compared with paired adjacent normal lung tissues, the PLK1 expression was increased in lung squamous cell carcinoma tissues. Furthermore, high expression of PLK1 protein was correlated with differentiated degree, clinical stage, tumor size, lymph node metastasis, and distant metastasis. The univariate and multivariate analyses showed PLK1 protein high expression was an unfavorable prognostic biomarker for lung squamous cell carcinoma patients. In conclusion, high expression of PLK1 is associated with the aggressive progression and poor prognosis in lung squamous cell carcinoma patients. PMID:28724602

Novel Applications of Ultrasound Technology to Visualize and Characterize Myofascial Trigger Points and Surrounding Soft Tissue

PubMed Central

Sikdar, Siddhartha; Shah, Jay P.; Gebreab, Tadesse; Yen, Ru-Huey; Gilliams, Elizabeth; Danoff, Jerome; Gerber, Lynn H.

2009-01-01

Objective Apply ultrasound (US) imaging techniques to better describe the characteristics of myofascial trigger points (MTrPs) and the immediately adjacent soft tissue. Design Descriptive (exploratory) study. Setting Biomedical research center. Participants 9 subjects meeting Travell and Simons’s criteria for MTrPs in a taut band in the upper trapezius. Interventions (None) Main Outcome Measures MTrPs were evaluated by 1) physical examination, 2) pressure algometry, and 3) three types of ultrasound imaging including grayscale (2D US), vibration sonoelastography (VSE), and Doppler. Methods Four sites in each patient were labeled based on physical examination as either active MTrP (spontaneously-painful, A-MTrP), latent MTrP (non-painful, L-MTrP), or normal myofascial tissue. US examination was performed on each subject by a team blinded to the physical findings. A 12-5 MHz US transducer was used. VSE was performed by color Doppler variance imaging while simultaneously inducing vibrations (~92Hz) with a handheld massage vibrator. Each site was assigned a tissue imaging score (TIS) as follows: 0 = uniform echogenicity and stiffness; 1 = focal hypoechoic region with stiff nodule; 2 = multiple hypoechoic regions with stiff nodules. Blood flow in the neighborhood of MTrPs was assessed using Doppler imaging. Each site was assigned a blood flow waveform score (BFS) as follows: 0 = normal arterial flow in muscle; 1 = elevated diastolic flow; 2 = high-resistance flow waveform with retrograde diastolic flow. Results MTrPs appeared as focal, hypoechoic regions on 2D US, indicating local changes in tissue echogenicity, and as focal regions of reduced vibration amplitude on VSE, indicating a localized stiff nodule. MTrPs were elliptical in shape, with a size of 0.16 ± 0.11 cm2. There were no significant differences in size between A-MTrPs and L-MTrPs. Sites containing MTrPs were more likely to have higher TIS compared to normal myofascial tissue (p<0.002). Small arteries (or enlarged arterioles) near A-MTrPs showed retrograde flow in diastole indicating a highly resistive vascular bed. A-MTrP sites were more likely to have higher BFS compared to L-MTrPs (p<0.021). Conclusions Preliminary findings show that, under the conditions of this investigation, US imaging techniques can be used to distinguish myofascial tissue containing MTrPs from normal myofascial tissue (lacking trigger points). Ultrasound enables visualization and some characterization of MTrPs and adjacent soft tissue. PMID:19887205

The prognostic significance of lymphatics in colorectal liver metastases.

PubMed

Muralidharan, Vijayaragavan; Nguyen, Linh; Banting, Jonathan; Christophi, Christopher

2014-01-01

Background. Colorectal Cancer (CRC) is the most common form of cancer diagnosed in Australia across both genders. Approximately, 40%-60% of patients with CRC develop metastasis, the liver being the most common site. Almost 70% of CRC mortality can be attributed to the development of liver metastasis. This study examines the pattern and density of lymphatics in colorectal liver metastases (CLM) as predictors of survival following hepatic resection for CLM. Methods. Patient tissue samples were obtained from the Victorian Cancer Biobank. Immunohistochemistry was used to examine the spatial differences in blood and lymphatic vessel densities between different regions within the tumor (CLM) and surrounding host tissue. Lymphatic vessel density (LVD) was assessed as a potential prognostic marker. Results. Patients with low lymphatic vessel density in the tumor centre, tumor periphery, and adjacent normal liver demonstrated a significant disease-free survival advantage compared to patients with high lymphatic vessel density (P = 0.01, P > 0.01, and P = 0.05, resp.). Lymphatic vessel density in the tumor centre and periphery and adjacent normal liver was an accurate predictive marker of disease-free survival (P = 0.05). Conclusion. Lymphatic vessel density in CLM appears to be an accurate predictor of recurrence and disease-free survival.

Six stroma-based RNA markers diagnostic for prostate cancer in European-Americans validated at the RNA and protein levels in patients in China

PubMed Central

Zhu, Jianguo; Pan, Cong; Jiang, Jun; Deng, Mingsen; Gao, Hengjun; Men, Bozhao; McClelland, Michael; Mercola, Dan; Zhong, Wei-De; Jia, Zhenyu

2015-01-01

We previously analyzed human prostate tissue containing stroma near to tumor and from cancer-negative tissues of volunteers. Over 100 candidate gene expression differences were identified and used to develop a classifier that could detect nearby tumor with an accuracy of 97% (sensitivity = 98% and specificity = 88%) based on 364 independent test cases from primarily European American cases. These stroma-based gene signatures have the potential to identify cancer patients among those with negative biopsies. In this study, we used prostate tissues from Chinese cases to validate six of these markers (CAV1, COL4A2, HSPB1, ITGB3, MAP1A and MCAM). In validation by real-time PCR, four genes (COL4A2, HSPB1, ITGB3, and MAP1A) demonstrated significantly lower expression in tumor-adjacent stroma compared to normal stroma (p value ≤ 0.05). Next, we tested whether these expression differences could be extended to the protein level. In IHC assays, all six selected proteins showed lower expression in tumor-adjacent stroma compared to the normal stroma, of which COL4A2, HSPB1 and ITGB3 showed significant differences (p value ≤ 0.05). These results suggest that biomarkers for diagnosing prostate cancer based on tumor microenvironment may be applicable across multiple racial groups. PMID:26158290

TPX2 expression is associated with poor survival in gastric cancer.

PubMed

Tomii, Chiharu; Inokuchi, Mikito; Takagi, Yoko; Ishikawa, Toshiaki; Otsuki, Sho; Uetake, Hiroyuki; Kojima, Kazuyuki; Kawano, Tatsuyuki

2017-01-09

Targeting protein for Xenopus kinesin-like protein 2 (TPX2) is a microtubule-associated protein required for microtubule formation in human cells. Several studies have demonstrated that TPX2 is overexpressed in multiple tumor types and promotes tumor growth and metastasis. However, there have been few reports regarding its role in gastric cancer. In this study, we evaluated TPX2 expression and investigated its correlations with gastric cancer clinicopathological features and prognosis. Tumor samples were obtained from 290 patients with gastric adenocarcinoma who had undergone gastrectomy. The expression of TPX2 protein was examined using immunohistochemical staining. TPX2 messenger RNA (mRNA) levels were evaluated using real-time quantitative reverse transcription PCR in 19 of the gastric cancer tumors and adjacent normal tissues. The mRNA levels of TPX2 were significantly higher in gastric cancer tissues than in matched adjacent normal tissues (p = 0.004). In the immunohistochemical analysis, TPX2 overexpression was found in 123 (42.4%) of 290 patients. High TPX2 expression was positively associated with age, type of histology, depth of tumor, lymph node metastasis, stage, and remote metastasis or recurrence. High TPX2 expression was significantly associated with poorer disease-specific survival (p = 0.004) and relapse-free interval (p = 0.013). Our results indicated that high TPX2 expression was associated with tumor progression and poor survival in gastric cancer.

Extraskeletal osteosarcoma, telangiectatic variant arising from the small bowel mesentery.

PubMed

Hussain, Muhammad I; Al-Akeely, Mohammed H; Alam, Mohammed K; Jasser, Nayel A

2011-09-01

Extraskeletal osteosarcoma (EOS) is a highly aggressive and rare malignant soft tissue tumor, characterized by the production of neoplastic osseous tissue without attachment to the bone or periosteum. It rarely involves the visceral organs. Only 3 cases of mesenteric EOS have been reported in English literature. Here, we describe a male patient of 40 years, who was diagnosed to have EOS arising from small bowel mesentery. This patient presented with lower gastrointestinal (GI) bleeding. Upper GI endoscopy and colonoscopy were normal. Computed tomography scan demonstrated a well defined multi-loculated mixed density mass lesion measuring about 13x7x7 cm in lower abdomen adjacent to small bowel loops with liver metastasis. Palliative en bloc resection of tumor with adjacent small bowel was performed. The histopathology revealed a telangiectatic type osteosarcoma of mesentery. Diagnosis of EOS, its management and the outcome in context of the current literature are discussed.

Hypomethylation of DNA from Benign and Malignant Human Colon Neoplasms

NASA Astrophysics Data System (ADS)

Goelz, Susan E.; Vogelstein, Bert; Hamilton, Stanley R.; Feinberg, Andrew P.

1985-04-01

The methylation state of DNA from human colon tissue displaying neoplastic growth was determined by means of restriction endonuclease analysis. When compared to DNA from adjacent normal tissue, DNA from both benign colon polyps and malignant carcinomas was substantially hypomethylated. With the use of probes for growth hormone, γ -globin, α -chorionic gonadotropin, and γ -crystallin, methylation changes were detected in all 23 neoplastic growths examined. Benign polyps were hypomethylated to a degree similar to that in malignant tissue. These results indicate that hypomethylation is a consistent biochemical characteristic of human colonic tumors and is an alteration in the DNA that precedes malignancy.

Th22 cells are associated with hepatocellular carcinoma development and progression

PubMed Central

Qin, Shanyu; Ma, Shijia; Huang, Xiaoli; Lu, Donghong

2014-01-01

Objective IL-22-producing CD4+ T helper cells (Th22 cells) have been identified as major inducers of tissue inflammation and immune responses. Currently, no previous study explored the role of Th22 cells in the pathogenesis of hepatocellular carcinoma (HCC). The study aimed to determine the biological function of Th22 cells and its effector IL-22 in HCC patients. Methods Forty-five HCC patients and 19 healthy controls were recruited and their peripheral blood was collected. The fresh HCC tissues, adjacent HCC tissues and ten normal liver tissues were also collected. Flow cytometry analysis was used to determine the frequencies of circulating Th22 cells and Th17 cells. Serum IL-22 levels were tested by enzyme-linked immunosorbent assay (ELISA). Immunohistochemical staining and real-time polymerase chain reaction (PCR) were used to detect IL-22 protein and mRNA in tissues specimens, respectively. Results Circulating Th22 cells, Th17 cells and serum IL-22 levels were significantly elevated in HCC patients compared with those of healthy controls (P<0.001). Th22 cells were showed to be positively correlated with IL-22 in HCC patients (P<0.05), but not in healthy controls. No significant differences were found in HCC patients with HBeAg positivity or negativity in term of Th22 cells and serum IL-22 levels. The expression of IL-22 protein and mRNA was highest in HCC tissues, followed by adjacent HCC tissues and normal liver tissues. Furthermore, Th22 cells, serum IL-22 levels and IL-22 mRNA were elevated at stage III-IV compared with stage I-II of HCC (P<0.05). Conclusions Elevation of circulating Th22 cells and IL-22 may be implicated in the pathogenesis of HCC, and potentially be cellular targets for therapeutic intervention. PMID:24826053

Microbial Dysbiosis Is Associated with Human Breast Cancer

PubMed Central

Xuan, Caiyun; Shamonki, Jaime M.; Chung, Alice; DiNome, Maggie L.; Chung, Maureen; Sieling, Peter A.; Lee, Delphine J.

2014-01-01

Breast cancer affects one in eight women in their lifetime. Though diet, age and genetic predisposition are established risk factors, the majority of breast cancers have unknown etiology. The human microbiota refers to the collection of microbes inhabiting the human body. Imbalance in microbial communities, or microbial dysbiosis, has been implicated in various human diseases including obesity, diabetes, and colon cancer. Therefore, we investigated the potential role of microbiota in breast cancer by next-generation sequencing using breast tumor tissue and paired normal adjacent tissue from the same patient. In a qualitative survey of the breast microbiota DNA, we found that the bacterium Methylobacterium radiotolerans is relatively enriched in tumor tissue, while the bacterium Sphingomonas yanoikuyae is relatively enriched in paired normal tissue. The relative abundances of these two bacterial species were inversely correlated in paired normal breast tissue but not in tumor tissue, indicating that dysbiosis is associated with breast cancer. Furthermore, the total bacterial DNA load was reduced in tumor versus paired normal and healthy breast tissue as determined by quantitative PCR. Interestingly, bacterial DNA load correlated inversely with advanced disease, a finding that could have broad implications in diagnosis and staging of breast cancer. Lastly, we observed lower basal levels of antibacterial response gene expression in tumor versus healthy breast tissue. Taken together, these data indicate that microbial DNA is present in the breast and that bacteria or their components may influence the local immune microenvironment. Our findings suggest a previously unrecognized link between dysbiosis and breast cancer which has potential diagnostic and therapeutic implications. PMID:24421902

Extensive Necrosis After Radiation for Cancer: Experiences in Surgical Management

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

BENNETT, JAMES E.

1963-06-01

Radionecrosis in skin and deeper tissues and its surgical repair are described in 16 cases. The observed epithelial changes included both atrophy and hypertrophy, but atrophy was the dominant feature. Epidermal hypertrophy, which preceded malignant change, developed more slowly and was less likely to occur in areas subjected to deep irradiation than in skin treated with multiple small doses of x-ray over a long period. The indolent ulceration that developed in skin augmented the changes in underlying tissues so that successful management of these ulcerations required adequate excision of the damaged area and replacement with fat-bearing pedicle flap tissue. Whenmore » adjacent flaps were used, permanent blood supply to the region was assured. In cases of radiotherapy for basal cell carcinoma of the scalp, skin necrosis resulted in skull exposure with subsequent osteomyelitis and/or bone necrosis. Excision included the full thickness of the skull, and pedicle flap tissue from the scalp was used for coverage. Cranioplasty was performed after good skin and soft tissue cover had been obtained. Therapeutic radiation of the neck invariably produces marked skin changes, and when ulceration occurs, the vulnerability of underlying structures demands surgical treatment. Lesions of the upper extremity can be excised and covered with direct pedicle flaps from the trunk. Therapeutic radiation of the retroperitoneal area may produce extensive visceral damage as well as injury to the anterior abdominal wall, and anterior suprapubic ulcerations are particularly difficult to deal with since mobile adjacent tissue is scarce. The avascular midline is a limiting factor in flap design. Abdominal flaps extending onto the thigh can be used, but these require multiple delaying procedures to insure adequate blood supply. Patients being managed by these procedures are described. Most patients underwent their operative procedures with few serious complications. While postoperative bleeding and infection are inherent hazards, most complications were traceable to errors in planning or in operative technique. When the primary procedure fails, it is often many weeks before the wound is again ready for coverage and the availability of adjacent tissue has been compromised by the operation. Therefore, it is necessary to mobilize generous amounts of normal tissue to replace the area of injury, for this may be considerably more extensive than external inspection suggests. In addition, retraction of the wound edges following excision can be considerable since surrounding normal tissue may be drawn toward the area of involvement by scar contracture. When transposition or distant pedicle flaps are used, the flaps must be designed initially to allow for coverage of the eventual wound. However, when adjacent flaps are used, they may be outlined at the beginning of the procedure and appropriate alterations are then made, as necessary, after excision of the area of involvement. It is concluded that operation is not advisable until there is pain or ulceration in the region of radiation injury. Preferred treatment consists of excision of all damaged tlssue with pedicle flap replacement.« less

Raman molecular imaging of brain frozen tissue sections.

PubMed

Kast, Rachel E; Auner, Gregory W; Rosenblum, Mark L; Mikkelsen, Tom; Yurgelevic, Sally M; Raghunathan, Aditya; Poisson, Laila M; Kalkanis, Steven N

2014-10-01

Raman spectroscopy provides a molecular signature of the region being studied. It is ideal for neurosurgical applications because it is non-destructive, label-free, not impacted by water concentration, and can map an entire region of tissue. The objective of this paper is to demonstrate the meaningful spatial molecular information provided by Raman spectroscopy for identification of regions of normal brain, necrosis, diffusely infiltrating glioma and solid glioblastoma (GBM). Five frozen section tissues (1 normal, 1 necrotic, 1 GBM, and 2 infiltrating glioma) were mapped in their entirety using a 300-µm-square step size. Smaller regions of interest were also mapped using a 25-µm step size. The relative concentrations of relevant biomolecules were mapped across all tissues and compared with adjacent hematoxylin and eosin-stained sections, allowing identification of normal, GBM, and necrotic regions. Raman peaks and peak ratios mapped included 1003, 1313, 1431, 1585, and 1659 cm(-1). Tissue maps identified boundaries of grey and white matter, necrosis, GBM, and infiltrating tumor. Complementary information, including relative concentration of lipids, protein, nucleic acid, and hemoglobin, was presented in a manner which can be easily adapted for in vivo tissue mapping. Raman spectroscopy can successfully provide label-free imaging of tissue characteristics with high accuracy. It can be translated to a surgical or laboratory tool for rapid, non-destructive imaging of tumor margins.

The expression and prognostic value of protein tyrosine kinase 6 in early-stage cervical squamous cell cancer.

PubMed

Wang, Xiao-Jing; Xiong, Ying; Ma, Ze-Biao; Xia, Jian-Chuan; Li, Yan-Fang

2016-06-16

Protein tyrosine kinase 6 (PTK6) is overexpressed in many epithelial tumors and predicts poor prognosis. However, PTK6 expression status and its role in cervical squamous cell cancer are unknown. This study aimed to investigate the expression level and clinical significance of PTK6 in early-stage cervical squamous cell cancer. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting analysis were performed to detect PTK6 mRNA and protein expression levels in 10 freshly frozen, early-stage cervical squamous cell cancer specimens and adjacent non-tumorous cervical tissues. The expression of PTK6 was detected using immunohistochemical staining in 150 formalin-fixed, paraffin-embedded, early-stage cervical squamous cell cancer sections and 10 normal cervical tissue sections. The mRNA and protein levels of PTK6 in cancer tissues were higher than those in adjacent non-tumorous cervical tissues. Immunohistochemical analysis showed that PTK6 was not expressed in normal cervical tissues but was overexpressed in the cytoplasm of cervical squamous cell cancer cells. The level of PTK6 expression was significantly associated with tumor grade (P = 0.020). The 5-year overall survival rate of patients with high PTK6 expression was lower than that of patients with low PTK6 expression (81.3% vs. 96.2%, P = 0.008). Multivariate Cox regression analysis showed that the expression level of PTK6 in cervical squamous cell cancer was an independent prognostic factor for patient survival (hazard ratio = 5.999, 95% confidence interval 1.622-22.191, P < 0.05). PTK6 is overexpressed in cervical squamous cell cancer. Increased PTK6 expression is associated with reduced 5-year overall survival. PTK6 expression is an independent prognostic predictor for cervical cancer.

CIP2A is a predictor of survival and a novel therapeutic target in bladder urothelial cell carcinoma.

PubMed

Xue, Yijun; Wu, Gengqing; Wang, Xiaoning; Zou, Xiaofeng; Zhang, Guoxi; Xiao, Rihai; Yuan, Yuanhu; Long, Dazhi; Yang, Jun; Wu, Yuting; Xu, Hui; Liu, Folin; Liu, Min

2013-03-01

Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a recently identified human oncoprotein that stabilizes the c-MYC protein. Herein, we aimed to investigate its expression pattern, clinical significance, and biological function in urothelial cell carcinoma (UCC) of the bladder. CIP2A expression was examined in 20 fresh bladder UCC tissues and paired adjacent normal bladder tissues by RT-PCR and Western blot. Immunohistochemistry for CIP2A was performed on additional 117 bladder UCC tissues. The clinical significance of CIP2A expression was analyzed. CIP2A downregulation was performed in bladder UCC cell line T24 with high abundance of CIP2A, and the effects of CIP2A silencing on cell proliferation, migration, invasion in vitro, and tumor growth in vivo were evaluated. We found that CIP2A expression was upregulated in bladder UCC tissues relative to adjacent normal bladder tissues. Clinicopathological analysis showed that CIP2A expression was significantly associated with tumor stage (P = 0.004), histological grade (P = 0.007), and lymph node status (P = 0.001). The Kaplan-Meier survival curves revealed that CIP2A expression was associated with poor prognosis in bladder UCC patients (log-rank value = 14.704, P < 0.001). CIP2A expression was an independent prognostic marker of overall patient survival in a multivariate analysis (P = 0.015). Knockdown of the CIP2A expression reduced cell proliferation, anchorage-independent growth, migration, invasion, and tumor growth in xenograft model mice. Our findings suggest that CIP2A is an independent predictor of poor prognosis of bladder UCC patients, and inhibition of its expression might be of therapeutic significance.

[Expression of Rictor and mTOR in colorectal cancer and their clinical significance].

PubMed

Wang, Li-Feng; Chen, Hai-Jin; Yu, Jin-Long; Qi, Jia; Lin, Xiao-Hua; Zou, Zhao-Wei

2016-03-01

To explore the expression of Rictor and mTOR in the colorectal cancer and their clinical significance. The expression levels of Rictor and mTOR in HCT116, SW480, LoVo and HCoEpiC cells were detected by indirect immunofluorescence and Western blotting. Sixty-two paraffin-embedded surgical specimens of colorectal cancer tissue and adjacent tissues were examined for Rictor expression using immunohistochemistry. The association of the expression levels of Rictor protein with the clinicopathologic features and the overall survival of the patients was analyzed. The expression level of Rictor was significantly higher in colorectal cancer tissues than in the adjacent tissues (P<0.05). The expression levels of Rictor and mTOR in the colon cancer cell lines were higher than those in human normal colon epithelial cell line HCoEpiC. The expression of Rictor was correlated with Dukes stage and lymphatic metastasis of the tumors but not with other clinicopathological parameter (P>0.05). Patients with Rictor expression had a lower overall survival rate than those without Rictor expression. Rictor overexpression is associated with the carcinogenesis and progression of colorectal cancer and can be an independent indicator for evaluating the prognosis of colorectal cancer patients.

CD34(+) fibrocytes in normal cervical stroma, cervical intraepithelial neoplasia III, and invasive squamous cell carcinoma of the cervix uteri.

PubMed

Barth, Peter J; Ramaswamy, Annette; Moll, Roland

2002-12-01

CD34(+) fibrocytes are widely distributed in normal connective tissues but have been reported to be absent within the stroma associated with invasive carcinomas. In the present study we investigated the presence and distribution of CD34(+) fibrocytes and alpha-smooth muscle actin (alpha-SMA) positive myofibroblasts in cervical intraepithelial neoplasia III (CIN III; n=8), invasive carcinoma of the cervix ( n=18) and adjacent normal cervical stroma. Normal cervical stroma and the stroma adjacent to CIN III disclosed a dense network of CD34(+) fibrocytes, whereas the stroma of invasive carcinoma was virtually free of this cell population. Early stromal invasion by squamous carcinoma was characterized by a focal loss of CD34(+) fibrocytes. alpha-SMA-positive myofibroblasts were not seen in the normal cervical stroma but occurred in six of eight cases of CIN III adjacent to the atypical epithelium. The stroma of invasive carcinoma was made up of large amounts of haphazardly arranged alpha-SMA-positive myofibroblasts. In the setting of the present study, a loss of CD34(+) fibrocytes was specific for stromal alterations associated with invasive carcinoma and proved to be a sensitive tool in detecting small foci of stromal invasion. Therefore, detection of a loss of CD34(+) fibrocytes may constitute an adjunctive tool in detecting (1) early stromal invasion and (2) invasive carcinoma in small biopsy specimens. Moreover, the present study shows that CD34(+) fibrocytes and myofibroblasts play an important role in stromal remodeling associated with invasive squamous cell carcinoma of the cervix.

High expression of AFAP1-AS1 is associated with poor survival and short-term recurrence in pancreatic ductal adenocarcinoma.

PubMed

Ye, Yibiao; Chen, Jie; Zhou, Yu; Fu, Zhiqiang; Zhou, Quanbo; Wang, YingXue; Gao, Wenchao; Zheng, ShangYou; Zhao, Xiaohui; Chen, Tao; Chen, Rufu

2015-04-30

Pancreatic ductal adenocarcinoma (PDAC) is still a lethal malignancy. Long noncoding RNAs (lncRNAs) have been shown to play a critical role in cancer development and progression. Here we identified overexpression of the lncRNA AFAP1-AS1 in PDAC patients and evaluated its prognostic and functional relevance. The global lncRNA expression profile in PDAC was measured by lncRNA microarray. Expression of AFAP1-AS1 was evaluated by reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR) in 90 PDAC tissue samples and adjacent normal tissues. The impact of AFAP1-AS1 expression on cell proliferation, migration, and invasion were evaluated in vitro using knockdown and ectopic expression strategies. Microarray analysis revealed that up-regulation of AFAP1-AS1 expression in PDAC tissues compared with normal adjacent tissues, which was confirmed by RT-qPCR in 69/90 cases (76.7%). Its overexpression was associated with lymph node metastasis, perineural invasion, and poor survival. When using AFAP1-AS1 as a prognostic marker, the areas under ROC curves were 0.8669 and 0.9370 for predicting tumor progression within 6 months and 1 year, respectively. In vitro functional experiments involving knockdown of AFAP1-AS1 resulted in attenuated PDAC cell proliferation, migration, and invasion. Ectopic expression of AFAP1-AS1 promoted cell proliferation, migration, and invasion. AFAP1-AS1 is a potential novel prognostic marker to predict the clinical outcome of PDAC patients after surgery and may be a rational target for therapy.

Peroxiredoxin 1 is a tumor-associated antigen in esophageal squamous cell carcinoma

PubMed Central

REN, PENGFEI; YE, HUA; DAI, LIPING; LIU, MEI; LIU, XINXIN; CHAI, YURONG; SHAO, QING; LI, YANG; LEI, NINGJING; PENG, BO; YAO, WU; ZHANG, JIANYING

2013-01-01

Peroxiredoxin 1 (Prdx1) is an antioxidant and plays an important role in H2O2-mediated cell signaling. We previously found that the expression level of Prdx1 was elevated in esophagus squamous cell carcinoma (ESCC) tissue using a proteomics approach. Since overexpressed protein can induce an autoimmune response, to further examine whether serum from ESCC patients exhibits immunoreactivity against Prdx1, autoantibody responses to Prdx1 were evaluated by ELISA, western blotting and indirect immunofluorescence assay in sera from patients with ESCC and normal individuals. Immunohistochemical study with tissue array slides and western blot analysis with cancer cell lines were also performed to analyze the protein expression profiles of Prdx1 in ESCC tissues and cancer cell lines. The results demonstrated that the positive rate of autoantibody against Prdx1 in ESCC sera was 13.2% (9/68), whereas this rate was 0% (0/89) in normal individuals. Data also showed that expression of Prdx1 was significantly increased in ESCC tissues when compared to expression in paired adjacent normal tissues (P<0.05). The data indicate that Prdx1 may contribute to malignant transformation of the esophagus, and may be used as a biomarker in the immunodiagnosis of ESCC. PMID:24009050

CT/FMT dual-model imaging of breast cancer based on peptide-lipid nanoparticles

NASA Astrophysics Data System (ADS)

Xu, Guoqiang; Lin, Qiaoya; Lian, Lichao; Qian, Yuan; Lu, Lisen; Zhang, Zhihong

2016-03-01

Breast cancer is one of the most harmful cancers in human. Its early diagnosis is expected to improve the patients' survival rate. X-ray computed tomography (CT) has been widely used in tumor detection for obtaining three-dimentional information. Fluorescence Molecular Tomography (FMT) imaging combined with near-infrared fluorescent dyes provides a powerful tool for the acquisition of molecular biodistribution information in deep tissues. Thus, the combination of CT and FMT imaging modalities allows us to better differentiate diseased tissues from normal tissues. Here we developed a tumor-targeting nanoparticle for dual-modality imaging based on a biocompatible HDL-mimicking peptide-phospholipid scaffold (HPPS) nanocarrier. By incorporation of CT contrast agents (iodinated oil) and far-infrared fluorescent dyes (DiR-BOA) into the hydrophobic core of HPPS, we obtained the FMT and CT signals simultaneously. Increased accumulation of the nanoparticles in the tumor lesions was achieved through the effect of the tumor-targeting peptide on the surface of nanoparticle. It resulted in excellent contrast between lesions and normal tissues. Together, the abilities to sensitively separate the lesions from adjacent normal tissues with the aid of a FMT/CT dual-model imaging approach make the targeting nanoparticles a useful tool for the diagnostics of breast cancer.

Investigation of metabolite changes in the transition from pre-invasive to invasive cervical cancer measured using (1)H and (31)P magic angle spinning MRS of intact tissue.

PubMed

De Silva, Sonali S; Payne, Geoffrey S; Thomas, Valerie; Carter, Paul G; Ind, Thomas E J; deSouza, Nandita M

2009-02-01

The aim of this study was to determine the metabolic changes in the transition from pre-invasive to invasive cervical cancer using high-resolution magic angle spinning (HR-MAS) MRS. Biopsy specimens were obtained from women with histologically normal cervix (n = 5), cervical intraepithelial neoplasia (CIN; mild, n = 5; moderate/severe, n = 40), and invasive cancer (n = 23). (1)H HR-MAS MRS data were acquired using a Bruker Avance 11.74 T spectrometer (Carr-Purcell-Meiboom-Gill sequence; TR = 4.8 s; TE = 135 ms; 512 scans; 41 min acquisition). (31)P HR-MAS spectra were obtained from the normal subjects and cancer patients only (as acetic acid applied before tissue sampling in patients with CIN impaired spectral quality) using a (1)H-decoupled pulse-acquire sequence (TR = 2.82 s; 2048 scans; 96 min acquisition). Peak assignments were based on values reported in the literature. Peak areas were measured using the AMARES algorithm. Estimated metabolite concentrations were compared between patient diagnostic categories and tissue histology using independent samples t tests. Comparisons based on patient category at diagnosis showed significantly higher estimated concentrations of choline (P = 0.0001) and phosphocholine (P = 0.002) in tissue from patients with cancer than from patients with high-grade dyskaryosis, but no differences between non-cancer groups. Division by histology of the sample also showed increases in choline (P = 0.002) and phosphocholine (P = 0.002) in cancer compared with high-grade CIN tissue. Phosphoethanolamine was increased in cancer compared with normal tissue (P = 0.0001). Estimated concentrations of alanine (P = 0.01) and creatine (P = 0.008) were significantly reduced in normal tissue from cancer patients compared with normal tissue from non-cancer patients. The estimated concentration of choline was significantly increased in CIN tissue from cancer patients compared with CIN tissue from non-cancer patients (P = 0.0001). Estimated concentrations of choline-containing metabolites increased from pre-invasive to invasive cervical cancer. Concurrent metabolite depletion occurs in normal tissue adjacent to cancer tissue. Copyright (c) 2008 John Wiley & Sons, Ltd.

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

PubMed Central

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

2015-01-01

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

Characterization of human breast cancer tissues by infrared imaging.

PubMed

Verdonck, M; Denayer, A; Delvaux, B; Garaud, S; De Wind, R; Desmedt, C; Sotiriou, C; Willard-Gallo, K; Goormaghtigh, E

2016-01-21

Fourier Transform InfraRed (FTIR) spectroscopy coupled to microscopy (IR imaging) has shown unique advantages in detecting morphological and molecular pathologic alterations in biological tissues. The aim of this study was to evaluate the potential of IR imaging as a diagnostic tool to identify characteristics of breast epithelial cells and the stroma. In this study a total of 19 breast tissue samples were obtained from 13 patients. For 6 of the patients, we also obtained Non-Adjacent Non-Tumor tissue samples. Infrared images were recorded on the main cell/tissue types identified in all breast tissue samples. Unsupervised Principal Component Analyses and supervised Partial Least Square Discriminant Analyses (PLS-DA) were used to discriminate spectra. Leave-one-out cross-validation was used to evaluate the performance of PLS-DA models. Our results show that IR imaging coupled with PLS-DA can efficiently identify the main cell types present in FFPE breast tissue sections, i.e. epithelial cells, lymphocytes, connective tissue, vascular tissue and erythrocytes. A second PLS-DA model could distinguish normal and tumor breast epithelial cells in the breast tissue sections. A patient-specific model reached particularly high sensitivity, specificity and MCC rates. Finally, we showed that the stroma located close or at distance from the tumor exhibits distinct spectral characteristics. In conclusion FTIR imaging combined with computational algorithms could be an accurate, rapid and objective tool to identify/quantify breast epithelial cells and differentiate tumor from normal breast tissue as well as normal from tumor-associated stroma, paving the way to the establishment of a potential complementary tool to ensure safe tumor margins.

Comprehensive analyses of imprinted differentially methylated regions reveal epigenetic and genetic characteristics in hepatoblastoma

PubMed Central

2013-01-01

Background Aberrant methylation at imprinted differentially methylated regions (DMRs) in human 11p15.5 has been reported in many tumors including hepatoblastoma. However, the methylation status of imprinted DMRs in imprinted loci scattered through the human genome has not been analyzed yet in any tumors. Methods The methylation statuses of 33 imprinted DMRs were analyzed in 12 hepatoblastomas and adjacent normal liver tissue by MALDI-TOF MS and pyrosequencing. Uniparental disomy (UPD) and copy number abnormalities were investigated with DNA polymorphisms. Results Among 33 DMRs analyzed, 18 showed aberrant methylation in at least 1 tumor. There was large deviation in the incidence of aberrant methylation among the DMRs. KvDMR1 and IGF2-DMR0 were the most frequently hypomethylated DMRs. INPP5Fv2-DMR and RB1-DMR were hypermethylated with high frequencies. Hypomethylation was observed at certain DMRs not only in tumors but also in a small number of adjacent histologically normal liver tissue, whereas hypermethylation was observed only in tumor samples. The methylation levels of long interspersed nuclear element-1 (LINE-1) did not show large differences between tumor tissue and normal liver controls. Chromosomal abnormalities were also found in some tumors. 11p15.5 and 20q13.3 loci showed the frequent occurrence of both genetic and epigenetic alterations. Conclusions Our analyses revealed tumor-specific aberrant hypermethylation at some imprinted DMRs in 12 hepatoblastomas with additional suggestion for the possibility of hypomethylation prior to tumor development. Some loci showed both genetic and epigenetic alterations with high frequencies. These findings will aid in understanding the development of hepatoblastoma. PMID:24373183

Gene Expression Profiling of Multiple Leiomyomata Uteri and Matched Normal Tissue from a Single Patient

PubMed Central

Dimitrova, Irina K.; Richer, Jennifer K.; Rudolph, Michael C.; Spoelstra, Nicole S.; Reno, Elaine M.; Medina, Theresa M.; Bradford, Andrew P.

2009-01-01

Objective To identify differentially expressed genes between fibroid and adjacent normal myometrium in an identical hormonal and genetic background. Design Array analysis of 3 leiomyomata and matched adjacent normal myometrium in a single patient. Setting University of Colorado Hospital. Patient(s) A single female undergoing medically indicated hysterectomy for symptomatic fibroids. Interventions(s) mRNA isolation and microarray analysis, reverse-transcriptase polymerase chain reaction, western blotting and immunohistochemistry. Main Outcome Measure(s) Changes in mRNA and protein levels in leiomyomata and matched normal myometrium. Result(s) Expression of 197 genes was increased and 619 decreased, significantly by at least 2 fold, in leiomyomata relative to normal myometrium. Expression profiles between tumors were similar and normal myometrial samples showed minimal variation. Changes in, and variation of, expression of selected genes were confirmed in additional normal and leiomyoma samples from multiple patients. Conclusion(s) Analysis of multiple tumors from a single patient confirmed changes in expression of genes described in previous, apparently disparate, studies and identified novel targets. Gene expression profiles in leiomyomata are consistent with increased activation of mitogenic pathways and inhibition of apoptosis. Down-regulation of genes implicated in invasion and metastasis, of cancers, was observed in fibroids. This expression pattern may underlie the benign nature of uterine leiomyomata and may aid in the differential diagnosis of leiomyosarcoma. PMID:18672237

Compound Astragalus and Salvia miltiorrhiza extracts suppress hepatocarcinogenesis by modulating transforming growth factor-β/Smad signaling.

PubMed

Hu, Xiangpeng; Rui, Wenjuan; Wu, Chao; He, Shufang; Jiang, Jiemei; Zhang, Xiaoxiang; Yang, Yan

2014-06-01

Previous studies showed Compound Astragalus and Salvia miltiorrhiza extract (CASE), extract from Astragalus membranaceus and Salvia miltiorhiza, significantly suppresses hepatocellular carcinoma (HCC) in rats induced by diethylinitrosamine (DEN), and in vitro experiments further demonstrated that CASE's anti-HepG2 cell invasion is associated with transforming growth factor-β (TGF-β). We hypothesized that CASE's suppression of HCC is modulated by TGF-β/Smad signaling, and we conducted this in vivo study to test this hypothesis. Rats were divided into the normal control, the DEN group, and three CASE (60, 120, and 240 mg/kg) treatment groups. The expression of phosphorylation(p) Smad both at C-terminal and linker region, plasminogen activator inhibitor 1, and Smad4 and Smad7 of liver tissues were measured and compared across the five groups. The positive staining of pSmad2L and pSmad3L increased both in hepatoma nodule areas and adjacent relatively normal liver tissues in rats treated with DEN, while the positive staining of pSmad2C and pSmad3C increased only in relatively normal liver tissues adjacent to hepatoma tissues. The elevated expression of pSmad2C, pSmad2L, pSmad3L, Smad4, and plasminogen activator inhibitor 1 proteins were suppressed by CASE in a dose-dependent manner. CASE treatment also significantly reduced the intranuclear amounts of pSmad2L and pSmad3L, and upregulated the elevation of pSmad3C positive cells and protein expression in a dose-dependent manner. The results suggest that CASE significantly suppresses HCC progression by mediating TGF-β/Smad signaling, especially by modulating Smad3 phosphorylation both at the C-terminal and linker region. © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

Pulmonary tumorlets with surrounding fibrous tissue--suspected carcinoma: case report and review of the literature.

PubMed

Alerić, Ivan; Mosler, Domagoj; Seiwerth, Sven; Polić, Ines Mlinarević; Mosler, Elvira Lazić

2014-06-01

Pulmonary tumorlets are small, often multiple nodular proliferations of pulmonary neuroendocrine cells. They are common incidental findings in chronic inflammatory pulmonary diseases. They can also be found in normal lung parenchyma and as one part of the continuum known as diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. In many cases, they are incidental histologic findings of no importance or clinical consequences, or they can be associated with a very slow progression of either obstructive or mixed obstructive/restrictive impairment with good prognosis. Only rarely, they metastasize to an adjacent lymph node or produce ectopic neuroendocrine products. When found during diagnostic examination, they represent a doubt to be a malignant tumor until proven otherwise, which is often impossible without biopsy or surgical removal of the adjacent lung lobe. Hereby, we present a patient with a persistent nodular lung structure after being treated for nonspecific symptoms, cough with non purulent sputum and pain among the scapulae, for a period of one month. He had otherwise normal clinical and laboratory findings, except for a mild mixed obstructive/restrictive pattern of impairment that was shown by lung spirometry. After 8 months, he underwent lobectomy of the medial lobe of the lung with partial lymphadenectomy, since the diagnostic methods applied could not define the nature of lung nodular infiltration. Histologic examination showed a few tumorlets surrounded by the fibrous tissue with a very dense lymphocyte infiltration. We present a review of the literature and emphasize the necessity to include tumorlets with adjacent fibrosis as part of the differential diagnosis of a solitary nodular lung structure.

Molecular Markers in Patients with Chronic Wounds to Guide Surgical Debridement

PubMed Central

Brem, Harold; Stojadinovic, Olivera; Diegelmann, Robert F; Entero, Hyacinth; Lee, Brian; Pastar, Irena; Golinko, Michael; Rosenberg, Harvey; Tomic-Canic, Marjana

2007-01-01

Chronic wounds, such as venous ulcers, are characterized by physiological impairments manifested by delays in healing, resulting in severe morbidity. Surgical debridement is routinely performed on chronic wounds because it stimulates healing. However, procedures are repeated many times on the same patient because, in contrast to tumor excision, there are no objective biological/molecular markers to guide the extent of debridement. To develop bioassays that can potentially guide surgical debridement, we assessed the pathogenesis of the patients’ wound tissue before and after wound debridement. We obtained biopsies from three patients at two locations, the nonhealing edge (prior to debridement) and the adjacent, nonulcerated skin of the venous ulcers (post debridement), and evaluated their histology, biological response to wounding (migration) and gene expression profile. We found that biopsies from the nonhealing edges exhibit distinct pathogenic morphology (hyperproliferative/hyperkeratotic epidermis; dermal fibrosis; increased procollagen synthesis). Fibroblasts deriving from this location exhibit impaired migration in comparison to the cells from adjacent nonulcerated biopsies, which exhibit normalization of morphology and normal migration capacity. The nonhealing edges have a specific, identifiable, and reproducible gene expression profile. The adjacent nonulcerated biopsies have their own distinctive reproducible gene expression profile, signifying that particular wound areas can be identified by gene expression profiling. We conclude that chronic ulcers contain distinct subpopulations of cells with different capacity to heal and that gene expression profiling can be utilized to identify them. In the future, molecular markers will be developed to identify the nonimpaired tissue, thereby making surgical debridement more accurate and more efficacious. PMID:17515955

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

Downregulation of SASH1 correlates with tumor progression and poor prognosis in ovarian carcinoma.

PubMed

Ren, Xiaoyan; Liu, Yifei; Tao, Yumei; Zhu, Guoxiang; Pei, Meilan; Zhang, Jianguo; Liu, Jian

2016-05-01

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.

Clinicopathological significance of c-MYC in esophageal squamous cell carcinoma.

PubMed

Lian, Yu; Niu, Xiangdong; Cai, Hui; Yang, Xiaojun; Ma, Haizhong; Ma, Shixun; Zhang, Yupeng; Chen, Yifeng

2017-07-01

Esophageal squamous cell carcinoma is one of the most common malignant tumors. The oncogene c-MYC is thought to be important in the initiation, promotion, and therapy resistance of cancer. In this study, we aim to investigate the clinicopathologic roles of c-MYC in esophageal squamous cell carcinoma tissue. This study is aimed at discovering and analyzing c-MYC expression in a series of human esophageal tissues. A total of 95 esophageal squamous cell carcinoma samples were analyzed by the western blotting and immunohistochemistry techniques. Then, correlation of c-MYC expression with clinicopathological features of esophageal squamous cell carcinoma patients was statistically analyzed. In most esophageal squamous cell carcinoma cases, the c-MYC expression was positive in tumor tissues. The positive rate of c-MYC expression in tumor tissues was 61.05%, obviously higher than the adjacent normal tissues (8.42%, 8/92) and atypical hyperplasia tissues (19.75%, 16/95). There was a statistical difference among adjacent normal tissues, atypical hyperplasia tissues, and tumor tissues. Overexpression of the c-MYC was detected in 61.05% (58/95) esophageal squamous cell carcinomas, which was significantly correlated with the degree of differentiation (p = 0.004). The positive rate of c-MYC expression was 40.0% in well-differentiated esophageal tissues, with a significantly statistical difference (p = 0.004). The positive rate of c-MYC was 41.5% in T1 + T2 esophageal tissues and 74.1% in T3 + T4 esophageal tissues, with a significantly statistical difference (p = 0.001). The positive rate of c-MYC was 45.0% in I + II esophageal tissues and 72.2% in III + IV esophageal tissues, with a significantly statistical difference (p = 0.011). The c-MYC expression strongly correlated with clinical staging (p = 0.011), differentiation degree (p = 0.004), lymph node metastasis (p = 0.003), and invasion depth (p = 0.001) of patients with esophageal squamous cell carcinoma. The c-MYC was differentially expressed in a series of human esophageal tissues, and the aberrant c-MYC expression could be a potential factor in carcinogenesis and progression of esophageal squamous cell carcinoma. There was a statistical signification for c-MYC in esophageal squamous cell carcinoma patients to analyze clinicopathological features. It possibly becomes a new diagnostic indicator of esophageal squamous cell carcinoma.

An Integrated Analysis of miRNA and mRNA Expressions in Non-Small Cell Lung Cancers

PubMed Central

Ma, Lina; Huang, Yanyan; Zhu, Wangyu; Zhou, Shiquan; Zhou, Jihang; Zeng, Fang; Liu, Xiaoguang; Zhang, Yongkui; Yu, Jun

2011-01-01

Using DNA microarrays, we generated both mRNA and miRNA expression data from 6 non-small cell lung cancer (NSCLC) tissues and their matching normal control from adjacent tissues to identify potential miRNA markers for diagnostics. We demonstrated that hsa-miR-96 is significantly and consistently up-regulated in all 6 NSCLCs. We validated this result in an independent set of 35 paired tumors and their adjacent normal tissues, as well as their sera that are collected before surgical resection or chemotherapy, and the results suggested that hsa-miR-96 may play an important role in NSCLC development and has great potential to be used as a noninvasive marker for diagnosing NSCLC. We predicted potential miRNA target mRNAs based on different methods (TargetScan and miRanda). Further classification of miRNA regulated genes based on their relationship with miRNAs revealed that hsa-miR-96 and certain other miRNAs tend to down-regulate their target mRNAs in NSCLC development, which have expression levels permissive to direct interaction between miRNAs and their target mRNAs. In addition, we identified a significant correlation of miRNA regulation with genes coincide with high density of CpG islands, which suggests that miRNA may represent a primary regulatory mechanism governing basic cellular functions and cell differentiations, and such mechanism may be complementary to DNA methylation in repressing or activating gene expression. PMID:22046296

Differential expression of galectin-1 and galectin-3 in thyroid tumors. Potential diagnostic implications.

PubMed Central

Xu, X. C.; el-Naggar, A. K.; Lotan, R.

1995-01-01

Carcinoma of the thyroid gland, the most frequently diagnosed endocrine malignancy, is often associated with early regional metastases. With the exception of papillary carcinoma, distinguishing benign from malignant thyroid neoplasms in the absence of metastatic disease is difficult. Recently, the vertebrate lectins galectin-1 and galectin-3 have been implicated in the regulation of cellular growth, differentiation, and malignant transformation of a variety of tissues. To determine whether these galectins have a role in thyroid neoplasia, we analyzed 32 specimens from thyroid malignancies (16 papillary, 7 follicular, 8 medullary carcinomas, and 1 metastasis to lymph node), 10 benign thyroid adenomas, 1 nodular goiter, and 33 specimens from adjacent normal thyroid tissue for the expression of galectin-1 and galectin-3 with immunohistochemical and immunoblotting techniques utilizing anti-galectin antibodies. All thyroid malignancies of epithelial origin (ie, papillary and follicular carcinomas) and a metastatic lymph node from a papillary carcinoma expressed high levels of both galectin-1 and galectin-3. The medullary thyroid carcinomas, which are of parafollicular C cell origin, showed a weaker and variable expression of these galectins. In contrast, neither benign thyroid adenomas nor adjacent normal thyroid tissue expressed galectin-1 or galectin-3. These results suggest that galectin-1 and galectin-3 may be associated with malignant transformation of thyroid epithelium and may potentially serve as markers for distinguishing benign thyroid adenomas from differentiated thyroid carcinomas. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:7677193

Unique activation of matrix metalloproteinase-9 within human liver metastasis from colorectal cancer.

PubMed Central

Zeng, Z. S.; Guillem, J. G.

1998-01-01

Experimental in vitro and animal data support an important role for matrix metalloproteinases (MMPs) in cancer invasion and metastasis via proteolytic degradation of the extracellular matrix (ECM). Our previous data have shown that MMP-9 mRNA is localized to the interface between liver metastasis and normal liver tissue, indicating that MMP-9 may play an important role in liver metastasis formation. In the present study, we analysed the cellular enzymatic expression of MMP-9 in 18 human colorectal cancer (CRC) liver metastasis specimens by enzyme-linked immunosorbent assay (ELISA) and zymography. ELISA analysis reveals that the latent form of MMP-9 is present in both liver metastasis and paired adjacent normal liver tissue. The mean level of the latent form of MMP-9 is 580+/-270 ng per mg total tissue protein (mean+/-s.e.) in liver metastasis vs 220+/-90 in normal liver tissue. However, this difference is not significantly different (P = 0.26). Using gelatin zymography, the 92-kDa band representative of the latent form is present in both liver metastasis and normal liver tissue. However, the 82 kDa band, representative of the active form of MMP-9, was seen only in liver metastasis. This was confirmed by Western blot analysis. Our observation of the unique presence of the active form of MMP-9 within liver metastasis suggests that proMMP-9 activation may be a pivotal event during CRC liver metastasis formation. Images Figure 3 Figure 4 PMID:9703281

In1-ghrelin, a splice variant of ghrelin gene, is associated with the evolution and aggressiveness of human neuroendocrine tumors: Evidence from clinical, cellular and molecular parameters.

PubMed

Luque, Raul M; Sampedro-Nuñez, Miguel; Gahete, Manuel D; Ramos-Levi, Ana; Ibáñez-Costa, Alejandro; Rivero-Cortés, Esther; Serrano-Somavilla, Ana; Adrados, Magdalena; Culler, Michael D; Castaño, Justo P; Marazuela, Mónica

2015-08-14

Ghrelin system comprises a complex family of peptides, receptors (GHSRs), and modifying enzymes [e.g. ghrelin-O-acyl-transferase (GOAT)] that control multiple pathophysiological processes. Aberrant alternative splicing is an emerging cancer hallmark that generates altered proteins with tumorigenic capacity. Indeed, In1-ghrelin and truncated-GHSR1b splicing variants can promote development/progression of certain endocrine-related cancers. Here, we determined the expression levels of key ghrelin system components in neuroendocrine tumor (NETs) and explored their potential functional role. Twenty-six patients with NETs were prospectively/retrospectively studied [72 samples from primary and metastatic tissues (30 normal/42 tumors)] and clinical data were obtained. The role of In1-ghrelin in aggressiveness was studied in vitro using NET cell lines (BON-1/QGP-1). In1-ghrelin, GOAT and GHSR1a/1b expression levels were elevated in tumoral compared to normal/adjacent tissues. Moreover, In1-ghrelin, GOAT, and GHSR1b expression levels were positively correlated within tumoral, but not within normal/adjacent samples, and were higher in patients with progressive vs. with stable/cured disease. Finally, In1-ghrelin increased aggressiveness (e.g. proliferation/migration) of NET cells. Altogether, our data strongly suggests a potential implication of ghrelin system in the pathogenesis and/or clinical outcome of NETs, and warrant further studies on their possible value for the future development of molecular biomarkers with diagnostic/prognostic/therapeutic value.

In1-ghrelin, a splice variant of ghrelin gene, is associated with the evolution and aggressiveness of human neuroendocrine tumors: Evidence from clinical, cellular and molecular parameters

PubMed Central

Gahete, Manuel D.; Ramos-Levi, Ana; Ibáñez-Costa, Alejandro; Rivero-Cortés, Esther; Serrano-Somavilla, Ana; Adrados, Magdalena; Culler, Michael D.; Castaño, Justo P.; Marazuela, Mónica

2015-01-01

Ghrelin system comprises a complex family of peptides, receptors (GHSRs), and modifying enzymes [e.g. ghrelin-O-acyl-transferase (GOAT)] that control multiple pathophysiological processes. Aberrant alternative splicing is an emerging cancer hallmark that generates altered proteins with tumorigenic capacity. Indeed, In1-ghrelin and truncated-GHSR1b splicing variants can promote development/progression of certain endocrine-related cancers. Here, we determined the expression levels of key ghrelin system components in neuroendocrine tumor (NETs) and explored their potential functional role. Twenty-six patients with NETs were prospectively/retrospectively studied [72 samples from primary and metastatic tissues (30 normal/42 tumors)] and clinical data were obtained. The role of In1-ghrelin in aggressiveness was studied in vitro using NET cell lines (BON-1/QGP-1). In1-ghrelin, GOAT and GHSR1a/1b expression levels were elevated in tumoral compared to normal/adjacent tissues. Moreover, In1-ghrelin, GOAT, and GHSR1b expression levels were positively correlated within tumoral, but not within normal/adjacent samples, and were higher in patients with progressive vs. with stable/cured disease. Finally, In1-ghrelin increased aggressiveness (e.g. proliferation/migration) of NET cells. Altogether, our data strongly suggests a potential implication of ghrelin system in the pathogenesis and/or clinical outcome of NETs, and warrant further studies on their possible value for the future development of molecular biomarkers with diagnostic/prognostic/therapeutic value. PMID:26124083

The Morphology of Smoke Inhalation Injury in Sheep,

DTIC Science & Technology

1991-01-01

exposure. Segments of intact epithelium (E) areethane. The specimens were dried by the critical point method adjacent to necrotic areas ( N ). The tracheal...magnification: X325. essentially normal lung ( N ). Original magnification: x125. 1484 The Journal of Trauma November 1991 The extent and severity of the injury...obstruction by desqapate netic endofronclia n tise acuand esulant ypoxa.’by desquamated necrotic endobronchial tissue. Accu- and resultant hypoxia.5 mulation

Comparison of non-Gaussian and Gaussian diffusion models of diffusion weighted imaging of rectal cancer at 3.0 T MRI.

PubMed

Zhang, Guangwen; Wang, Shuangshuang; Wen, Didi; Zhang, Jing; Wei, Xiaocheng; Ma, Wanling; Zhao, Weiwei; Wang, Mian; Wu, Guosheng; Zhang, Jinsong

2016-12-09

Water molecular diffusion in vivo tissue is much more complicated. We aimed to compare non-Gaussian diffusion models of diffusion-weighted imaging (DWI) including intra-voxel incoherent motion (IVIM), stretched-exponential model (SEM) and Gaussian diffusion model at 3.0 T MRI in patients with rectal cancer, and to determine the optimal model for investigating the water diffusion properties and characterization of rectal carcinoma. Fifty-nine consecutive patients with pathologically confirmed rectal adenocarcinoma underwent DWI with 16 b-values at a 3.0 T MRI system. DWI signals were fitted to the mono-exponential and non-Gaussian diffusion models (IVIM-mono, IVIM-bi and SEM) on primary tumor and adjacent normal rectal tissue. Parameters of standard apparent diffusion coefficient (ADC), slow- and fast-ADC, fraction of fast ADC (f), α value and distributed diffusion coefficient (DDC) were generated and compared between the tumor and normal tissues. The SEM exhibited the best fitting results of actual DWI signal in rectal cancer and the normal rectal wall (R 2  = 0.998, 0.999 respectively). The DDC achieved relatively high area under the curve (AUC = 0.980) in differentiating tumor from normal rectal wall. Non-Gaussian diffusion models could assess tissue properties more accurately than the ADC derived Gaussian diffusion model. SEM may be used as a potential optimal model for characterization of rectal cancer.

Potential involvement of leptin in carcinogenesis of hepatocellular carcinoma.

PubMed

Wang, Xiu-Jie; Yuan, Shu-Lan; Lu, Qing; Lu, Yan-Rong; Zhang, Jie; Liu, Yan; Wang, Wen-Dong

2004-09-01

To investigate the potential involvement of leptin in carcinogenesis of hepatocellular carcinoma (HCC) and to elucidate the etiology, carcinogenesis and progress of HCC. Expressions of Ob gene product, leptin and its receptor, Ob-R were investigated in 36 cases of HCC specimens and corresponding adjacent non-tumorous liver tissues with immunohistochemical staining. The effect of leptin on proliferation of Chang liver cell line and liver cancer cell line SMMC-7721 was studied with cell proliferation assay (MTT). Leptin expression was detected in 36 cases of adjacent non-tumorous liver tissues (36/36, 100%) with moderate (++) to strong (+++) intensity; and in 72.22%(26/36) of HCC with weaker (+) intensity (P<0.05). Thirty of 36 (83.33%) cases of adjacent non-tumorous liver tissues were positive for Ob-R, with moderate (++) to strong (+++) intensity. In HCC, 11/36 (30.56%) cases were positive, with weak (+) intensity (P<0.05). In cell proliferation assay, leptin inhibited the proliferation of Chang liver cells. The cell survival rate was 10-13% lower than that of the untreated cells (P>0.05). Leptin had little effect on the proliferation of liver cancer cells (P>0.05). High level expression and decreased or absent expression of leptin and its receptor in adjacent non-tumorous liver cells and HCC cells, inhibitory effect of leptin on the proliferation of normal Chang liver cells and no effect of leptin on proliferation of liver cancer cells, may provide new insights into the carcinogenesis and progression of human HCC. It could be assumed that leptin acting as an inhibitor and/or promoter, is involved in the process of carcinogenesis and progress of human HCC. Copyright 2004 The WJG Press ISSN

Stomatin-like protein 2 is overexpressed in epithelial ovarian cancer and predicts poor patient survival.

PubMed

Sun, Fei; Ding, Wen; He, Jie-Hua; Wang, Xiao-Jing; Ma, Ze-Biao; Li, Yan-Fang

2015-10-20

Stomatin-like protein 2 (SLP-2, also known as STOML2) is a stomatin homologue of uncertain function. SLP-2 overexpression has been suggested to be associated with cancer progression, resulting in adverse clinical outcomes in patients. Our study aim to investigate SLP-2 expression in epithelial ovarian cancer cells and its correlation with patient survival. SLP-2 mRNA and protein expression levels were analysed in five epithelial ovarian cancer cell lines and normal ovarian epithelial cells using real-time PCR and western blotting analysis. SLP-2 expression was investigated in eight matched-pair samples of epithelial ovarian cancer and adjacent noncancerous tissues from the same patients. Using immunohistochemistry, we examined the protein expression of paraffin-embedded specimens from 140 patients with epithelial ovarian cancer, 20 cases with borderline ovarian tumours, 20 cases with benign ovarian tumours, and 20 cases with normal ovarian tissues. Statistical analyses were applied to evaluate the clinicopathological significance of SLP-2 expression. SLP-2 mRNA and protein expression levels were significantly up-regulated in epithelial ovarian cancer cell lines and cancer tissues compared with normal ovarian epithelial cells and adjacent noncancerous ovarian tissues. Immunohistochemistry analysis revealed that the relative overexpression of SLP-2 was detected in 73.6 % (103/140) of the epithelial ovarian cancer specimens, 45.0 % (9/20) of the borderline ovarian specimens, 30.0 % (6/20) of the benign ovarian specimens and none of the normal ovarian specimens. SLP-2 protein expression in epithelial ovarian cancer was significantly correlated with the tumour stage (P < 0.001). Epithelial ovarian cancer patients with higher SLP-2 protein expression levels had shorter progress free survival and overall survival times compared to patients with lower SLP-2 protein expression levels. Multivariate analyses showed that SLP-2 expression levels were an independent prognostic factor for survival in epithelial ovarian cancer patients. SLP-2 mRNA and proteins were overexpressed in epithelial ovarian cancer tissues. SLP-2 protein overexpression was associated with advanced stage disease. Patients with higher SLP-2 protein expression had shorter progress free survival and poor overall survival times. Thus, SLP-2 protein expression was an independent prognostic factor for patients with epithelial ovarian cancer.

Microscopic fluorescence spectral analysis of basal cell carcinomas

NASA Astrophysics Data System (ADS)

He, Qingli; Lui, Harvey; Zloty, David; Cowan, Bryce; Warshawski, Larry; McLean, David I.; Zeng, Haishan

2007-05-01

Background and Objectives. Laser-induced autofluorescence (LIAF) is a promising tool for cancer diagnosis. This method is based on the differences in autofluorescence spectra between normal and cancerous tissues, but the underlined mechanisms are not well understood. The objective of this research is to study the microscopic origins and intrinsic fluorescence properties of basal cell carcinoma (BCC) for better understanding of the mechanism of in vivo fluorescence detection and margin delineation of BCCs on skin patients. A home-made micro- spectrophotometer (MSP) system was used to image the fluorophore distribution and to measure the fluorescence spectra of various microscopic structures and regions on frozen tissue sections. Materials and Methods. BCC tissue samples were obtained from 14 patients undergoing surgical resections. After surgical removal, each tissue sample was immediately embedded in OCT medium and snap-frozen in liquid nitrogen. The frozen tissue block was then cut into 16-μm thickness sections using a cryostat microtome and placed on microscopic glass slides. The sections for fluorescence study were kept unstained and unfixed, and then analyzed by the MSP system. The adjacent tissue sections were H&E stained for histopathological examination and also served to help identify various microstructures on the adjacent unstained sections. The MSP system has all the functions of a conventional microscope, plus the ability of performing spectral analysis on selected micro-areas of a microscopic sample. For tissue fluorescence analysis, 442nm He-Cd laser light is used to illuminate and excite the unstained tissue sections. A 473-nm long pass filter was inserted behind the microscope objective to block the transmitted laser light while passing longer wavelength fluorescence signal. The fluorescence image of the sample can be viewed through the eyepieces and also recorded by a CCD camera. An optical fiber is mounted onto the image plane of the photograph port of the microscope to collect light from a specific micro area of the sample. The collected light is transmitted via the fiber to a disperserve type CCD spectrometer for spectral analysis. Results. The measurement results showed significant spectral differences between normal and cancerous tissues. For normal tissue regions, the spectral results agreed with our previous findings on autofluorescence of normal skin sections. For the cancerous regions, the epidermis showed very weak fluorescence signal, while the stratum corneum exhibited fluorescence emissions peaking at about 510 nm. In the dermis, the basal cell island and a band of surrounding areas showed very weak fluorescence signal, while distal dermis above and below the basal cell island showed greater fluorescence signal but with different spectral shapes. The very weak autofluorescence from the basal cell island and its surrounding area may be attributed to their degenerative properties that limited the production of collagens. Conclusions. The obtained microscopic results very well explain the in vivo fluorescence properties of BCC lesions in that they have decreased fluorescence intensity compared to the surrounding normal skin. The intrinsic spectra of various microstructures and the microscopic fluorescence images (corresponding fluorophore distribution in tissue) obtained in this study will be used for further theoretical modeling of in vivo fluorescence spectroscopy and imaging of skin cancers.

MicroRNA-361-5p Inhibits Cancer Cell Growth by Targeting CXCR6 in Hepatocellular Carcinoma.

PubMed

Sun, Jian-Jun; Chen, Guo-Yong; Xie, Zhan-Tao

2016-01-01

A growing body of evidence supports the notion that MicroRNAs (miRNAs) function as key regulators of tumorigenesis. In the present study, the expression and roles of miRNA-361-5p were explored in hepatocellular carcinoma (HCC). Quantitative real-time PCR was used to detect the expression miR-361-5p in HCC tissues and pair-matched adjacent normal tissues. MTT and BrdU assays were used to identify the role of miR-361-5p in the regulation of proliferation and invasion of HCC cells. Using bioinformatics analysis, luciferase reporter assays and Western blots were used to identify the molecular target of miR-361-5p. nude mice were used to detect the anti-tumor role of miR-361-5p in vivo. miR-361-5p was down-regulated in HCC tissues in comparison to adjacent normal tissues, due to hypermethylation at its promoter region. Overexpression of miR-361-5p suppressed proliferation and invasion of HCC cells. Chemokine (C-X-C Motif) receptor 6 (CXCR6) was identified as a target of miR-361-5p. Indeed, knockdown of CXCR6 photocopied, while overexpression of CXCR6 largely attenuated the anti-proliferative effect of miR-361-5p. More importantly, in vivo studies demonstrated that forced expression of miR-361-5p significantly inhibited tumor growth in the nude mice. Our results indicate that miR-361-5p acts as a tumor suppressor and might serve as a novel therapeutic target for the treatment of HCC patients. © 2016 The Author(s) Published by S. Karger AG, Basel.

GAS5 modulated autophagy is a mechanism modulating cisplatin sensitivity in NSCLC cells.

PubMed

Zhang, N; Yang, G-Q; Shao, X-M; Wei, L

2016-06-01

In this study, we investigated the association between lncRNA GAS5 and cisplatin (DDP) resistance in NSCLC and further studied the regulative effect of GAS5 on autophagy and DDP resistance. GAS5 expression in cancerous and adjacent normal tissues from 15 NSCLC patients received neoadjuvant chemotherapy and the following surgery were measured using qRT-PCR analysis. GAS5 gain-and-loss study was performed using A549 and A549/DDP cells as an in-vitro model to investigate the effect of GAS5 on autophagy and cisplatin sensitivity. NSCLC tissues had a substantially lower expression of GAS5 than adjacent normal tissues. The NSCLC tissues from patients with progressive disease (PD) had even lower GAS5 expression. GAS5 knockdown increased DDP IC50 of A549 cells, while GAS5 overexpression decreased DDP IC50 of A549/DDP cells. A549/DDP cells had significantly higher basal autophagy than A549 cells. GAS5 knockdown resulted in decreased autophagy in A549 cells, while GAS5 overexpression led to increased autophagy in A549/DDP cells. Treatment with 3-MA, an autophagy inhibitor, significantly decreased DDP IC50 and promoted DDP-induced cell apoptosis in A549 cells. In addition, 3-MA also partly reversed the effect of GAS5 knockdown. In A549/DDP cells, GAS5 showed the similar effect as 3-MA in reducing DPP IC50 and promoting DDP-induced apoptosis and also presented synergic effect with 3-MA. GAS5 downregulation is associated with cisplatin resistance in NSCLC. GAS5 can inhibit autophagy and therefore enhance cisplatin sensitivity in NSCLC cells.

Cancer testis antigen OY-TES-1: analysis of protein expression in ovarian cancer with tissue microarrays.

PubMed

Fan, R; Huang, W; Luo, B; Zhang, Q M; Xiao, S W; Xie, X X

2015-01-01

Revised manuscript accepted for publication March 5, Objectives: The purpose of this study was to determine the potential of cancer testis antigen OY-TES-1 as a vaccine for ovarian cancer (OC). A tissue microarray (TMA) containing 107 samples from OC tissues and 48 samples from OC adjacent tissues was analyzed by immunohistochemistry with the OY-TES-1 polyclonal antibody. The correlation between OY-TES-1 and clinic pathological traits of OC was statistically analyzed. The expression of OY-TES-1 protein was found in 81% (87/107) of OC tissues and 56% (27/48) of OC adjacent tissues. The immunostaining intensity of OY-TES-1 in OC tissues was significantly higher than that in OC adjacent tissues tested (p = 0.040). OC adjacent tissues only demonstrated lower immunostaining intensity, whereas some of OC tissues presented higher immunostaining intensity and majority showed the heterogeneity of protein distribution. There was no statistically significant correlation found between OY-TES-1 expression and any other clinicopathological traits such as age, FIGO stage, pathological grade, and histological type. OY-TES-1 was expressed in OC tissues with a high proportion, and some of OC tissues presented OY-TES-1 expression in high level vs OC adjacent tissues. OY-TES-1 could be an attractive target for immunotherapy for OC in the future.

CIP2A down regulation enhances the sensitivity of pancreatic cancer cells to gemcitabine.

PubMed

Xu, Peng; Yao, Jie; He, Jin; Zhao, Long; Wang, Xiaodong; Li, Zhennan; Qian, Jianjun

2016-03-22

Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncoprotein which participates in inhibiting tumor apoptosis in pancreatic cancer cells. Using immunohistochemical staining, we investigated the expression of CIP2A protein in 72 cases of human pancreatic ductal adenocarcinoma (PDAC) tissue and 27 cases of adjacent normal pancreatic tissue. The positive rate of CIP2A protein expression in pancreatic cancer tissue was70.83 %, which was significantly higher than that in adjacent non- cancerous pancreatic tissue (11.11%). The expression of CIP2A was found to be correlated with TNM stage, but not correlated with age, gender, tumor location, smoking status, alcohol consumption, diabetes, high blood pressure, BMI, tumor size, lymph node metastasis or distant metastases. Kaplan- Meier survival analysis showed that patients with positive CIP2A protein expression had a lower overall survival rate than patients without CIP2A expression. COX regression analysis indicated that expression of CIP2A was an independent prognostic factor for pancreatic ductal adenocarcinoma. In addition, down-regulation of CIP2A inhibited cell proliferation and increased sensitivity to gemcitabine in pancreatic cancer cells by decreasing AKT signaling pathway. Our results indicated that down-regulation of CIP2A could be a novel therapeutic strategy for pancreatic cancer.

Identification of DEP domain-containing proteins by a machine learning method and experimental analysis of their expression in human HCC tissues

NASA Astrophysics Data System (ADS)

Liao, Zhijun; Wang, Xinrui; Zeng, Yeting; Zou, Quan

2016-12-01

The Dishevelled/EGL-10/Pleckstrin (DEP) domain-containing (DEPDC) proteins have seven members. However, whether this superfamily can be distinguished from other proteins based only on the amino acid sequences, remains unknown. Here, we describe a computational method to segregate DEPDCs and non-DEPDCs. First, we examined the Pfam numbers of the known DEPDCs and used the longest sequences for each Pfam to construct a phylogenetic tree. Subsequently, we extracted 188-dimensional (188D) and 20D features of DEPDCs and non-DEPDCs and classified them with random forest classifier. We also mined the motifs of human DEPDCs to find the related domains. Finally, we designed experimental verification methods of human DEPDC expression at the mRNA level in hepatocellular carcinoma (HCC) and adjacent normal tissues. The phylogenetic analysis showed that the DEPDCs superfamily can be divided into three clusters. Moreover, the 188D and 20D features can both be used to effectively distinguish the two protein types. Motif analysis revealed that the DEP and RhoGAP domain was common in human DEPDCs, human HCC and the adjacent tissues that widely expressed DEPDCs. However, their regulation was not identical. In conclusion, we successfully constructed a binary classifier for DEPDCs and experimentally verified their expression in human HCC tissues.

A rare eicosanoid precursor analogue, sciadonic acid (5Z,11Z,14Z-20:3), detected in vivo in hormone positive breast cancer tissue.

PubMed

Park, H G; Zhang, J Y; Foster, C; Sudilovsky, D; Schwed, D A; Mecenas, J; Devapatla, S; Lawrence, P; Kothapalli, K S D; Brenna, J T

2018-07-01

Numerous genetic alterations of HSA 11q13 are found frequently in several cancer types, including breast cancer (BC). The 11q13 locus harbors FADS2 encoding Δ6 desaturation which is not functional in several cancer cell lines, including hormone positive MCF7 BC cells. In vitro, the non-functional FADS2 activity unmasks 18:2n-6 elongation to 20:2n-6 and Δ5 desaturation by FADS1 to yield 5Z,11Z,14Z-20:3 (sciadonic acid) rather than 5Z,8Z,11Z,14Z-20:4 (arachidonic acid). In this pilot study we aimed to determine whether 5,11,14-20:3 appears in vivo in hormone positive human BC tissue. Fatty acids were profiled in surgically removed human breast tumor and adjacent normal tissue (n = 9). Sciadonic acid was detected in three of nine breast tumor samples and was below detect limits in normal breast tissue. The internal Δ8 double bond of arachidonic acid is required for normal eicosanoid synthesis but is missing in sciadonic acid. This pilot study demonstrates for the first time in vivo sciadonic acid in hormone positive BC tissue, warranting a larger survey study to further evaluate its appearance and the functional implications. Copyright © 2018. Published by Elsevier Ltd.

Quantitative proteomic profiling of paired cancerous and normal colon epithelial cells isolated freshly from colorectal cancer patients.

PubMed

Tu, Chengjian; Mojica, Wilfrido; Straubinger, Robert M; Li, Jun; Shen, Shichen; Qu, Miao; Nie, Lei; Roberts, Rick; An, Bo; Qu, Jun

2017-05-01

The heterogeneous structure in tumor tissues from colorectal cancer (CRC) patients excludes an informative comparison between tumors and adjacent normal tissues. Here, we develop and apply a strategy to compare paired cancerous (CEC) versus normal (NEC) epithelial cells enriched from patients and discover potential biomarkers and therapeutic targets for CRC. CEC and NEC cells are respectively isolated from five different tumor and normal locations in the resected colon tissue from each patient (N = 12 patients) using an optimized epithelial cell adhesion molecule (EpCAM)-based enrichment approach. An ion current-based quantitative method is employed to perform comparative proteomic analysis for each patient. A total of 458 altered proteins that are common among >75% of patients are observed and selected for further investigation. Besides known findings such as deregulation of mitochondrial function, tricarboxylic acid cycle, and RNA post-transcriptional modification, functional analysis further revealed RAN signaling pathway, small nucleolar ribonucleoproteins (snoRNPs), and infection by RNA viruses are altered in CEC cells. A selection of the altered proteins of interest is validated by immunohistochemistry analyses. The informative comparison between matched CEC and NEC enhances our understanding of molecular mechanisms of CRC development and provides biomarker candidates and new pathways for therapeutic intervention. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Coherent Raman Scattering Microscopy for Evaluation of Head and Neck Carcinoma.

PubMed

Hoesli, Rebecca C; Orringer, Daniel A; McHugh, Jonathan B; Spector, Matthew E

2017-09-01

Objective We aim to describe a novel, label-free, real-time imaging technique, coherent Raman scattering (CRS) microscopy, for histopathological evaluation of head and neck cancer. We evaluated the ability of CRS microscopy to delineate between tumor and nonneoplastic tissue in tissue samples from patients with head and neck cancer. Study Design Prospective case series. Setting Tertiary care medical center. Subjects and Methods Patients eligible were surgical candidates with biopsy-proven, previously untreated head and neck carcinoma and were consented preoperatively for participation in this study. Tissue was collected from 50 patients, and after confirmation of tumor and normal specimens by hematoxylin and eosin (H&E), there were 42 tumor samples and 42 normal adjacent controls. Results There were 42 confirmed carcinoma specimens on H&E, and CRS microscopy identified 37 as carcinoma. Of the 42 normal specimens, CRS microscopy identified 40 as normal. This resulted in a sensitivity of 88.1% and specificity of 95.2% in distinguishing between neoplastic and nonneoplastic images. Conclusion CRS microscopy is a unique label-free imaging technique that can provide rapid, high-resolution images and can accurately determine the presence of head and neck carcinoma. This holds potential for implementation into standard practice, allowing frozen margin evaluation even at institutions without a histopathology laboratory.

Pulsed-High Intensity Focused Ultrasound (HIFU) Exposures for Enhanced Delivery of Therapeutics: Mechanisms and Applications

NASA Astrophysics Data System (ADS)

Frenkel, Victor; Deng, Cheri; O'Neill, Brian E.; Quijano, Jade; Stone, Michael J.; Dromi, Sergio; Hunter, Finie; Xie, Jianwu; Quinn, Timothy P.; Wood, Bradford J.; Li, King C. P.

2006-05-01

The majority of focused ultrasound applications today involve long, continuous exposures that produce significant temperature elevations for tissue ablation and irreversible coagulative necrosis. Comparatively little has been done with non-continuous (or, pulsed) exposures that can produce primarily mechanical effects with only minimal heat. Our investigations have shown that pulsed-HIFU exposures can non-invasively and non-destructively enhance the delivery of both systemically and locally injected materials (e.g. imaging agents, optical probes, and plasmid DNA) in both normal and cancerous tissues. It is hypothesized that the enhancing effects are directly linked to tissue displacement from locally-generated radiation forces. In normal tissue, it is thought that shear forces are produced between adjacent tissue regions experiencing non-uniform displacement. The resulting strain opens cellular junctions in both the vasculature and the parenchyma, increasing extravasation and interstitial diffusion, respectively. In solid tumors, improved delivery is thought to also be related to both an increase in fluid exchange that leads to decreased interstitial pressure, and disruptions of fibrillar collagen in the extracellular matrix. Preliminary experiments are presented that were carried out to help elucidate the mechanisms by which enhanced delivery was achieved, and possible directions for future investigations are discussed.

High intensity focused ultrasound ablation of goat liver in vivo: Pathologic changes of portal vein and the "heat-sink" effect.

PubMed

Jiang, F; He, M; Liu, Y J; Wang, Z B; Zhang, L; Bai, J

2013-01-01

The purpose of this study was to evaluate pathological changes of the portal vein (PV) and the effects on main branches of the hepatic PV during HIFU (high-intensity focused ultrasound) sonication when liver tissue adjacent to the main branches of hepatic PV was ablated. Normal liver tissue at 0mm, 5mm, 10mm away from the hepatic portal vein in 50 healthy goats was ablated with magnetic resonance image-guided HIFU (MRgHIFU). MRI showed a non-perfusion region at the target area but did not show any significant changes of the PV immediately after HIFU. The histological examination 1 day after HIFU showed coagulative necrosis at the target area, revealed deep-dyed swelling collagen (CS) fibers and vessel wall fracture (VWF) in the PV adjacent to the target area; however, no CS or VWF was observed in the PV 1 week after HIFU ablation. The energy required to ablate the foci at 0mm was 21% more than that at 10mm from the PV (p<0.05); the energy needed to ablate foci 5mm away from the PV was 10% more than that at 10mm from the PV (p<0.05). We concluded that minor injury of the hepatic portal vein may occur when ablating the adjacent liver tissue, and the acoustic energy deposition is related to the distance to the portal vein. Copyright © 2012 Elsevier B.V. All rights reserved.

Epigenetic Silencing of the MLH1 Promoter in Relation to the Development of Gastric Cancer and its use as a Biomarker for Patients with Microsatellite Instability: a Systematic Analysis.

PubMed

Hu, Guimei; Qin, Lijun; Zhang, Xinjun; Ye, Guoliang; Huang, Tao

2018-01-01

Human mutL homolog 1 (MLH1) promoter methylation was reported in gastric cancer (GC). This study determined the clinicopathological, prognostic, and diagnostic effects of MLH1 promoter methylation in GC. The combined odds ratio (OR) or hazard ratio (HR) and their corresponding 95% confidence intervals (95% CI) were calculated. The pooled sensitivity, specificity, and area under the curve (AUC) were analyzed. A total of 4654 GC patients and 3669 non-malignant controls were identified in this systematic analysis. MLH1 promoter methylation was significantly higher in GC samples than in gastric adenomas, chronic gastritis, adjacent tissues, normal gastric mucosa, and normal healthy blood samples, but it exhibited a similar frequency in GC vs. intestinal metaplasia and dysplasia samples. MLH1 promoter methylation correlated with age and microsatellite instability (MSI), but it was not associated with gender, H. pylori infection, smoking, drinking behaviors, pathological histology, tumor differentiation, clinical stage, lymph node status, distant metastasis, or overall survival of GC. MLH1 promoter methylation exhibited a poor sensitivity value (< 0.5) in patients with GC compared with adjacent tissues, gastric adenomas, chronic gastritis, normal gastric mucosa, and normal healthy blood samples. The pooled sensitivity, specificity, and AUC of MLH1 promoter methylation in GC with MSI vs. GC with microsatellite stability (MSS) samples were 0.64, 0.96, and 0.90, respectively. Our results suggest that the detection of MLH1 promoter methylation may be a potential prognostic biomarker for GC patients with MSI. © 2018 The Author(s). Published by S. Karger AG, Basel.

Studies of a novel photosensitizer Pd-bacteriopheophorbide (Tookad) for the prostate cancer PDT in canine model

NASA Astrophysics Data System (ADS)

Huang, Zheng; Chen, Qun; Brun, Pierre-Herve; Wilson, Brian C.; Scherz, Avigdor; Salomon, Yoram; Luck, David L.; Beckers, Jill; Hetzel, Fred W.

2003-12-01

Photodynamic therapy (PDT) mediated with vascular acting photosensitizer pd-bacteriopheophorbide (Tookad), is investigated as an alternative modality for the total ablation of prostate cancer. In vivo normal canine prostate is used as the animal model. Interstitial PDT was performed by irradiating the surgically exposed prostates with a diode laser (763 nm, 150 mW/cm) to activate the i.v. infused photosensitizer drug. The effects of two-session PDT were evaluated. The prostate and its adjacent tissues were harvested and subjected to histopathological examination. At one-week, post second-session PDT, the animals recovered well with little or no urethral complications. Prostatic urethra and prostate adjacent tissues (bladder and underlying colon) were well preserved. Two-session PDT or one single session PDT induced a similar extent of damage. PDT induced prostate lesions were characterized by marked hemorrhagic necrosis. Maximum lesion size of over 3 cm in dimension could be achieved with a single 1-cm interstitial treatment, suggesting the therapy is very effective in ablating prostatic tissue. Pharmacokinetic studies show that the photosensitizer is cleared rapidly from the circulation. In conclusion, the novel photosensitizer Tookad mediated PDT may provide an effective alternative to treat prostate cancer.

Dysfunctional oligodendrocyte progenitor cell (OPC) populations may inhibit repopulation of OPC depleted tissue.

PubMed

Chari, D M; Huang, W L; Blakemore, W F

2003-09-15

We have attempted to extend a previously described rat model of focal oligodendrocyte progenitor cell (OPC) depletion, using 40 Gy X-irradiation (Chari and Blakemore [2002] Glia 37:307-313), to the adult mouse spinal cord, to examine the ability of OPCs present in adjacent normal areas to colonise areas of progenitor depletion. In contrast to rat, OPCs in the mouse spinal cord appeared to be a comparatively radiation-resistant population, as 30-35% of OPCs survived in X-irradiated tissue (whereas <1% of OPCs survive in X-irradiated rat spinal cord). The numbers of surviving OPCs remained constant with time indicating that this population was incapable of regenerating itself in response to OPC loss. Additionally, these OPCs did not contribute to remyelination of axons when demyelinating lesions were placed in X-irradiated tissue, suggesting that the surviving cells are functionally impaired. Importantly, the length of the OPC-depleted area did not diminish with time, as would be expected if progressive repopulation of OPC-depleted areas by OPCs from normal areas was occurring. Our findings therefore raise the possibility that the presence of a residual dysfunctional OPC population may inhibit colonisation of such areas by normal OPCs. Copyright 2003 Wiley-Liss, Inc.

[Topographological-anatomic changes in the structure of temporo-mandibular joint in case of fracture of the mandible condylar process at cervical level].

PubMed

Volkov, S I; Bazhenov, D V; Semkin, V A

2011-01-01

Pathological changes in soft tissues surrounding the fracture site as well as in the structural elements of temporo-mandibular joint always occured in condylar process fracture with shift at cervical mandibular jaw level. Other changes were also seen in the joint on the opposite normal side. Modelling of condylar process fracture at mandibular cervical level by means of three-dimensional computer model of temporo-mandibular joint contributed to proper understanding of this pathology emergence as well as to prediction and elimination of disorders arising in adjacent to the fracture site tissues.

Preneoplastic lesion growth driven by the death of adjacent normal stem cells

PubMed Central

Chao, Dennis L.; Eck, J. Thomas; Brash, Douglas E.; Maley, Carlo C.; Luebeck, E. Georg

2008-01-01

Clonal expansion of premalignant lesions is an important step in the progression to cancer. This process is commonly considered to be a consequence of sustaining a proliferative mutation. Here, we investigate whether the growth trajectory of clones can be better described by a model in which clone growth does not depend on a proliferative advantage. We developed a simple computer model of clonal expansion in an epithelium in which mutant clones can only colonize space left unoccupied by the death of adjacent normal stem cells. In this model, competition for space occurs along the frontier between mutant and normal territories, and both the shapes and the growth rates of lesions are governed by the differences between mutant and normal cells' replication or apoptosis rates. The behavior of this model of clonal expansion along a mutant clone's frontier, when apoptosis of both normal and mutant cells is included, matches the growth of UVB-induced p53-mutant clones in mouse dorsal epidermis better than a standard exponential growth model that does not include tissue architecture. The model predicts precancer cell mutation and death rates that agree with biological observations. These results support the hypothesis that clonal expansion of premalignant lesions can be driven by agents, such as ionizing or nonionizing radiation, that cause cell killing but do not directly stimulate cell replication. PMID:18815380

Clinical responses to focused ultrasound applied to women with vulval intraepithelial neoplasia.

PubMed

Jia, Ying; Wu, Jin; Xu, Man; Tang, Liangdan; Li, Chengzhi; Luo, Ming; Lou, Meng

2014-11-01

Focused ultrasound waves penetrate superficial tissues and are aimed toward the target tissues at specific depths to exert their biological effects. Focused ultrasound has been applied for a number of clinical indications, including vulval dystrophies and low-grade vulval disease. This study aimed to assess the efficacy and safety of focused ultrasound treatment of high-grade vulval intraepithelial neoplasia (VIN). Eighteen women with high-grade VIN were recruited and treated with focused ultrasound. During each posttreatment follow-up, the safety of, side effects of, and clinical responses to focused ultrasound were evaluated by a standardized protocol, including symptoms, clinical appearance, and histologic findings. All patients completed the designed follow-ups. In most cases, superficial mild to moderate swelling and blisters were seen in the focused ultrasound-treated skin but not in adjacent normal skin. Of the 18 patients, 16 showed complete histologic regression and resolution of symptoms 6 months after treatment. Of the other 2 patients, 1 showed complete regression after a second focused ultrasound treatment. The other patient did not respond to the focused ultrasound treatment and underwent a partial vulvectomy 6 months after treatment. None of the patients developed invasive carcinoma of the vulva during the follow-up period. One patient had local pruritus that was not alleviated by anti-inflammatory medication and local care. The complete responses observed in women with high-grade VIN treated by focused ultrasound, together with the preservation of adjacent normal tissue, suggest that focused ultrasound may be considered for treatment of high-grade VIN. © 2014 by the American Institute of Ultrasound in Medicine.

miRNA-148a serves as a prognostic factor and suppresses migration and invasion through Wnt1 in non-small cell lung cancer.

PubMed

Chen, Yong; Min, Lingfeng; Ren, Chuanli; Xu, Xingxiang; Yang, Jianqi; Sun, Xinchen; Wang, Tao; Wang, Fang; Sun, Changjiang; Zhang, Xizhi

2017-01-01

Lung cancer is the leading cause of cancer death in the world, and aberrant expression of miRNA is a common feature during the cancer initiation and development. Our previous study showed that levels of miRNA-148a assessed by quantitative real-time polymerase chain reaction (qRT-PCR) were a good prognosis factor for non-small cell lung cancer (NSCLC) patients. In this study, we used high-throughput formalin-fixed and paraffin-embedded (FFPE) lung cancer tissue arrays and in situ hybridization (ISH) to determine the clinical significances of miRNA-148a and aimed to find novel target of miRNA-148a in lung cancer. Our results showed that there were 86 of 159 patients with low miRNA-148a expression and miRNA-148a was significantly down-regulated in primary cancer tissues when compared with their adjacent normal lung tissues. Low expression of miRNA-148a was strongly associated with high tumor grade, lymph node (LN) metastasis and a higher risk of tumor-related death in NSCLC. Lentivirus mediated overexpression of miRNA-148a inhibited migration and invasion of A549 and H1299 lung cancer cells. Furthermore, we validated Wnt1 as a direct target of miRNA-148a. Our data showed that the Wnt1 expression was negatively correlated with the expression of miRNA-148a in both primary cancer tissues and their corresponding adjacent normal lung tissues. In addition, overexpression of miRNA-148a inhibited Wnt1 protein expression in cancer cells. And knocking down of Wnt-1 by siRNA had the similar effect of miRNA-148a overexpression on cell migration and invasion in lung cancer cells. In conclusion, our results suggest that miRNA-148a inhibited cell migration and invasion through targeting Wnt1 and this might provide a new insight into the molecular mechanisms of lung cancer metastasis.

Chronic Electrical Stimulation with a Suprachoroidal Retinal Prosthesis: A Preclinical Safety and Efficacy Study

PubMed Central

Nayagam, David A. X.; Williams, Richard A.; Allen, Penelope J.; Shivdasani, Mohit N.; Luu, Chi D.; Salinas-LaRosa, Cesar M.; Finch, Sue; Ayton, Lauren N.; Saunders, Alexia L.; McPhedran, Michelle; McGowan, Ceara; Villalobos, Joel; Fallon, James B.; Wise, Andrew K.; Yeoh, Jonathan; Xu, Jin; Feng, Helen; Millard, Rodney; McWade, Melanie; Thien, Patrick C.; Williams, Chris E.; Shepherd, Robert K.

2014-01-01

Purpose To assess the safety and efficacy of chronic electrical stimulation of the retina with a suprachoroidal visual prosthesis. Methods Seven normally-sighted feline subjects were implanted for 96–143 days with a suprachoroidal electrode array and six were chronically stimulated for 70–105 days at levels that activated the visual cortex. Charge balanced, biphasic, current pulses were delivered to platinum electrodes in a monopolar stimulation mode. Retinal integrity/function and the mechanical stability of the implant were assessed monthly using electroretinography (ERG), optical coherence tomography (OCT) and fundus photography. Electrode impedances were measured weekly and electrically-evoked visual cortex potentials (eEVCPs) were measured monthly to verify that chronic stimuli were suprathreshold. At the end of the chronic stimulation period, thresholds were confirmed with multi-unit recordings from the visual cortex. Randomized, blinded histological assessments were performed by two pathologists to compare the stimulated and non-stimulated retina and adjacent tissue. Results All subjects tolerated the surgical and stimulation procedure with no evidence of discomfort or unexpected adverse outcomes. After an initial post-operative settling period, electrode arrays were mechanically stable. Mean electrode impedances were stable between 11–15 kΩ during the implantation period. Visually-evoked ERGs & OCT were normal, and mean eEVCP thresholds did not substantially differ over time. In 81 of 84 electrode-adjacent tissue samples examined, there were no discernible histopathological differences between stimulated and unstimulated tissue. In the remaining three tissue samples there were minor focal fibroblastic and acute inflammatory responses. Conclusions Chronic suprathreshold electrical stimulation of the retina using a suprachoroidal electrode array evoked a minimal tissue response and no adverse clinical or histological findings. Moreover, thresholds and electrode impedance remained stable for stimulation durations of up to 15 weeks. This study has demonstrated the safety and efficacy of suprachoroidal stimulation with charge balanced stimulus currents. PMID:24853376

Analysis of p53 gene mutations in human gliomas by polymerase chain reaction-based single-strand conformation polymorphism and DNA sequencing.

PubMed

Sarkar, F H; Kupsky, W J; Li, Y W; Sreepathi, P

1994-03-01

Mutations in the p53 gene have been recognized in brain tumors, and clonal expansion of p53 mutant cells has been shown to be associated with glioma progression. However, studies on the p53 gene have been limited by the need for frozen tissues. We have developed a method utilizing polymerase chain reaction (PCR) for the direct analysis of p53 mutation by single-strand conformation polymorphism (SSCP) and by direct DNA sequencing of the p53 gene using a single 10-microns paraffin-embedded tissue section. We applied this method to screen for p53 gene mutations in exons 5-8 in human gliomas utilizing paraffin-embedded tissues. Twenty paraffin blocks containing tumor were selected from surgical specimens from 17 different adult patients. Tumors included six anaplastic astrocytomas (AAs), nine glioblastomas (GBs), and two mixed malignant gliomas (MMGs). The tissue section on the stained glass slide was used to guide microdissection of an unstained adjacent tissue section to ensure > 90% of the tumor cell population for p53 mutational analysis. Simultaneously, microdissection of the tissue was also carried out to obtain normal tissue from adjacent areas as a control. Mutations in the p53 gene were identified in 3 of 17 (18%) patients by PCR-SSCP analysis and subsequently confirmed by PCR-based DNA sequencing. Mutations in exon 5 resulting in amino acid substitution were found in one thalamic AA (codon 158, CGC > CTT: Arg > Leu) and one cerebral hemispheric GB (codon 151, CCG > CTG: Pro > Leu).(ABSTRACT TRUNCATED AT 250 WORDS)

Aberrant DNA methylation at genes associated with a stem cell-like phenotype in cholangiocarcinoma tumours

PubMed Central

Dai, Wei; Siddiq, Afshan; Walley, Andrew J; Limpaiboon, Temduang; Brown, Robert

2013-01-01

Genetic abnormalities of cholangiocarcinoma have been widely studied; however, epigenomic changes related to cholangiocarcinogenesis have been less well characterised. We have profiled the DNA methylomes of 28 primary cholangiocarcinoma and six matched adjacent normal tissues using Infinium’s HumanMethylation27 BeadChips with the aim of identifying gene sets aberrantly epigenetically regulated in this tumour type. Using a linear model for microarray data we identified 1610 differentially methylated autosomal CpG sites with 809 CpG sites (representing 603 genes) being hypermethylated and 801 CpG sites (representing 712 genes) being hypomethylated in cholangiocarcinoma versus adjacent normal tissues (false discovery rate ≤ 0.05). Gene ontology and gene set enrichment analyses identified gene sets significantly associated with hypermethylation at linked CpG sites in cholangiocarcinoma including homeobox genes and target genes of PRC2, EED, SUZ12 and histone H3 trimethylation at lysine 27. We confirmed frequent hypermethylation at the homeobox genes HOXA9 and HOXD9 by bisulfite pyrosequencing in a larger cohort of cholangiocarcinoma (n = 102). Our findings indicate a key role for hypermethylation of multiple CpG sites at genes associated with a stem cell-like phenotype as a common molecular aberration in cholangiocarcinoma. These data have implications for cholangiocarcinogenesis, as well as possible novel treatment options using histone methyltransferase inhibitors. PMID:24089088

tRNA modification profiles of the fast-proliferating cancer cells

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

Dong, Chao; Niu, Leilei; Song, Wei

Despite the recent progress in RNA modification study, a comprehensive modification profile is still lacking for mammalian cells. Using a quantitative HPLC/MS/MS assay, we present here a study where RNA modifications are examined in term of the major RNA species. With paired slow- and fast-proliferating cell lines, distinct RNA modification profiles are first revealed for diverse RNA species. Compared to mRNAs, increased ribose and nucleobase modifications are shown for the highly-structured tRNAs and rRNAs, lending support to their contribution to the formation of high-order structures. This study also reveals a dynamic tRNA modification profile in the fast-proliferating cells. In additionmore » to cultured cells, this unique tRNA profile has been further confirmed with endometrial cancers and their adjacent normal tissues. Taken together, the results indicate that tRNA is a actively regulated RNA species in the fast-proliferating cancer cells, and suggest that they may play a more active role in biological process than expected. -- Highlights: •RNA modifications were first examined in term of the major RNA species. •A dynamic tRNA modifications was characterized for the fast-proliferating cells. •The unique tRNA profile was confirmed with endometrial cancers and their adjacent normal tissues. •tRNA was predicted as an actively regulated RNA species in the fast-proliferating cancer cells.« less

Creation of a virtual cutaneous tissue bank

NASA Astrophysics Data System (ADS)

LaFramboise, William A.; Shah, Sujal; Hoy, R. W.; Letbetter, D.; Petrosko, P.; Vennare, R.; Johnson, Peter C.

2000-04-01

Cellular and non-cellular constituents of skin contain fundamental morphometric features and structural patterns that correlate with tissue function. High resolution digital image acquisitions performed using an automated system and proprietary software to assemble adjacent images and create a contiguous, lossless, digital representation of individual microscope slide specimens. Serial extraction, evaluation and statistical analysis of cutaneous feature is performed utilizing an automated analysis system, to derive normal cutaneous parameters comprising essential structural skin components. Automated digital cutaneous analysis allows for fast extraction of microanatomic dat with accuracy approximating manual measurement. The process provides rapid assessment of feature both within individual specimens and across sample populations. The images, component data, and statistical analysis comprise a bioinformatics database to serve as an architectural blueprint for skin tissue engineering and as a diagnostic standard of comparison for pathologic specimens.

Thermal therapy techniques for skin and superficial tissue disease

NASA Astrophysics Data System (ADS)

Stauffer, Paul R.

2000-01-01

There are numerous diseases and abnormal growths and conditions that afflict the skin and underlying superficial tissues. In addition to cancers such as primary, recurrent, and metastatic melanomas and carcinomas, there are many non-malignant conditions such as psoriasis plaques, port wine stains, warts, and superficial cut and bum wounds. Many of these clinical conditions have been shown responsive to treatment with thermal therapy - either low temperature freezing (cryotherapy),. moderate temperature warming to about 41-45°C (hyperthermia), or high temperature (>50°C) ablation or coagulation necrosis therapy. Because both very low and very high temperature therapies are for the most part non-selectively destructive in nature, they normally are used for applications where therapy can be localized precisely in the desired target and some necrosis of adjacent normal tissues is acceptable. With the exception of precision controlled cryotherapy or laser surgery (e.g. wart, mole, tattoo and port wine stain removal) or focal thermal surgery of small deep-seated nodules, it is generally preferred to use moderate thermal therapy (hyperthermia) in the treatment of skin and subcutaneous tissue disease in order to preserve the protective barrier characteristic of intact skin within the target region while inducing more subtle long term therapeutic improvement in the disease condition. This type of subtle thermal therapy is usually administered in combination with one or more other therapies such as radiation or chemotherapy - something with a differential effect on the target and surrounding normal tissues that can be magnified by the adjuvant use of heat.

MicroRNA-9 suppresses the growth, migration, and invasion of malignant melanoma cells via targeting NRP1.

PubMed

Xu, Dan; Chen, Xiaofeng; He, Quanyong; Luo, Chengqun

2016-01-01

MicroRNAs (miRs) are a class of small noncoding RNAs that negatively regulate the gene expression by directly binding to the 3' untranslated region of their target mRNA, thus resulting in mRNA degradation or translational repression. miR-9 has recently been demonstrated to play a role in the development and progression of malignant melanoma (MM), but the regulatory mechanism of miR-9 in the malignant phenotypes of MM still remains largely unknown. In this study, a total of 73 pairs of MM tissues and adjacent normal tissues were collected. Real-time reverse transcription polymerase chain reaction and Western blot were used to detect the mRNA and protein expression of miR-9. MTT assay, wound healing assay, and transwell assay were conducted to determine the cell proliferation, migration, and invasion. Luciferase reporter assay was used to determine the targeting relationship between miR-9 and NRP1. Our data demonstrated that miR-9 expression was significantly downregulated in MM tissues compared with that in adjacent normal tissues. The decreased miR-9 level was significantly associated with the tumor stage and metastasis of MM. We also found that the expression level of miR-9 was decreased in MM cell lines (G361, B16, A375, and HME1) compared with normal skin HACAT cells. Ectopic expression of miR-9 led to a significant decrease in the ability of proliferation, migration, and invasion in A375 cells. NRP1 was further identified as a direct target gene of miR-9, and the protein expression of NRP1 was negatively regulated by miR-9 in A375 cells. Furthermore, overexpression of NRP1 reversed the suppressive effects of miR-9 on the malignant phenotypes of A375 cells. In vivo study revealed that miR-9 overexpression decreased the tumor growth, while overexpression of NRP1 increased MM growth. In summary, our findings suggest that the miR-9/NRP1 axis may serve as a potential target for the treatment of MM.

The up-regulation of miR-300 in gastric cancer and its effects on cells malignancy

PubMed Central

Shen, Zhen; Li, Chunsheng; Zhang, Kai; Yu, Wei; Xiao, Huijie; Li, Bo; Liu, Tongjun

2015-01-01

Objective: In this study, we investigated the role of miR-300 in regulating cell proliferation and invasion of gastric cancer cells. Methods: MicroRNA and protein expression patterns were compared between gastric cancer tissue and normal tissue and between two different prognostic groups. The up-regulation of miR-300 was confirmed by real-time reverse transcription polymerase chain reaction and its expression was analyzed in AGS gastric cancer cells. Results: We observed that miR-300 expression was frequently and dramatically up-regulated in human gastric cancer tissues and cell lines compared with the matched adjacent normal tissues and cells. We further showed that transient and stable over-expression of miR-300 could promote cell proliferation and cell cycle progression. Moreover, p53, a key inhibitor of cell cycle, was verified as a direct target of miR-300, suggesting that miR-300 might promote gastric cancer cell proliferation and invasion by increasing p53 expression. Conclusion: Our findings indicated that miR-300 up-regulation might exert some sort of antagonistic function by targeting p53 in gastric cancer cell proliferation during gastric tumorigenesis. PMID:26221215

The up-regulation of miR-300 in gastric cancer and its effects on cells malignancy.

PubMed

Shen, Zhen; Li, Chunsheng; Zhang, Kai; Yu, Wei; Xiao, Huijie; Li, Bo; Liu, Tongjun

2015-01-01

In this study, we investigated the role of miR-300 in regulating cell proliferation and invasion of gastric cancer cells. MicroRNA and protein expression patterns were compared between gastric cancer tissue and normal tissue and between two different prognostic groups. The up-regulation of miR-300 was confirmed by real-time reverse transcription polymerase chain reaction and its expression was analyzed in AGS gastric cancer cells. We observed that miR-300 expression was frequently and dramatically up-regulated in human gastric cancer tissues and cell lines compared with the matched adjacent normal tissues and cells. We further showed that transient and stable over-expression of miR-300 could promote cell proliferation and cell cycle progression. Moreover, p53, a key inhibitor of cell cycle, was verified as a direct target of miR-300, suggesting that miR-300 might promote gastric cancer cell proliferation and invasion by increasing p53 expression. Our findings indicated that miR-300 up-regulation might exert some sort of antagonistic function by targeting p53 in gastric cancer cell proliferation during gastric tumorigenesis.

MiR-300 regulate the malignancy of breast cancer by targeting p53.

PubMed

Xu, Xiao-Heng; Li, Da-Wei; Feng, Hui; Chen, Hong-Mei; Song, Yan-Qiu

2015-01-01

In this study, we investigated the role of miR-300 in regulating cell proliferation and invasion of breast cancer (BC) cells. MicroRNA and protein expression patterns were compared between breast cancer tissue and normal tissue and between two different prognostic groups. The up-regulation of miR-300 was confirmed by real-time reverse transcription polymerase chain reaction and its expression was analyzed in MCF-7 breast cancer cells. We observed that miR-300 expression was frequently and dramatically up-regulated in human breast cancer tissues and cell lines compared with the matched adjacent normal tissues and cells. We further showed that transient and stable over-expression of miR-300 could promote cell proliferation and cell cycle progression. Moreover, p53, a key inhibitor of cell cycle, was verified as a direct target of miR-300, suggesting that miR-300 might promote breast cancer cell proliferation and invasion by regulating p53 expression. Our findings indicated that miR-300 up-regulation might exert some sort of antagonistic function by targeting p53 in breast cancer cell proliferation during breast tumorigenesis.

MiR-300 regulate the malignancy of breast cancer by targeting p53

PubMed Central

Xu, Xiao-Heng; Li, Da-Wei; Feng, Hui; Chen, Hong-Mei; Song, Yan-Qiu

2015-01-01

Objective: In this study, we investigated the role of miR-300 in regulating cell proliferation and invasion of breast cancer (BC) cells. Methods: MicroRNA and protein expression patterns were compared between breast cancer tissue and normal tissue and between two different prognostic groups. The up-regulation of miR-300 was confirmed by real-time reverse transcription polymerase chain reaction and its expression was analyzed in MCF-7 breast cancer cells. Results: We observed that miR-300 expression was frequently and dramatically up-regulated in human breast cancer tissues and cell lines compared with the matched adjacent normal tissues and cells. We further showed that transient and stable over-expression of miR-300 could promote cell proliferation and cell cycle progression. Moreover, p53, a key inhibitor of cell cycle, was verified as a direct target of miR-300, suggesting that miR-300 might promote breast cancer cell proliferation and invasion by regulating p53 expression. Conclusion: Our findings indicated that miR-300 up-regulation might exert some sort of antagonistic function by targeting p53 in breast cancer cell proliferation during breast tumorigenesis. PMID:26221232

Gene Expression Profiling of Gastric Cancer

PubMed Central

Marimuthu, Arivusudar; Jacob, Harrys K.C.; Jakharia, Aniruddha; Subbannayya, Yashwanth; Keerthikumar, Shivakumar; Kashyap, Manoj Kumar; Goel, Renu; Balakrishnan, Lavanya; Dwivedi, Sutopa; Pathare, Swapnali; Dikshit, Jyoti Bajpai; Maharudraiah, Jagadeesha; Singh, Sujay; Sameer Kumar, Ghantasala S; Vijayakumar, M.; Veerendra Kumar, Kariyanakatte Veeraiah; Premalatha, Chennagiri Shrinivasamurthy; Tata, Pramila; Hariharan, Ramesh; Roa, Juan Carlos; Prasad, T.S.K; Chaerkady, Raghothama; Kumar, Rekha Vijay; Pandey, Akhilesh

2015-01-01

Gastric cancer is the second leading cause of cancer death worldwide, both in men and women. A genomewide gene expression analysis was carried out to identify differentially expressed genes in gastric adenocarcinoma tissues as compared to adjacent normal tissues. We used Agilent’s whole human genome oligonucleotide microarray platform representing ~41,000 genes to carry out gene expression analysis. Two-color microarray analysis was employed to directly compare the expression of genes between tumor and normal tissues. Through this approach, we identified several previously known candidate genes along with a number of novel candidate genes in gastric cancer. Testican-1 (SPOCK1) was one of the novel molecules that was 10-fold upregulated in tumors. Using tissue microarrays, we validated the expression of testican-1 by immunohistochemical staining. It was overexpressed in 56% (160/282) of the cases tested. Pathway analysis led to the identification of several networks in which SPOCK1 was among the topmost networks of interacting genes. By gene enrichment analysis, we identified several genes involved in cell adhesion and cell proliferation to be significantly upregulated while those corresponding to metabolic pathways were significantly downregulated. The differentially expressed genes identified in this study are candidate biomarkers for gastric adenoacarcinoma. PMID:27030788

Sciatic endometriosis induces mechanical hypersensitivity, segmental nerve damage, and robust local inflammation in rats

PubMed Central

Chen, S.; Xie, W.; Strong, J. A.; Jiang, J.; Zhang, J.-M.

2015-01-01

Background Endometriosis is a common cause of pain including radicular pain. Ectopic endometrial tissue may directly affect peripheral nerves including the sciatic, which has not been modelled in animals. Methods We developed a rat model for sciatic endometriosis by grafting a piece of autologous uterine tissue around the sciatic nerve. Control animals underwent a similar surgery but received a graft of pelvic fat tissue. Results The uterine grafts survived and developed fluid filled cysts; the adjacent nerve showed signs of swelling and damage. Mechanical and cold hypersensitivity and allodynia of the ipsilateral hindpaw developed gradually over the first two weeks after the surgery, peaked at 2 to 5 weeks, and was almost resolved by 7 weeks. Control animals showed only minor changes in these pain behaviors. Histological signs of inflammation in the uterine graft and in the adjacent nerve were observed at 3 weeks but were resolving by 7 weeks. In vivo fiber recording showed increased spontaneous activity, especially of C fibers, in sciatic nerve proximal to the uterine graft. Several pro-inflammatory cytokines including interluekin-18, VEGF, fractalkine, and MIP-1α, were elevated in the uterine graft plus sciatic nerve samples, compared to samples from normal nerve or nerve plus fat graft. Growth associated protein 43 (GAP43), a marker of regenerating nerve fibers, was observed in the adjacent sciatic nerve as well as in the uterine graft. Conclusions This model shared many features with other rat models of endometriosis, but also had some unique features more closely related to neuropathic pain models. PMID:26688332

Immunoperoxidase localization of a high-molecular-weight mucin recognized by monoclonal antibody 1D3.

PubMed

Gangopadhyay, A; Bhattacharya, M; Chatterjee, S K; Barlow, J J; Tsukada, Y

1985-04-01

The distribution of an antigen recognized by murine monoclonal antibody 1D3 (Bhattacharya, M., Chatterjee, S.K., Barlow, J. J., and Fuji, H. Cancer Res., 42: 1650-1654, 1982) was investigated in various types of human malignant and normal adult tissues by indirect immunoperoxidase assay in fixed paraffin-embedded sections. One hundred percent of ovarian mucinous cystadenocarcinomas expressed high levels of the antigen with intense staining of 80 to 100% of the tumoral area, thus confirming our previous finding with radioimmunoassay and absorption analyses. About 51% of colonic carcinomas, 33% of gastric carcinomas, and 22% of pancreatic carcinomas were also positive for this high-molecular-weight mucoprotein antigen. All other ovarian and nonovarian carcinomas tested including carcinoma of lung, breast, endometrium, cervix, and prostate were not stained by 1D3. In addition, sarcomas, melanomas, and lymphomas also did not express any detectable level of the antigen. When surveyed against various normal adult tissues, 1D3 had reactivity limited to the colon. Normal colon, however, exhibited reduced staining intensities compared to tumors or to the apparently normal colon adjacent to tumors. The antigen thus appears to be a colorectal tissue-specific antigen showing increased levels in ovarian mucinous cystadenocarcinomas and in some gastrointestinal tumors. 1D3 antigen is a potential tumor marker for mucinous ovarian and colonic tumors.

Newer concepts in the pathophysiology of ischemic heart disease.

PubMed

Kirk, E S; Factor, S; Sonnenblick, E H

1984-11-01

Thus the thrust of these studies suggests that blood flow is the overwhelming factor in determining the consequences of the imbalance of oxygen supply and demand. Moreover, the factors that determine the requirements for tissue survival in the presence of deep ischemia are not the same as those shown for the normal myocardium in figure 1. In deep ischemia, contraction ceases, and metabolism shifts from aerobic to anaerobic pathways. Survival rather than contractile function then becomes the agenda. Not only does supply tend to overshadow demand in determining extent of transmural necrosis, but the anatomical pattern of supply precisely delineates the region at risk following a coronary occlusion as well as the ultimate extent of infarction. These views are summarized in the model presented in figures 12 and 13. The anatomic distribution of the ligated artery determines the lateral limits of the ischemic region (Fig. 12) and thus the lateral extension of necrosis (Fig. 13). The extension of the necrosis across the heart wall depends largely on the status of perfusion within the ischemic region. Extension of an infarct, should it occur, has to be explained by other mechanisms. These might include: (i) vascular obstruction in adjacent vascular systems that were not involved in the first occlusion, (ii) relative ischemia in the normal tissue surrounding the ischemic tissue due to an increased wall stress at the demarcation between contracting and noncontracting tissue, or (9) interruption of vessels supplying large interdigitations of normal tissue within the originally ischemic tissue due to changes associated with the process of infarction of ischemia. Alternatively, much that is called extension of infarction may involve more of the wall transmurally without lateral extension. Additional features of the development of myocardial infarction in figures 12 and 13 include: (i) the development of collateral vessel function resulting in an increased capacity to supply the ischemic area, and (ii) a redistribution of collateral blood flow from necrotic to surviving myocardium within the ischemic area. Thus, as coronary collaterals develop, collateral blood flow becomes increasingly heterogeneous within the ischemic area. Following a coronary occlusion, blood flow is reduced more in the subendocardium, and infarction occurs. Resistance to flow in infarcting tissue increase and causes a redistribution of flow to adjacent surviving layers of myocardium that life toward the epicardium. The process continues and combined with the enlargement of collateral vessels results in a sufficient flow to the epicardial layers so that they may survive.

Mapping Lipid Alterations in Traumatically Injured Rat Spinal Cord by Desorption Electrospray Ionization Imaging Mass Spectrometry

PubMed Central

Girod, Marion; Shi, Yunzhou; Cheng, Ji-Xin; Cooks, R. Graham

2010-01-01

Desorption electrospray ionization (DESI) mass spectrometry is used in an imaging mode to interrogate the lipid profiles of 15 µm thin tissues cross sections of injured rat spinal cord and normal healthy tissue. Increased relative intensities of fatty acids, diacylglycerols and lysolipids (between +120% and +240%) as well as a small decrease in intensities of lipids (−30%) were visualized in the lesion epi-center and adjacent areas after spinal cord injury. This indicates the hydrolysis of lipids during the demyelination process due to activation of phospholipase A2 enzyme. In addition, signals corresponding to oxidative degradation products, such as prostaglandin and hydroxyeicosatetraenoic acid, exhibited increased signal intensity by a factor of two in the negative ion mode in lesions relative to the normal healthy tissue. Analysis of malondialdehyde, a product of lipid peroxidation and marker of oxidative stress, was accomplished in the ambient environment using reactive DESI mass spectrometry imaging. This was achieved by electrospraying reagent solution containing dinitrophenylhydrazine as high velocity charged droplets onto the tissue section. The hydrazine reacts selectively and rapidly with the carbonyl groups of malondialdehyde and signal intensity of twice the intensity was detected in the lesions compared to healthy spinal cord. With a small amount of tissue sample, DESI-MS imaging provides information on the composition and distribution of specific compounds (limited by the occurrence of isomeric lipids with very similar fragmentation patterns) in lesions after spinal cord injury in comparison with normal healthy tissue allowing identification of the extent of the lesion and its repair. PMID:21142140

Cooperation of hTERT, SV40 T Antigen and Oncogenic Ras in Tumorigenesis: A Cell Transplantation Model Using Bovine Adrenocortical Cells1

PubMed Central

Thomas, Michael; Suwa, Tetsuya; Yang, Lianqing; Zhao, Lifang; Hawks, Christina L; Hornsby, Peter J

2002-01-01

Abstract Expression of TERT, the reverse transcriptase component of telomerase, is necessary to convert normal human cells to cancer cells. Despite this, “telomerization” by hTERT does not appear to alter the normal properties of cells. In a cell transplantation model in which bovine adrenocortical cells form vascularized tissue structures beneath the kidney capsule in scid mice, telomerization does not perturb the functional tissue-forming capacity of the cells. This cell transplantation model was used to study the cooperation of hTERT with SV40 T antigen (SV40 TAg) and oncogenic Ras in tumorigenesis. Only cells expressing all three genes were tumorigenic; this required large T, but not small t, antigen. These cells produced a continuously expanding tissue mass; they were invasive with respect to adjacent organs and eventually destroyed the kidney. Cells expressing only hTERT or only Ras produced minimally altered tissues. In contrast, SV40 TAg alone produced noninvasive nodules beneath the kidney capsule that had high proliferation rates balanced by high rates of apoptosis. The use of cell transplantation techniques in a cell type that is able to form tissue structures with or without full neoplastic conversion allows the phenotypes produced by individual cooperating oncogenes to be observed. PMID:12407443

Neocortical Transplants in the Mammalian Brain Lack a Blood-Brain Barrier to Macromolecules

NASA Astrophysics Data System (ADS)

Rosenstein, Jeffrey M.

1987-02-01

In order to determine whether the blood-brain barrier was present in transplants of central nervous tissue, fetal neocortex, which already possesses blood-brain and blood-cerebrospinal fluid barriers to protein, was grafted into the undamaged fourth ventricle or directly into the neocortex of recipient rats. Horseradish peroxidase or a conjugated human immunoglobulin G-peroxidase molecule was systemically administered into the host. These proteins were detected within the cortical transplants within 2 minutes regardless of the age of the donor or postoperative time. At later times these compounds, which normally do not cross the blood-brain barrier, inundated the grafts and adjacent host brain and also entered the cerebrospinal fluid. Endogenous serum albumin detected immunocytochemically in untreated hosts had a comparable although less extensive distribution. Thus, transplants of fetal central nervous tissue have permanent barrier dysfunction, probably due to microvascular changes, and are not integrated physiologically within the host. Blood-borne compounds, either systemically administered or naturally occurring, which should never contact normal brain tissue, have direct access to these transplants and might affect neuronal function.

Preliminary dosimetric study on feasibility of multi-beam boron neutron capture therapy in patients with diffuse intrinsic pontine glioma without craniotomy.

PubMed

Lee, Jia-Cheng; Chuang, Keh-Shih; Chen, Yi-Wei; Hsu, Fang-Yuh; Chou, Fong-In; Yen, Sang-Hue; Wu, Yuan-Hung

2017-01-01

Diffuse intrinsic pontine glioma is a very frustrating disease. Since the tumor infiltrates the brain stem, surgical removal is often impossible. For conventional radiotherapy, the dose constraint of the brain stem impedes attempts at further dose escalation. Boron neutron capture therapy (BNCT), a targeted radiotherapy, carries the potential to selectively irradiate tumors with an adequate dose while sparing adjacent normal tissue. In this study, 12 consecutive patients treated with conventional radiotherapy in our institute were reviewed to evaluate the feasibility of BNCT. NCTPlan Ver. 1.1.44 was used for dose calculations. Compared with two and three fields, the average maximal dose to the normal brain may be lowered to 7.35 ± 0.72 Gy-Eq by four-field irradiation. The mean ratio of minimal dose to clinical target volume and maximal dose to normal tissue was 2.41 ± 0.26 by four-field irradiation. A therapeutic benefit may be expected with multi-field boron neutron capture therapy to treat diffuse intrinsic pontine glioma without craniotomy, while the maximal dose to the normal brain would be minimized by using the four-field setting.

Preliminary dosimetric study on feasibility of multi-beam boron neutron capture therapy in patients with diffuse intrinsic pontine glioma without craniotomy

PubMed Central

Lee, Jia-Cheng; Chuang, Keh-Shih; Chen, Yi-Wei; Hsu, Fang-Yuh; Chou, Fong-In; Yen, Sang-Hue

2017-01-01

Diffuse intrinsic pontine glioma is a very frustrating disease. Since the tumor infiltrates the brain stem, surgical removal is often impossible. For conventional radiotherapy, the dose constraint of the brain stem impedes attempts at further dose escalation. Boron neutron capture therapy (BNCT), a targeted radiotherapy, carries the potential to selectively irradiate tumors with an adequate dose while sparing adjacent normal tissue. In this study, 12 consecutive patients treated with conventional radiotherapy in our institute were reviewed to evaluate the feasibility of BNCT. NCTPlan Ver. 1.1.44 was used for dose calculations. Compared with two and three fields, the average maximal dose to the normal brain may be lowered to 7.35 ± 0.72 Gy-Eq by four-field irradiation. The mean ratio of minimal dose to clinical target volume and maximal dose to normal tissue was 2.41 ± 0.26 by four-field irradiation. A therapeutic benefit may be expected with multi-field boron neutron capture therapy to treat diffuse intrinsic pontine glioma without craniotomy, while the maximal dose to the normal brain would be minimized by using the four-field setting. PMID:28662135

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

Goodman, L.R.; Teplick, S.K.; Kay, H.

The normal CT anatomy of the sternum was studied in 35 patients. In addition to the normal appearance of the sternum, normal variants that may mimic desease were often noted. In the manubrium, part of the posterior cortical margin was unsharp and irregular in 34 of 35 patients. Part of the anterior cortical margin was indistinct in 20 of the 35 patients. Angulation of the CT gantry to a position more nearly perpendicular to the manubrium improved the definition of the cortical margins. The body of the sternum was ovoid to rectangular and usually had sharp cortical margins. Sections throughmore » the manubriosternal joint and xyphoid often demonstrated irregular mottled calcifications and indistinct margins again simulating bony lesions. The rib insertions, sternal clavicular joints, and adjacent soft-tissue appearance also were evaluated.« less

Isolation and Characterization of Prostate Cancer Stem Cells

DTIC Science & Technology

2012-08-01

guidelines. Adjacent prostate tissue was snap frozen in liquid Nitrogen or fixed in formalin and paraffin-embedded to evaluate anatomy and glandular...phenotypically normal and fertile [35]. We examined the prostate at 8 and 20 weeks of age and found no difference in gross anatomy and histology among WT...gross anatomy of the prostate of WT and CD1662/2 mice at 8 weeks of age, scale bar: 2 mm. Bottom: HE staining of DLP section from WT and CD1662/2 mice

CPTAC Releases Cancer Proteome Confirmatory Breast Study Data | Office of Cancer Clinical Proteomics Research

Cancer.gov

An estimated 252,710 new cases of female breast cancer, accounting for 15% of all new cancer cases, occurred in 2017. To better understand proteogenomic abnormalities in breast cancer, the National Cancer Institute (NCI) Clinical Proteomic Tumor Analysis Consortium (CPTAC) announces the release of the cancer proteome confirmatory breast study data. The goal of the study was to comprehensively characterize the proteome and phosphoproteome on approximately 100 prospectively collected breast tumor and adjacent normal tissues.

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

PubMed Central

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

2014-01-01

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

In Vivo and In Vitro Effects of ATM/ATR Signaling Pathway on Proliferation, Apoptosis, and Radiosensitivity of Nasopharyngeal Carcinoma Cells.

PubMed

Wang, Ming; Liu, Gang; Shan, Guo-Ping; Wang, Bing-Bing

2017-08-01

The study investigated the ability of ataxia-telangiectasia mutated (ATM)/Rad3-related (ATR) signaling pathway to influence the proliferation, apoptosis, and radiosensitivity of nasopharyngeal carcinoma (NPC) cells. NPC tissues and corresponding adjacent normal tissues were collected from 143 NPC patients. The NPC CNE2 cells were assigned into a control group, X-ray group, CGK-733 group, and X-ray+CGK-733 group. The mRNA levels of ATM and ATR were evaluated using quantitative real-time polymerase chain reaction (qRT-PCR) and the protein levels of ATM and ATR using western blotting. The positive expression of ATM and ATR in tissues and nude mouse tumor tissues was determined by immunohistochemistry. Cell proliferation, migration, invasion, and apoptosis rates were analyzed by the 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di- phenytetrazoliumromide (MTT) assay, scratch test, transwell assay, and flow cytometry, respectively. A nude mouse model of NPC was established to observe tumor volume and growth. The mRNA levels of ATR and ATM and the expression of ATR and ATM protein in NPC tissues were significantly higher than those in adjacent normal tissues. The colony formation assay showed that the colony-forming rate decreased, showing radiation dose-dependent and CGK-733 concentration-dependent manners. Expression of ATM, ATR, Chk1, and Chk2 was evidently increased in the X-ray, CGK-733, and X-ray+CGK-733groups compared with the control group, and the aforementioned expression was highest in the X-ray+CGK-733 group among the four groups. The cell proliferation, invasion, and migration were decreased, tumor volume decreased and cell apoptosis increased in the X-ray, CGK-733, and X-ray+CGK-733 groups compared with the control group; the X-ray+CGK-733 group exhibited lowest cell proliferation, invasion and migration, smallest tumor volume, and highest cell apoptosis among the four groups. Inhibition of ATM/ATR signaling pathway reduces proliferation and enhances apoptosis and radiosensitivity of NPC cells.

Determination of the Nonlethal Margin Inside the Visible 'Ice-Ball' During Percutaneous Cryoablation of Renal Tissue

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

Georgiades, Christos, E-mail: g_christos@hotmail.com; Rodriguez, Ronald, E-mail: rrodrig@jhmi.edu; Azene, Ezana, E-mail: eazene1@jhmi.edu

2013-06-15

Objective. The study was designed to determine the distance between the visible 'ice-ball' and the lethal temperature isotherm for normal renal tissue during cryoablation. Methods. The Animal Care Committee approved the study. Nine adult swine were used: three to determine the optimum tissue stain and six to test the hypotheses. They were anesthetized and the left renal artery was catheterized under fluoroscopy. Under MR guidance, the kidney was ablated and (at end of a complete ablation) the nonfrozen renal tissue (surrounding the 'ice-ball') was stained via renal artery catheter. Kidneys were explanted and sent for slide preparation and examination. Frommore » each slide, we measured the maximum, minimum, and an in-between distance from the stained to the lethal tissue boundaries (margin). We examined each slide for evidence of 'heat pump' effect. Results. A total of 126 measurements of the margin (visible 'ice-ball'-lethal margin) were made. These measurements were obtained from 29 slides prepared from the 6 test animals. Mean width was 0.75 {+-} 0.44 mm (maximum 1.15 {+-} 0.51 mm). It was found to increase adjacent to large blood vessels. No 'heat pump' effect was noted within the lethal zone. Data are limited to normal swine renal tissue. Conclusions. Considering the effects of the 'heat pump' phenomenon for normal renal tissue, the margin was measured to be 1.15 {+-} 0.51 mm. To approximate the efficacy of the 'gold standard' (partial nephrectomy, {approx}98 %), a minimum margin of 3 mm is recommended (3 Multiplication-Sign SD). Given these assumptions and extrapolating for renal cancer, which reportedly is more cryoresistant with a lethal temperature of -40 Degree-Sign C, the recommended margin is 6 mm.« less

Secretagogin is a novel marker for neuroendocrine differentiation.

PubMed

Birkenkamp-Demtröder, Karin; Wagner, Ludwig; Brandt Sørensen, Flemming; Bording Astrup, Lone; Gartner, Wolfgang; Scherübl, Hans; Heine, Bernhard; Christiansen, Peer; Ørntoft, Torben Falck

2005-01-01

Our previous microarray-based studies identified secretagogin to be highly expressed in normal colon mucosa compared to basal expression in colon adenocarcinomas. The aim of this study was to analyze the differential expression of secretagogin in normal mucosa, adenocarcinomas, and neuroendocrine tumors. Western blotting, immunohistochemistry, immunofluorescence microscopy and ELISA were applied. Western blot analysis detected a 32-kDa secretagogin band in samples from normal mucosa. Immunohistochemical analyses on tissue specimens showed that secretagogin is exclusively expressed in neuroendocrine cells and nerve cells in normal mucosa of the digestive tract. Tissues adjacent to benign hyperplasic polyps and adenomas showed a decreased number of secretagogin-expressing neuroendocrine cells. Secretagogin co-localized with neuroendocrine markers (chromogranin A, neuron-specific enolase, synaptophysin) in neuroendocrine cells in crypts of normal mucosa, and in tumor cells of carcinoids. Secretagogin was strongly expressed in the cytosol and the nucleus of 19 well-differentiated neuroendocrine carcinoids and carcinoid metastases, as well as in neuroendocrine tumors from the lung, pancreas and adrenal gland. Secretagogin was detected in plasma from carcinoid patients with distant metastasis. Combined immunohistochemical analysis of secretagogin and FK506-binding protein 65, a protein de novo synthesized in adenocarcinomas, distinguished well-differentiated carcinoids, adenocarcinoids and undifferentiated carcinomas. We conclude that secretagogin is a novel marker for neuroendocrine differentiation.

Preclinical studies of vascular acting photosensitizer bacteriopheophorbide for the treatment of prostate cancer

NASA Astrophysics Data System (ADS)

Hetzel, Fred W.; Chen, Qun; Luck, David; Beckers, Jill; Huang, Zheng

2004-06-01

Photodynamic therapy (PDT) mediated with vascular acting photosensitizer pd-bacteriopheophorbide (Tookad), is investigated as an alternative modality for the total ablation of prostate cancer. In vivo normal canine prostate is used as the animal model. Interstitial PDT was performed by irradiating the surgically exposed prostates with a diode laser (763 nm, 150 mW/cm) to activate the IV infused photosensitizer drug. The prostate and its adjacent tissues were harvested and subjected to histopathological examination. At one-week post PDT, the animals recovered well with little or no urethral complications. Prostatic urethra and prostate adjacent tissues (bladder and underlying colon) were well preserved. PDT induced prostate lesions were characterized by marked hemorrhagic necrosis. Prostate lesions could be detected by MRI scan as early as 48 h post PDT. Maximum lesion size of 1.5 cm3 and 2.9 cm3 could be achieved at 50 J/cm and 100 J/cm, respectively, with interstitial treatment using a single 1-cm diffuser fiber, suggesting the Tookad-PDT is very effective in ablating prostatic tissue. Pharmacokinetic studies show that the photosensitizer is cleared rapidly from the circulation. In conclusion, the novel photosensitizer Tookad mediated PDT may provide an effective alternative to treat localized prostate cancer.

Downregulation of FOXP2 promoter human hepatocellular carcinoma cell invasion.

PubMed

Yan, Xia; Zhou, Huiling; Zhang, Tingting; Xu, Pan; Zhang, Shusen; Huang, Wei; Yang, Linlin; Gu, Xingxing; Ni, Runzhou; Zhang, Tianyi

2015-12-01

Hepatocellular carcinoma (HCC) is a major health concern with a high morbidity and mortality rate worldwide. However, the mechanism underlying hepatocarcinogenesis remains unclear. Forkhead box P2 (FOXP2) has been implicated in various human cancer types. However, the role of FOXP2 in HCC remains unknown. Western blot and immunohistochemistry were used to measure the expression of FOXP2 protein in HCC and adjacent normal tissues in 50 patients. Wound healing and transwell assays were used to determine the cell invasion ability. We showed that the level of FOXP2 was significantly reduced in HCC compared with the adjacent non-tumorous tissue. There was statistical significance between the expression of FOXP2 and vein invasion (P = 0.017), number of tumor nodes (P = 0.028), and AFP (P = 0.033). Low expression of FOXP2 correlated with poor survival. Moreover, wound healing and transwell assays showed that FOXP2 could decrease cell invasion and affect the expression of vimentin and E-cadherin. Our results suggested that FOXP2 expression was downregulated in HCC tumor tissues, and reduced FOXP2 expression was associated with poor overall survival. In addition, downregulation of FOXP2 significantly enhanced cell invasiveness. These findings uncover that FOXP2 might be a new prognostic factor and be closely correlated with HCC cell invasion.

CDX1 protein expression in normal, metaplastic, and neoplastic human alimentary tract epithelium.

PubMed

Silberg, D G; Furth, E E; Taylor, J K; Schuck, T; Chiou, T; Traber, P G

1997-08-01

CDX1 is an intestine-specific transcription factor expressed early in intestinal development that may be involved in regulation of proliferation and differentiation of intestinal epithelial cells. We examined the pattern of CDX1 protein expression in metaplastic and neoplastic tissue to provide insight into its possible role in abnormal differentiation. Tissue samples were stained by immunohistochemistry using an affinity-purified, polyclonal antibody against a peptide epitope of CDX1. Specific nuclear staining was found in epithelial cells of the small intestine and colon. Esophagus and stomach did not express CDX1 protein; however, adjacent areas of intestinal metaplastic tissue intensely stained for CDX1. Adenocarcinomas of the stomach and esophagus had both positive and negative nuclear staining for CDX1. Colonic epithelial cells in adenomatous polyps and adenocarcinomas had a decreased intensity of staining compared with normal colonic crypts in the same specimen. CDX1 may be important in the transition from normal gastric and esophageal epithelium to intestinal-type metaplasia. The variability in expression of CDX1 in gastric and esophageal adenocarcinomas suggests more than one pathway in the development of these carcinomas. The decrease of CDX1 in colonic adenocarcinomas may indicate a role for CDX1 in growth regulation and in the maintenance of the differentiated phenotype.

Metastasis Infiltration: An Investigation of the Postoperative Brain-Tumor Interface

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

Raore, Bethwel; Schniederjan, Matthew; Prabhu, Roshan

Purpose: This study aims to evaluate brain infiltration of metastatic tumor cells past the main tumor resection margin to assess the biological basis for the use of stereotactic radiosurgery treatment of the tumor resection cavity and visualized resection edge or clinical target volume. Methods and Materials: Resection margin tissue was obtained after gross total resection of a small group of metastatic lesions from a variety of primary sources. The tissue at the border of the tumor and brain tissue was carefully oriented and processed to evaluate the presence of tumor cells within brain tissue and their distance from the resectionmore » margin. Results: Microscopic assessment of the radially oriented tissue samples showed no tumor cells infiltrating the surrounding brain tissue. Among the positive findings were reactive astrocytosis observed on the brain tissue immediately adjacent to the tumor resection bed margin. Conclusions: The lack of evidence of metastatic tumor cell infiltration into surrounding brain suggests the need to target only a narrow depth of the resection cavity margin to minimize normal tissue injury and prevent treatment size-dependent stereotactic radiosurgery complications.« less

Methylation of S100A8 is a promising diagnosis and prognostic marker in hepatocellular carcinoma.

PubMed

Liu, Kun; Zhang, Yuening; Zhang, Chengdong; Zhang, Qinle; Li, Jiatong; Xiao, Feifan; Li, Yingfang; Zhang, Ruoheng; Dou, Dongwei; Liang, Jiezhen; Qin, Jian; Lin, Zhidi; Zhao, Dong; Jiang, Min; Liang, Zhenxin; Su, Jie; Gupta, Vanaparthy Pranay; He, Min; Yang, Xiaoli

2016-08-30

The abnormality of DNA methylation is one of the major epigenetic alterations in the human hepatocellular carcinoma (HCC). We have assessed the global genomic DNA methylation profiles in human HCC patients by using the Infinium Human Methylation27 BeadChip. A CpG loci of S100A8 was found to be significantly hypomethylated in HCC.Pooled meta-analysis of five validation public datasets demonstrated its methylation level was significantly lower for HCC compared to paired adjacent normal tissues. Quantitative pyrosequencing analysis also showed that the S100A8 methylation level was decreased in cancer tissues (31.90%±13.31%) than that in the paired adjacent normal tissues (65.33%±3.64%, p<0.01). The area under the ROC curve (AUC) value was 0.950 (p<0.01). Kaplan-Meier survival curves revealed that hypomethylation of S100A8 was associated with shortened overall survival (OS) and progression-free survival (PFS) (log rank p<0.05). Multivariate Cox proportional hazards model also indicated significantly shorter OS (HR, 1.709; 95 % CI, 1.127-2.591) and PFS (HR, 1.767; 95 % CI, 1.168-2.974) were observed in the low-methylation-level group compared to the high-methylation-level group. Furthermore, S100A8 overexpression in Huh7 and MHCC-97H hepatoma cell lines led to increased cell proliferation, migration, invasion, and tumor growth. These findings suggested S100A8 methylation to be served as potential diagnosis and prognosis marker for HCC. S100A8 also may play as a tumor promoter in HCC.

Methylation of S100A8 is a promising diagnosis and prognostic marker in hepatocellular carcinoma

PubMed Central

Xiao, Feifan; Li, Yingfang; Zhang, Ruoheng; Dou, Dongwei; Liang, Jiezhen; Qin, Jian; Lin, Zhidi; Zhao, Dong; Jiang, Min; Liang, Zhenxin; Su, Jie; Gupta, Vanaparthy Pranay; He, Min; Yang, Xiaoli

2016-01-01

The abnormality of DNA methylation is one of the major epigenetic alterations in the human hepatocellular carcinoma (HCC). We have assessed the global genomic DNA methylation profiles in human HCC patients by using the Infinium Human Methylation27 BeadChip. A CpG loci of S100A8 was found to be significantly hypomethylated in HCC. Pooled meta-analysis of five validation public datasets demonstrated its methylation level was significantly lower for HCC compared to paired adjacent normal tissues. Quantitative pyrosequencing analysis also showed that the S100A8 methylation level was decreased in cancer tissues (31.90%±13.31%) than that in the paired adjacent normal tissues (65.33%±3.64%, p<0.01). The area under the ROC curve (AUC) value was 0.950 (p<0.01). Kaplan-Meier survival curves revealed that hypomethylation of S100A8 was associated with shortened overall survival (OS) and progression-free survival (PFS) (log rank p<0.05). Multivariate Cox proportional hazards model also indicated significantly shorter OS (HR, 1.709; 95 % CI, 1.127–2.591) and PFS (HR, 1.767; 95 % CI, 1.168–2.974) were observed in the low-methylation-level group compared to the high-methylation-level group. Furthermore, S100A8 overexpression in Huh7 and MHCC-97H hepatoma cell lines led to increased cell proliferation, migration, invasion, and tumor growth. These findings suggested S100A8 methylation to be served as potential diagnosis and prognosis marker for HCC. S100A8 also may play as a tumor promoter in HCC. PMID:27462864

Prognostic value of tripartite motif containing 29 expression in patients with gastric cancer following surgical resection.

PubMed

Wang, Chenghu; Zhou, Yi; Chen, Beibei; Yuan, Weiwei; Huang, Jinxi

2018-04-01

Tripartite motif containing 29 (TRIM29) dysregulation serves an important function in the progression of numerous types of cancer, but its function in the prognosis of patients with gastric cancer remains unknown. The present study assessed the prognostic value of TRIM29 in patients with gastric cancer following surgical resection. A total of 243 fresh gastric adenocarcinoma and adjacent normal tissues were continuously retrieved from patients who underwent curative surgery for gastric cancer at the Cancer Hospital of Henan Province (Zhengzhou, China) between January 2005 and December 2011. The reverse transcription-quantitative polymerase chain reaction was performed to assess TRIM29 expression. The association between TRIM29 expression and clinicopathological features and prognosis was subsequently evaluated. The results of the present study revealed that the expression of TRIM29 was increased in the gastric cancer tissues compared with the normal adjacent tissues, and that upregulated expression of TRIM29 was associated with tumor cell differentiation, tumor stage, lymph node metastasis, and tumor-node-metastasis (TNM) stage. In the training and validation data, high TRIM29 expression was associated with poor overall survival in patients with gastric cancer. Furthermore, multivariate analysis identified that TRIM29 expression was an independent prognostic factor for overall survival, in addition to TNM stage and Lauren classification. Combining TRIM29 expression with the TNM staging system generated a novel predictive model that exhibited improved prognostic accuracy for overall survival in patients with gastric cancer. The present study revealed that TRIM29 was an independent adverse prognostic factor in patients with gastric cancer. Incorporating TRIM29 expression level into the TNM staging system may improve risk stratification and render prognosis more accurate in patients with gastric cancer.

Metastasis-associated gene 1 expression in human medulloblastoma and its association with invasion and metastasis in medulloblastoma Daoy cell lines.

PubMed

Chen, Y S; Li, S P; Xiao, H; Xie, Z Y; Tan, M X; Liu, B; Zhang, W M

2016-06-17

This study aims to investigate the expression of metastasis-associated gene 1 (MTA1) in human medulloblastoma, and its significance in the invasion and metastasis in a medulloblastoma cell line. Positive expression rate of MTA1 protein in medulloblastoma and adjacent normal tissues collected from 29 medulloblastoma patients was detected by immunohistochemistry assay in vivo. In in vitro experiments, Daoy cells were transfected with MTA1-targeted small interfering RNA (siRNA, MTA1-siRNA group), niRNA (MTA1-niRNA group), and plasmid vectors (control group). Transfection efficiency was evaluated by PT-PCR and western blot; cell adhesion, migration, and invasion capacity was assessed by adhesion assays, scratch assays, and transwell chamber invasion assays, respectively. Results indicated that the positive expression rate of MTA1 protein in the medulloblastoma tissues was higher as compared with that of the adjacent normal tissues (P < 0.05). In addition, mRNA and protein expression of MTA1 in the MTA1-siRNA group was lower than that in the control and MTA1- niRNA groups (P < 0.05). Adhesion, migration, and invasion capacity of Daoy cells in the MTA1-siRNA group was inhibited as compared with the control and MTA1-niRNA groups (P < 0.05). In conclusion, MTA1 expression was increased in medulloblastoma cells, while MTA1 knockdown in medulloblastoma cells inhibited MTA1 expression. In addition, MTA1 knockdown inhibited the adhesion, migration, and invasive capabilities of medulloblastoma cells. It is possible that MTA1 can serve as a biomarker and a potential therapeutic target for medulloblastoma.

FBXW7 expression affects the response to chemoradiotherapy and overall survival among patients with oral squamous cell carcinoma: A single-center retrospective study.

PubMed

Arita, Hidetaka; Nagata, Masashi; Yoshida, Ryoji; Matsuoka, Yuichiro; Hirosue, Akiyuki; Kawahara, Kenta; Sakata, Junki; Nakashima, Hikaru; Kojima, Taku; Toya, Ryo; Murakami, Ryuji; Hiraki, Akimitsu; Shinohara, Masanori; Nakayama, Hideki

2017-10-01

FBXW7 (F-box and WD repeat domain containing-7) is a tumor suppressor protein that regulates the degradation of various oncoproteins in several malignancies. However, limited information is available regarding FBXW7 expression in oral squamous cell carcinoma. Therefore, this study aimed to determine the clinical significance of FBXW7 expression in oral squamous cell carcinoma. The FBXW7 expression patterns in oral squamous cell carcinoma and adjacent normal tissues from 15 patients who underwent radical resection were evaluated using quantitative real-time polymerase chain reaction and immunohistochemical staining. In addition, immunohistochemistry was performed using paraffin-embedded sections from biopsy specimens obtained from 110 patients with oral squamous cell carcinoma who underwent surgery after 5 fluorouracil-based chemoradiotherapy. The associations of FBXW7 expression with various clinicopathological features and prognosis were evaluated in these patients. As a results, in the 15 matched samples, the FBXW7 expression was significantly decreased in the oral squamous cell carcinoma tissues compared to that in the adjacent normal tissues. In the clinicopathological analysis, compared to high protein expression, low FBXW7 expression was found to significantly associate with a poor histological response to preoperative chemoradiotherapy. Kaplan-Meier curve analysis revealed that low FBXW7 expression was significantly associated with a poor prognosis, and FBXW7 expression was found to be an independent predictor of overall survival in the multivariate analysis. Our results suggest that FBXW7 may function as a tumor suppressor protein in oral squamous cell carcinoma. In addition, FBXW7 could be a potential biomarker for predicting not only the clinical response to chemoradiotherapy but also overall survival in patients with oral squamous cell carcinoma.

Expression Levels and Clinical Significance of miR-21-5p, miR-let-7a, and miR-34c-5p in Laryngeal Squamous Cell Carcinoma

PubMed Central

Gioacchini, Federico M.; Çeka, Artan; Rubini, Corrado; Ferrante, Luigi; Procopio, Antonio D.; Olivieri, Fabiola

2017-01-01

Objective Altered microRNAs (miRNAs) expression has been found in many cancer types, including laryngeal squamous cell carcinoma (LSCC). The aim of this study was to determine the role and clinical value of three LSCC-related miRs, such as miR-21-5p, miR-let-7a, and miR-34c-5p in a homogeneous cohort of patients with primary LSCC treated by primary surgery. Methods Expression levels of miR-21-5p, miR-let-7a, and miR-34c-5p were detected in 43 pairs of LSCC and adjacent normal tissues by reverse-transcription quantitative PCR. Overall survival and disease-free survival were evaluated using the Kaplan–Meier method, and multivariate analysis was performed using the Cox proportional hazard analysis. Results miR-21-5p is significantly upregulated, while miR-let-7a is significantly downregulated in LSCC tumor tissues compared with the corresponding adjacent normal tissues. The downregulation of miR-34c-5p expression significantly correlated with a shorter disease-free survival and, in the multivariate analysis, low miR-34c-5p expression was associated with an increased risk of recurrence. Conclusions miR-21-5p, miR-let-7a, and miR-34c-5p seem to play a critical role in LSCC carcinogenesis and might have a diagnostic and prognostic clinical value. The miR-let-7a levels could have a predictive role for lymph node metastases and miR-34c-5p might be a promising biomarker of patient outcome. PMID:29082244

Clinicopathological Characteristics of Patients with Gastric Cancer according to the Expression of LIN28A.

PubMed

Park, Chan Hyuk; Lee, Jung Hwa; Lee, Na Keum; Lee, Yong Chan; Lee, Sang Kil

2016-09-15

Although LIN28A is known to potentially play a role in the oncogenesis of various cancers, whether LIN28A expression is a predictor of poor prognosis in patients with gastric cancer has not been fully explored. We sought to evaluate clinicopathological characteristics according to the expression of LIN28A in numerous gastric cancer tissue samples. LIN28A expression was evaluated by immunohistochemical (IHC) analysis of a tissue microarray comprising 288 gastric cancer tissues and 288 adjacent normal tissues. Clinicopathological characteristics, including overall survival, were compared according to LIN28A expression. The IHC staining score was lower for the cancer tissues than the normal tissues (p<0.001). However, no significant differences were observed in the clinicopathological characteristics between the low and high LIN28A expression groups. In addition, the 5-year overall survival rate did not differ between the two groups: 75.3% (95% confidence interval [CI], 69.3% to 81.7%) versus 71.6% (95% CI, 63.3% to 80.9%) for low versus high expression, respectively. The expression of LIN28A did not appear to play a distinct role in predicting the clinicopathological characteristics of patients with gastric cancer. In addition, LIN28A expression was not an independently associated factor for overall survival in patients with gastric cancer.

Preclinical studies of photodynamic therapy of intracranial tissues

NASA Astrophysics Data System (ADS)

Lilge, Lothar D.; Sepers, Marja; Park, Jane; O'Carroll, Cindy; Pournazari, Poupak; Prosper, Joe; Wilson, Brian C.

1997-05-01

The applicability and limitations of the photodynamic threshold model were investigated for an intracranial tumor (VX2) and normal brain tissues in a rabbit model. Photodynamic threshold values for four different photosensitizers, i.e., Photofrin, 5(delta) -aminolaevulinic acid (5(delta) -ALA) induced Protoporphyrin IX (PPIX), Tin Ethyl Etiopurpurin (SnET2), and chloroaluminum phthalocyanine (AlClPc), were determined based on measured light fluence distributions, macroscopic photosensitizer concentration in various brain structures, and histologically determined extent of tissue necrosis following PDT. For Photofrin, AlClPc, and SnET2, normal brain displayed a significantly lower threshold value than VX2 tumor. For 5(delta) -ALA induced PPIX and SnET2 no or very little white matter damage, equalling to very high or infinite threshold values, was observed. Additionally, the latter two photosensitizers showed significantly lower uptake in white matter compared to other brain structures and VX2 tumor. Normal brain structures lacking a blood- brain-barrier, such as the choroid plexus and the meninges, showed high photosensitizer uptake for all photosensitizers, and, hence, are at risk when exposed to light. Results to date suggest that the photodynamic threshold values iares valid for white matter, cortex and VX2 tumor. For clinical PDT of intracranial neoplasms 5(delta) -ALA induced PPIX and SnET2 appear to be the most promising for selective tumor necrosis.However, the photosensitizer concentration in each normal brain structure and the fluence distribution throughout the treatment volume and adjacent tissues at risk must be monitored to maximize the selectivity of PDT for intracranial tumors.

Astrogliosis and impaired aquaporin-4 and dystrophin systems in idiopathic normal pressure hydrocephalus.

PubMed

Eide, P K; Hansson, H-A

2017-06-19

Idiopathic normal pressure hydrocephalus (iNPH) is one subtype of dementia that may improve following drainage of cerebrospinal fluid (CSF). This prospective observational study explored whether expression of the water channel aquaporin-4 (AQP4) and the anchoring molecule dystrophin 71 (Dp71) are altered at astrocytic perivascular endfeet and in adjacent neuropil of iNPH patient. Observations were related to measurements of pulsatile and static intracranial pressure (ICP). The study included iNPH patients undergoing overnight monitoring of the pulsatile/static ICP in whom a biopsy was taken from the frontal cerebral cortex during placement of the ICP sensor. Reference (Ref) biopsies were sampled from 13 patients who underwent brain surgery for epilepsy, tumours or cerebral aneurysms. The brain tissue specimens were examined by light microscopy, immunohistochemistry, densitometry and morphometry. iNPH patients responding to surgery (n = 44) had elevated pulsatile ICP, indicative of impaired intracranial compliance. As compared to the Ref patients, the cortical biopsies of iNPH patients revealed prominent astrogliosis and reduced expression of AQP4 and Dp71 immunoreactivities in the astrocytic perivascular endfeet and in parts of the adjacent neuropil. There was a significant correlation between degree of astrogliosis and reduction of AQP4 and Dp71 at astrocytic perivascular endfeet. Idiopathic normal pressure hydrocephalus patients responding to CSF diversion present with abnormal pulsatile ICP, indicative of impaired intracranial compliance. A main histopathological finding was astrogliosis and reduction of AQP4 and of Dp71 in astrocytic perivascular endfeet. We propose that the altered AQP4 and Dp71 complex contributes to the subischaemia prevalent in the brain tissue of iNPH. © 2017 British Neuropathological Society.

Wide excision of soft tissues adjacent to the ovary and fallopian tube does not impair the ovarian reserve in women undergoing prophylactic bilateral salpingectomy: results from a randomized, controlled trial.

PubMed

Venturella, Roberta; Morelli, Michele; Lico, Daniela; Di Cello, Annalisa; Rocca, Morena; Sacchinelli, Angela; Mocciaro, Rita; D'Alessandro, Pietro; Maiorana, Antonio; Gizzo, Salvatore; Zullo, Fulvio

2015-11-01

To study the effects of the wide excision of soft tissues adjacent to the ovary and fallopian tube on ovarian function and surgical outcomes in women undergoing laparoscopic bilateral prophylactic salpingectomy. Randomized, controlled trial. Teaching hospital. One hundred eighty-six women undergoing laparoscopic surgery for uterine myoma (n = 143) or tubal surgical sterilization (n = 43). Patients were randomly divided into two groups. In group A (n = 91), standard salpingectomy was performed. In group B (n = 95), the mesosalpinx was removed within the tubes. Prior to and 3 months after surgery, antimüllerian hormone (AMH), FSH, three-dimensional antral follicle count (AFC), vascular index (VI), flow index (FI), vascular-flow index (VFI), and OvAge were recorded for each patient. Ovarian reserve modification (Δ) before and after surgery was assessed as the primary outcome. Operative time, variation of the hemoglobin level (ΔHb), postoperative hospital stay, postoperative return to normal activity, and complication rate were assessed as secondary outcomes. No significant difference was observed between groups for ΔAMH, ΔFSH, ΔAFC, ΔVI, ΔFI, ΔVFI, and ΔOvAge. Moreover, the groups were similar for operative time, ΔHb, postoperative hospital stay, postoperative return to normal activity, and complication rate. Even when the surgical excision includes the removal of the mesosalpinx, salpingectomy does not damage the ovarian reserve. Moreover, wide salpingectomy with excision of the mesosalpinx did not alter blood loss, hospitalization stay, or return to normal activities. NCT02086370. Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Aberrant upregulation of MUC4 mucin expression in cutaneous condyloma acuminatum and squamous cell carcinoma suggests a potential role in the diagnosis and therapy of skin diseases.

PubMed

Chakraborty, Subhankar; Swanson, Benjamin J; Bonthu, Neelima; Batra, Surinder K

2010-07-01

Mucins comprise a family of high-molecular-weight glycoproteins. MUC4, a large transmembrane mucin, has recently emerged as a novel marker for diagnosis, prognosis and therapy in several malignancies. However, its role in skin pathologies remains unknown. The aim of this study was to analyse the expression of MUC4 in cutaneous pathologies by immunohistochemistry for potential diagnostic, prognostic and therapeutic applications. A total of 330 tissue spots representing the normal skin, and benign and malignant cutaneous diseases, were analysed after staining with the monoclonal antibody to human MUC4 (clone 8G7). While the normal epidermis showed a negative to weak-positive expression of MUC4, its expression was significantly upregulated in squamous cell carcinomas (SCCs) where the intensity of staining correlated negatively with tumour grade and positively with age. A moderately strong MUC4 expression was also noted in 2/20 cancer adjacent normal skin and 2/21 chronically inflamed skin tissues, while 10/19 cases of vulval condyloma acuminate, 3/12 of vulval hyperplasia and 2 cases of verruca vulgaris also showed strong MUC4 positivity. Malignant melanoma, basal cell carcinoma and cutaneous cysts were negative. The results indicate that MUC4 expression is aberrantly upregulated in cutaneous SCCs, vulval condylomas and verruca vulgaris. Further, it appears that MUC4 expression in the skin may be modulated by chronic inflammation and the presence of an adjacent cutaneous malignancy in certain cases. These observations suggest a novel role for MUC4 mucin in the pathogenesis of cutaneous SCC and a possible application as a diagnostic and/or prognostic marker in cutaneous pathologies.

Synchrotron X-ray microtransections: a non invasive approach for epileptic seizures arising from eloquent cortical areas

PubMed Central

Pouyatos, B.; Nemoz, C.; Chabrol, T.; Potez, M.; Bräuer, E.; Renaud, L.; Pernet-Gallay, K.; Estève, F.; David, O.; Kahane, P.; Laissue, J. A.; Depaulis, A.; Serduc, R.

2016-01-01

Synchrotron-generated X-ray (SRX) microbeams deposit high radiation doses to submillimetric targets whilst minimizing irradiation of neighboring healthy tissue. We developed a new radiosurgical method which demonstrably transects cortical brain tissue without affecting adjacent regions. We made such image-guided SRX microtransections in the left somatosensory cortex in a rat model of generalized epilepsy using high radiation doses (820 Gy) in thin (200 μm) parallel slices of tissue. This procedure, targeting the brain volume from which seizures arose, altered the abnormal neuronal activities for at least 9 weeks, as evidenced by a decrease of seizure power and coherence between tissue slices in comparison to the contralateral cortex. The brain tissue located between transections stayed histologically normal, while the irradiated micro-slices remained devoid of myelin and neurons two months after irradiation. This pre-clinical proof of concept highlights the translational potential of non-invasive SRX transections for treating epilepsies that are not eligible for resective surgery. PMID:27264273

Synchrotron X-ray microtransections: a non invasive approach for epileptic seizures arising from eloquent cortical areas

NASA Astrophysics Data System (ADS)

Pouyatos, B.; Nemoz, C.; Chabrol, T.; Potez, M.; Bräuer, E.; Renaud, L.; Pernet-Gallay, K.; Estève, F.; David, O.; Kahane, P.; Laissue, J. A.; Depaulis, A.; Serduc, R.

2016-06-01

Synchrotron-generated X-ray (SRX) microbeams deposit high radiation doses to submillimetric targets whilst minimizing irradiation of neighboring healthy tissue. We developed a new radiosurgical method which demonstrably transects cortical brain tissue without affecting adjacent regions. We made such image-guided SRX microtransections in the left somatosensory cortex in a rat model of generalized epilepsy using high radiation doses (820 Gy) in thin (200 μm) parallel slices of tissue. This procedure, targeting the brain volume from which seizures arose, altered the abnormal neuronal activities for at least 9 weeks, as evidenced by a decrease of seizure power and coherence between tissue slices in comparison to the contralateral cortex. The brain tissue located between transections stayed histologically normal, while the irradiated micro-slices remained devoid of myelin and neurons two months after irradiation. This pre-clinical proof of concept highlights the translational potential of non-invasive SRX transections for treating epilepsies that are not eligible for resective surgery.

Predictive Genes in Adjacent Normal Tissue Are Preferentially Altered by sCNV during Tumorigenesis in Liver Cancer and May Rate Limiting

PubMed Central

Lamb, John R.; Zhang, Chunsheng; Xie, Tao; Wang, Kai; Zhang, Bin; Hao, Ke; Chudin, Eugene; Fraser, Hunter B.; Millstein, Joshua; Ferguson, Mark; Suver, Christine; Ivanovska, Irena; Scott, Martin; Philippar, Ulrike; Bansal, Dimple; Zhang, Zhan; Burchard, Julja; Smith, Ryan; Greenawalt, Danielle; Cleary, Michele; Derry, Jonathan; Loboda, Andrey; Watters, James; Poon, Ronnie T. P.; Fan, Sheung T.; Yeung, Chun; Lee, Nikki P. Y.; Guinney, Justin; Molony, Cliona; Emilsson, Valur; Buser-Doepner, Carolyn; Zhu, Jun; Friend, Stephen; Mao, Mao; Shaw, Peter M.; Dai, Hongyue; Luk, John M.; Schadt, Eric E.

2011-01-01

Background In hepatocellular carcinoma (HCC) genes predictive of survival have been found in both adjacent normal (AN) and tumor (TU) tissues. The relationships between these two sets of predictive genes and the general process of tumorigenesis and disease progression remains unclear. Methodology/Principal Findings Here we have investigated HCC tumorigenesis by comparing gene expression, DNA copy number variation and survival using ∼250 AN and TU samples representing, respectively, the pre-cancer state, and the result of tumorigenesis. Genes that participate in tumorigenesis were defined using a gene-gene correlation meta-analysis procedure that compared AN versus TU tissues. Genes predictive of survival in AN (AN-survival genes) were found to be enriched in the differential gene-gene correlation gene set indicating that they directly participate in the process of tumorigenesis. Additionally the AN-survival genes were mostly not predictive after tumorigenesis in TU tissue and this transition was associated with and could largely be explained by the effect of somatic DNA copy number variation (sCNV) in cis and in trans. The data was consistent with the variance of AN-survival genes being rate-limiting steps in tumorigenesis and this was confirmed using a treatment that promotes HCC tumorigenesis that selectively altered AN-survival genes and genes differentially correlated between AN and TU. Conclusions/Significance This suggests that the process of tumor evolution involves rate-limiting steps related to the background from which the tumor evolved where these were frequently predictive of clinical outcome. Additionally treatments that alter the likelihood of tumorigenesis occurring may act by altering AN-survival genes, suggesting that the process can be manipulated. Further sCNV explains a substantial fraction of tumor specific expression and may therefore be a causal driver of tumor evolution in HCC and perhaps many solid tumor types. PMID:21750698

Tissue Expanders and Proton Beam Radiotherapy: What You Need to Know

PubMed Central

Howarth, Ashley L.; Niska, Joshua R.; Brooks, Kenneth; Anand, Aman; Bues, Martin; Vargas, Carlos E.

2017-01-01

Summary: Proton beam radiotherapy (PBR) has gained acceptance for the treatment of breast cancer because of unique beam characteristics that allow superior dose distributions with optimal dose to the target and limited collateral damage to adjacent normal tissue, especially to the heart and lungs. To determine the compatibility of breast tissue expanders (TEs) with PBR, we evaluated the structural and dosimetric properties of 2 ex vivo models: 1 model with internal struts and another model without an internal structure. Although the struts appeared to have minimal impact, we found that the metal TE port alters PBR dynamics, which may increase proton beam range uncertainty. Therefore, submuscular TE placement may be preferable to subcutaneous TE placement to reduce the interaction of the TE and proton beam. This will reduce range uncertainty and allow for more ideal radiation dose distribution. PMID:28740794

Magnetic resonance guided high-intensity focused ultrasound ablation of musculoskeletal tumors

PubMed Central

Avedian, Raffi S.; Gold, Garry; Ghanouni, Pejman; Pauly, Kim Butts

2015-01-01

This article reviews the fundamental principles and clinical experimental uses of magnetic resonance guided high-intensity focused ultrasound (MRgHIFU) ablation of musculoskeletal tumors. MRgHIFU is a noninvasive treatment modality that takes advantage of the ability of magnetic resonance to measure tissue temperature and uses this technology to guide high-intensity focused ultrasound waves to a specific focus within the human body that results in heat generation and complete thermal necrosis of the targeted tissue. Adjacent normal tissues are spared because of the accurate delivery of thermal energy, as well as, local blood perfusion that provides a cooling effect. MRgHIFU is approved by the Food and Drug Administration for the treatment of uterine fibroids and is used on an experimental basis to treat breast, prostate, liver, bone, and brain tumors. PMID:26120376

TUSC3 induces autophagy in human non-small cell lung cancer cells through Wnt/β-catenin signaling

PubMed Central

Peng, Yun; Cao, Jun; Yao, Xiao-Yi; Wang, Jian-Xin; Zhong, Mei-Zuo; Gan, Ping-Ping; Li, Jian-Huang

2017-01-01

We investigated the effects of tumor suppressor candidate 3 (TUSC3) on autophagy in human non-small cell lung cancer (NSCLC) cells. A total of 118 NSCLC patients (88 males and 30 females) who underwent surgery at our institute were enrolled in the study. Immunohistochemical analysis revealed that TUSC3 protein expression was lower in NSCLC specimens than adjacent normal tissue. Correspondingly, there was greater methylation of TUSC3 in NSCLC than adjacent normal tissue. After transient transfection of A549 NSCLC cells with constructs designed to up-regulate or down-regulate TUSC3 expression, we analyzed the effects of inhibiting the Wnt pathway (XAV939) and autophagy (chloroquine, CQ) on the behavior of NSCLC cells. We also performed TOP/FOP-Flash reporter assays, MTT assays, Annexin V-FITC/propidium iodide staining, and acridine orange staining to evaluate Wnt/β-catenin signaling, cell proliferation, apoptosis, and autophagy, respectively. Expression of Wnt/β-catenin pathway components and autophagy-related proteins was analyzed using qRT-PCR and Western blotting. We found that TUSC3 inhibited cell proliferation and promoted both apoptosis and autophagy in A549 cells. In addition, TUSC3 increased expression of autophagy-related proteins. It also increased expression of Wnt/β-catenin signaling pathway components and promoted nuclear transfer of β-catenin, resulting in activation of Wnt/β-catenin signaling. TUSC3 thus induces autophagy in human NSCLC cells through activation of the Wnt/β-catenin signaling pathway. PMID:28881786

TUSC3 induces autophagy in human non-small cell lung cancer cells through Wnt/β-catenin signaling.

PubMed

Peng, Yun; Cao, Jun; Yao, Xiao-Yi; Wang, Jian-Xin; Zhong, Mei-Zuo; Gan, Ping-Ping; Li, Jian-Huang

2017-08-08

We investigated the effects of tumor suppressor candidate 3 ( TUSC3 ) on autophagy in human non-small cell lung cancer (NSCLC) cells. A total of 118 NSCLC patients (88 males and 30 females) who underwent surgery at our institute were enrolled in the study. Immunohistochemical analysis revealed that TUSC3 protein expression was lower in NSCLC specimens than adjacent normal tissue. Correspondingly, there was greater methylation of TUSC3 in NSCLC than adjacent normal tissue. After transient transfection of A549 NSCLC cells with constructs designed to up-regulate or down-regulate TUSC3 expression, we analyzed the effects of inhibiting the Wnt pathway (XAV939) and autophagy (chloroquine, CQ) on the behavior of NSCLC cells. We also performed TOP/FOP-Flash reporter assays, MTT assays, Annexin V-FITC/propidium iodide staining, and acridine orange staining to evaluate Wnt/β-catenin signaling, cell proliferation, apoptosis, and autophagy, respectively. Expression of Wnt/β-catenin pathway components and autophagy-related proteins was analyzed using qRT-PCR and Western blotting. We found that TUSC3 inhibited cell proliferation and promoted both apoptosis and autophagy in A549 cells. In addition, TUSC3 increased expression of autophagy-related proteins. It also increased expression of Wnt/β-catenin signaling pathway components and promoted nuclear transfer of β-catenin, resulting in activation of Wnt/β-catenin signaling. TUSC3 thus induces autophagy in human NSCLC cells through activation of the Wnt/β-catenin signaling pathway.

Reduced m6A mRNA methylation is correlated with the progression of human cervical cancer

PubMed Central

Kong, Beihua; Song, Chen; Cong, Jianglin; Hou, Jianqing; Wang, Shaoguang

2017-01-01

The m6A mRNA methylation involves in mRNA splicing, degradation and translation. Recent studies have revealed that reduced m6A mRNA methylation might promote cancer development. However, the role of m6A mRNA methylation in cervical cancer development remains unknown. Therefore, we investigated the role of m6A methylation in cervical cancer in the current study. We first evaluated the m6A mRNA methylation level in 286 pairs of cervical cancer samples and their adjacent normal tissues by dot blot assay. Then the role of m6A on patient survival rates and cervical cancer progression were assessed. The m6A level was significantly reduced in the cervical cancer when comparing with the adjacent normal tissue. The m6A level reduction was significantly correlated with the FIGO stage, tumor size, differentiation, lymph invasion and cancer recurrence. It was also shown to be an independent prognostic indicator of disease-free survival and overall survival for patients with cervical cancer. Reducing m6A level via manipulating the m6A regulators expression promoted cervical cancer cell proliferation. And increasing m6A level significantly suppressed tumor development both in vitro and in vivo. Our results showed that the reduced m6A level is tightly associated with cervical cancer development and m6A mRNA methylation might be a potential therapeutic target in cervical cancer. PMID:29228737

[Tripartite-motif protein 25 and pyruvate kinase M2 protein expression in non-small cell lung cancer].

PubMed

Jing, Huai-Zhi; Qiu, Feng; Chen, Shi-Zhi; Su, Lin; Qu, Can

2015-03-01

To investigate the expression of tripartite-motif protein 25 (TRIM25) and pyruvate kinase M2 (PKM2) protein in non-small cell lung cancer (NSCLC) and explore their role in the occurrence and progression of NSCLC. The expressions of TRIM25 and PKM2 protein were detected in 60 NSCLC specimens and 20 adjacent normal lung tissue (>5 cm from the lesions) with immunofluorescence histochemical method and in 10 fresh specimens of NSCLC with Western blotting. The results were analyzed in relation with the clinicopathological features of the patients. The positivity rates of TRIM25 expression was 45% in the 60 lung carcinoma specimens, significantly higher than that in the 20 normal lung tissues (10%, P=0.005). TRIM25 protein was expressed in 28.6% of lung adenocarcinoma tissues and in 59.4% of squamous carcinoma tissues (P=0.017). TRIM25 protein expression was positively correlated with the TNM stages and lymph node metastasis of NSCLC (P<0.05). The expressions of PKM2 protein in 60 cases of lung carcinoma was 73.3%,while in 20 cases of normal lung tissues the expressions was 30%(P=0.001). The positivity rates of PKM2 expression differed significantly between lung adenocarcinoma and squamous carcinoma (57.1% vs 87.5%, P=0.008). An inverse correlation was noted between TRIM25 and PKM2 expressions (P=0.026). TRIM25 and PKM2 protein may participate in the occurrence and progression of NSCLC, and their expressions are inversely correlated.

Detecting skin malignancy using elastic light scattering spectroscopy

NASA Astrophysics Data System (ADS)

Canpolat, Murat; Akman, Ayşe; Çiftçioğlu, M. Akif; Alpsoy, Erkan

2007-07-01

We have used elastic light scattering spectroscopy to differentiate between malign and benign skin lesions. The system consists of a UV spectrometer, a single optical fiber probe and a laptop. The single optical fiber probe was used for both delivery and detection of white light to tissue and from the tissue. The single optical fiber probe received singly scattered photons rather than diffused photons in tissue. Therefore, the spectra are correlated with morphological differences of the cells. It has been shown that spectra of malign skin lesions are different than spectra of benign skin lesions. While slopes of the spectra taken on benign lesions or normal skin tissues were positive, slopes of the spectra taken on malign skin lesions tissues were negative. In vivo experiments were conducted on 20 lesions from 18 patients (11 men with mean age of 68 +/- 9 years and 7 women with mean age of 52 +/- 20 years) applied to the Department of Dermatology and Venerology. Before the biopsy, spectra were taken on the lesion and adjacent (approximately 1 cm distant) normal-appearing skin. Spectra of the normal skin were used as a control group. The spectra were correlated to the pathology results with sensitivity and specificity of 82% and 89%, respectively. Due to small diameter of fiber probe and limited number of sampling (15), some positive cases are missed, which is lowered the sensitivity of the system. The results are promising and could suggest that the system may be able to detect malignant skin lesion non-invasively and in real time.

Anti-EGFRvIII Chimeric Antigen Receptor-Modified T Cells for Adoptive Cell Therapy of Glioblastoma

PubMed Central

Ren, Pei-pei; Li, Ming; Li, Tian-fang; Han, Shuang-yin

2017-01-01

Glioblastoma (GBM) is one of the most devastating brain tumors with poor prognosis and high mortality. Although radical surgical treatment with subsequent radiation and chemotherapy can improve the survival, the efficacy of such regimens is insufficient because the GBM cells can spread and destroy normal brain structures. Moreover, these non-specific treatments may damage adjacent healthy brain tissue. It is thus imperative to develop novel therapies to precisely target invasive tumor cells without damaging normal tissues. Immunotherapy is a promising approach due to its capability to suppress the growth of various tumors in preclinical model and clinical trials. Adoptive cell therapy (ACT) using T cells engineered with chimeric antigen receptor (CAR) targeting an ideal molecular marker in GBM, e.g. epidermal growth factor receptor type III (EGFRvIII) has demonstrated a satisfactory efficacy in treating malignant brain tumors. Here we summarize the recent progresses in immunotherapeutic strategy using CAR-modified T cells oriented to EGFRvIII against GBM. PMID:28302023

The expression of MACC1 and its role in the proliferation and apoptosis of salivary adenoid cystic carcinoma.

PubMed

Li, Haifeng; Liao, Xiaoying; Liu, Yeqing; Shen, Zhuojian; Gan, Xiangfeng; Li, Haigang; Huang, Zhiquan

2015-11-01

The objective of this study was to investigate the relationship between metastasis-associated in colon cancer-1 and patient clinical characteristics. We also examined the role of metastasis-associated in colon cancer-1 in the proliferation and apoptosis in adenoid cystic carcinoma. Metastasis-associated in colon cancer-1 expression was analysed in 65 paraffin-embedded tissue specimens of salivary adenoid cystic carcinoma and 25 adjacent non-cancerous tissues by immunohistochemistry (IHC). We used RNA interference technology to silence metastasis-associated in colon cancer-1 expression in ACCM cells. Cell Counting Kit-8 tests, transwell experiments and flow cytometry were used to test the proliferation, cisplatin resistance, migration, invasion and apoptosis of ACCM cells. Metastasis-associated in colon cancer-1 nuclear and cytoplasmic expression in salivary adenoid cystic carcinoma tissue was higher than in the adjacent normal salivary tissue. The expression level was closely associated with tumour histological grading, perineural invasion and surrounding tumour invasion. The downregulation of metastasis-associated in colon cancer-1 expression inhibited proliferation and induced apoptosis in ACCM cells. The knock-down of metastasis-associated in colon cancer-1 expression had no effect on migration, invasion and chemoresistance. Metastasis-associated in colon cancer-1 may have an important role in tumour development in adenoid cystic carcinoma. Metastasis-associated in colon cancer-1 is a potential biomarker for adenoid cystic carcinoma. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Decreased expression of the ATM gene linked to poor prognosis for gastric cancer of different nationalities in Xinjiang.

PubMed

Han, Mei; Ma, Lanying; Qu, Yanli; Tang, Yong

2017-08-01

To explore the clinicopathological significance of ATM gene in the occurrence and prognosis of gastric cancer (GC) from different nationalities in Xinjiang. The expression of ATM in 385 patients with GC (including 98 Uygurs, 231 Hans and 56 Kazaks) and its corresponding adjacent tissues were examined by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry assay to, analyze its correlations with clinicopathological features and prognosis of GC. The ATM expression in GC tissues was significantly decreased when compared to that in adjacent normal tissues of Uygur, Han and Kazak patients in Xinjiang, while Uygurs and Kazaks were much lower than Hans in the ATM expression of GC tissues (all P<0.05). Kaplan-Meier analysis showed that Uygur and Kazak patients with ATM-negative tumors had a markedly lower survival rate than patients in Hans (P=0.028), and GC patients with ATM negative expression presented more unfavorable overall survival rate than those with positive expression among the three different nationalities (all P<0.05). Multivariate Cox regression analysis revealed that nationality, ATM expression, TNM staging, depth of invasion, and lymph node metastasis were independent factors affecting the prognosis of GC patients in Xinjiang (all P<0.05). ATM was downregulated in GC patients in Xinjiang, especially for Uygurs and Kazaks, which suggested ATM to be an independent indicator of prognosis for GC therapy. Copyright © 2017 Elsevier GmbH. All rights reserved.

Immuno-proteomic discovery of tumor tissue autoantigens identifies olfactomedin 4, CD11b, and integrin alpha-2 as markers of colorectal cancer with liver metastases.

PubMed

Yang, Qian; Bavi, Prashant; Wang, Julia Y; Roehrl, Michael H

2017-09-25

Late-stage colorectal cancer with liver metastasis is common and affords poor prognosis, yet there is a dearth of reliable biomarkers. Cancer is often characterized by an increase in serologic autoantibodies. Hence, we embarked on an immuno-proteomic strategy by using autoantibodies to discover antigens in tumor tissue as potential cancer markers. Matched sets of tissues from primary colon cancer, liver metastases, and adjacent benign tissues were obtained from colon cancer patients. Tissue proteins were extracted, and autoantigens were uncovered by immunoblotting with autoantibodies and sequenced by mass spectrometry. Informatics analyses identified 48 proteins that were found in tumor only but were absent in normal tissue. Five of these were reproducibly found in two independent experiments, including olfactomedin 4 (OLFM4), CD11b, integrin α2 (ITGA2), periostin, and thrombospondin-2. Further confirmation with tissue from 43 patients by Western blotting, immunohistochemistry, and tissue microarray deemed OLFM4, CD11b, and ITGA2 to be significantly overexpressed in both primary colon tumors and liver metastases. These tumor tissue autoantigens may serve as promising markers for developing differential diagnostics and immunotherapies for colorectal cancers, in particular, those with tendency to progress to liver metastases. Late-stage colorectal cancer with liver metastasis is common and affords poor prognosis, yet there is a dearth of reliable biomarkers. Cancer is often characterized by an increase in serologic autoantibodies. Cancer tissue immunogens - antigens capable of inducing specific antibody production in patients - are promising targets for development of precision diagnostics and immunotherapies. In our manuscript, we describe on an immuno-proteomic strategy by using autoantibodies to discover antigens in tumor tissue as potential cancer markers. Matched sets of tissues from primary colon cancer, liver metastases, and adjacent benign tissues were analyzed. Putative autoantigens were first uncovered by immunoblotting with autoantibodies and sequenced by mass spectrometry. Informatics analyses identified 48 proteins that were found in tumor only but were absent in normal tissue. Using follow-up validation in two independent cohorts, we discovered that OLFM4, CD11b, and ITGA2 are proteins that are overexpressed in both primary colon tumors and liver metastases. We highlight the possible roles of these 3 proteins in carcinogenesis and tumor microenvironment and the implications for autoantigenic immune recognition. More generally, colon cancer biomarkers with autoantigenic properties, like the ones we describe in our manuscript, may open new opportunities for diagnosis, molecular classification, and therapy of colorectal cancer, particularly of aggressive tumors with tendency to progress to liver metastases. The autoantigenic properties of biomarkers are also expected to be of great relevance for immunotherapeutic development. Copyright © 2017. Published by Elsevier B.V.

Biologic fixation through bridge plating for comminuted shaft fracture of the clavicle: technical aspects and prospective clinical experience with a minimum of 12-month follow-up.

PubMed

Jung, Gu Hee; Park, Chang-Min; Kim, Jae-Do

2013-12-01

For comminuted shaft fracture of clavicle, the operative goal, aside from sound bone healing without complications of direct reduction, is maintenance of the original length in order to maintain the normal biomechanics of adjacent joint. Our bridge plating technique utilizing distraction through a lumbar spreader was expected to be effective for restoring clavicular length with soft tissue preservation. However, there are two disadvantages. First, there is more exposure to radiation compared to conventional plating; and second, it is difficult to control the rotational alignment. Despite these disadvantages, our technique has important benefits, in particular, the ability to preserve clavicular length without soft tissue injury around the fracture site.

Colon Cancer Associated Transcript-1 (CCAT1) Expression in Adenocarcinoma of the Stomach.

PubMed

Mizrahi, Ido; Mazeh, Haggi; Grinbaum, Ronit; Beglaibter, Nahum; Wilschanski, Michael; Pavlov, Vera; Adileh, Muchamad; Stojadinovic, Alexander; Avital, Itzhak; Gure, Ali Osmay; Halle, David; Nissan, Aviram

2015-01-01

Long non-coding RNAs (lncRNAs) have been shown to have functional roles in cancer biology and are dys-regulated in many tumors. Colon Cancer Associated Transcript -1 (CCAT1) is a lncRNA, previously shown to be significantly up-regulated in colon cancer. The aim of this study is to determine expression levels of CCAT1 in gastric carcinoma (GC). Tissue samples were obtained from patients undergoing resection for gastric carcinoma (n=19). For each patient, tumor tissue and normal appearing gastric mucosa were taken. Normal gastric tissues obtained from morbidly obese patients, undergoing laparoscopic sleeve gastrectomy served as normal controls (n=19). A human gastric carcinoma cell line (AGS) served as positive control. RNA was extracted from all tissue samples and CCAT1 expression was analyzed using quantitative real time-PCR (qRT-PCR). Low expression of CCAT1 was identified in normal gastric mucosa samples obtained from morbidly obese patients [mean Relative Quantity (RQ) = 1.95±0.4]. AGS human gastric carcinoma cell line showed an elevated level of CCAT1 expression (RQ=8.02). Expression levels of CCAT1 were approximately 10.8 fold higher in GC samples than in samples taken from the negative control group (RQ=21.1±5 vs. RQ=1.95±0.4, respectively, p<0.001). Interestingly, CCAT1 expression was significantly overexpressed in adjacent normal tissues when compared to the negative control group (RQ = 15.25±2 vs. RQ=1.95±0.4, respectively, p<0.001). Tissues obtained from recurrent GC cases showed the highest expression levels (RQ = 88.8±31; p<0.001). Expression levels increased with tumor stage (T4- 36.4±15, T3- 16.1±6, T2- 4.7±1), however this did not reach statistical significance (p=0.2). There was no difference in CCAT1 expression between intestinal and diffuse type GC (RQ=22.4±7 vs. 22.4±16, respectively, p=0.9). Within the normal gastric tissue samples, no significant difference in CCAT1 expression was observed in helicobacter pylori negative and positive patients (RQ= 2.4±0.9 vs. 0.93±0.2, respectively, p=0.13). CCAT1 is up-regulated in gastric cancer, and may serve as a potential bio-marker for early detection and surveillance.

Bio-Imaging of Colorectal Cancer Models Using Near Infrared Labeled Epidermal Growth Factor

PubMed Central

Cohen, Gadi; Lecht, Shimon; Arien-Zakay, Hadar; Ettinger, Keren; Amsalem, Orit; Oron-Herman, Mor; Yavin, Eylon; Prus, Diana; Benita, Simon; Nissan, Aviram; Lazarovici, Philip

2012-01-01

Novel strategies that target the epidermal growth factor receptor (EGFR) have led to the clinical development of monoclonal antibodies, which treat metastatic colorectal cancer (mCRC) but only subgroups of patients with increased wild type KRAS and EGFR gene copy, respond to these agents. Furthermore, resistance to EGFR blockade inevitably occurred, making future therapy difficult. Novel bio-imaging (BOI) methods may assist in quantization of EGFR in mCRC tissue thus complementing the immunohistochemistry methodology, in guiding the future treatment of these patients. The aim of the present study was to explore the usefulness of near infrared-labeled EGF (EGF-NIR) for bio-imaging of CRC using in vitro and in vivo orthotopic tumor CRC models and ex vivo human CRC tissues. We describe the preparation and characterization of EGF-NIR and investigate binding, using BOI of a panel of CRC cell culture models resembling heterogeneity of human CRC tissues. EGF-NIR was specifically and selectively bound by EGFR expressing CRC cells, the intensity of EGF-NIR signal to background ratio (SBR) reflected EGFR levels, dose-response and time course imaging experiments provided optimal conditions for quantization of EGFR levels by BOI. EGF-NIR imaging of mice with HT-29 orthotopic CRC tumor indicated that EGF-NIR is more slowly cleared from the tumor and the highest SBR between tumor and normal adjacent tissue was achieved two days post-injection. Furthermore, images of dissected tissues demonstrated accumulation of EGF-NIR in the tumor and liver. EGF-NIR specifically and strongly labeled EGFR positive human CRC tissues while adjacent CRC tissue and EGFR negative tissues expressed weak NIR signals. This study emphasizes the use of EGF-NIR for preclinical studies. Combined with other methods, EGF-NIR could provide an additional bio-imaging specific tool in the standardization of measurements of EGFR expression in CRC tissues. PMID:23144978

Bio-imaging of colorectal cancer models using near infrared labeled epidermal growth factor.

PubMed

Cohen, Gadi; Lecht, Shimon; Arien-Zakay, Hadar; Ettinger, Keren; Amsalem, Orit; Oron-Herman, Mor; Yavin, Eylon; Prus, Diana; Benita, Simon; Nissan, Aviram; Lazarovici, Philip

2012-01-01

Novel strategies that target the epidermal growth factor receptor (EGFR) have led to the clinical development of monoclonal antibodies, which treat metastatic colorectal cancer (mCRC) but only subgroups of patients with increased wild type KRAS and EGFR gene copy, respond to these agents. Furthermore, resistance to EGFR blockade inevitably occurred, making future therapy difficult. Novel bio-imaging (BOI) methods may assist in quantization of EGFR in mCRC tissue thus complementing the immunohistochemistry methodology, in guiding the future treatment of these patients. The aim of the present study was to explore the usefulness of near infrared-labeled EGF (EGF-NIR) for bio-imaging of CRC using in vitro and in vivo orthotopic tumor CRC models and ex vivo human CRC tissues. We describe the preparation and characterization of EGF-NIR and investigate binding, using BOI of a panel of CRC cell culture models resembling heterogeneity of human CRC tissues. EGF-NIR was specifically and selectively bound by EGFR expressing CRC cells, the intensity of EGF-NIR signal to background ratio (SBR) reflected EGFR levels, dose-response and time course imaging experiments provided optimal conditions for quantization of EGFR levels by BOI. EGF-NIR imaging of mice with HT-29 orthotopic CRC tumor indicated that EGF-NIR is more slowly cleared from the tumor and the highest SBR between tumor and normal adjacent tissue was achieved two days post-injection. Furthermore, images of dissected tissues demonstrated accumulation of EGF-NIR in the tumor and liver. EGF-NIR specifically and strongly labeled EGFR positive human CRC tissues while adjacent CRC tissue and EGFR negative tissues expressed weak NIR signals. This study emphasizes the use of EGF-NIR for preclinical studies. Combined with other methods, EGF-NIR could provide an additional bio-imaging specific tool in the standardization of measurements of EGFR expression in CRC tissues.

Modeling the Morphogenesis of Epidermal Tissues on the Surface of a 3D Last

NASA Astrophysics Data System (ADS)

McCleery, W. Tyler; Crews, Sarah M.; Mashburn, David N.; Veldhuis, Jim; Brodland, G. Wayne; Hutson, M. Shane

2014-03-01

Embryogenesis in the fruit fly Drosophila melanogaster is coordinated by the interaction of cells in adjacent tissues. For some events of embryogenesis, e.g., dorsal closure, two-dimensional models have been sufficient to elucidate the relevant cell and tissue mechanics. Here, we describe a new three-dimensional cell-level finite element model for investigating germ band retraction - a morphogenetic event where one epidermal tissue, the germ band, initially wraps around the posterior end of the ellipsoidal embryo. This tissue then retracts with a mechanical assist from contraction of cells in a second epidermal tissue, the amnioserosa. To speed simulation run times and focus on the relevant tissues, we only model epidermal tissue interactions. Epidermal cells are defined as polygons constrained to lie on the surface of the ellipsoidal last, but have adjustable parameters such as edge tensions and cell pressures. Tissue movements are simulated by balancing these dynamic cell-level forces with viscous resistance and allowing cells to exchange neighbors. Our choice of modeling parameters is informed by in vivo measurements of cell-level forces using laser microsurgery. We use this model to investigate the multicellular stress fields in normal and aberrant development.

Generation of Chimeric RNAs by cis-splicing of adjacent genes (cis-SAGe) in mammals.

PubMed

Zhuo, Jian-Shu; Jing, Xiao-Yan; Du, Xin; Yang, Xiu-Qin

2018-02-20

Chimeric RNA molecules, possessing exons from two or more independent genes, are traditionally believed to be produced by chromosome rearrangement. However, recent studies revealed that cis-splicing of adjacent genes (cis- SAGe) is one of the major mechanisms underlying the formation of chimeric RNAs. cis-SAGe refers to intergenic splicing of directly adjacent genes with the same transcriptional orientation, resulting in read-through transcripts, termed chimeric RNAs, which contain sequences from two or more parental genes. cis-SAGe was first identified in tumor cells, since then its potential in carcinogenesis has attracted extensive attention. More and more scientists are focusing on it. With the development of research, cis-SAGe was found to be ubiquitous in various normal tissues, and might make a crucial contribution to the formation of novel genes in the evolution of genomes. In this review, we summarize the splicing pattern, expression characteristics, possible mechanisms, and significance of cis-SAGe in mammals. This review will be helpful for general understanding of the current status and development tendency of cis-SAGe.

Detection of Metastatic Breast and Thyroid Cancer in Lymph Nodes by Desorption Electrospray Ionization Mass Spectrometry Imaging

NASA Astrophysics Data System (ADS)

Zhang, Jialing; Feider, Clara L.; Nagi, Chandandeep; Yu, Wendong; Carter, Stacey A.; Suliburk, James; Cao, Hop S. Tran; Eberlin, Livia S.

2017-06-01

Ambient ionization mass spectrometry has been widely applied to image lipids and metabolites in primary cancer tissues with the purpose of detecting and understanding metabolic changes associated with cancer development and progression. Here, we report the use of desorption electrospray ionization mass spectrometry (DESI-MS) to image metastatic breast and thyroid cancer in human lymph node tissues. Our results show clear alterations in lipid and metabolite distributions detected in the mass spectra profiles from 42 samples of metastatic thyroid tumors, metastatic breast tumors, and normal lymph node tissues. 2D DESI-MS ion images of selected molecular species allowed discrimination and visualization of specific histologic features within tissue sections, including regions of metastatic cancer, adjacent normal lymph node, and fibrosis or adipose tissues, which strongly correlated with pathologic findings. In thyroid cancer metastasis, increased relative abundances of ceramides and glycerophosphoinisitols were observed. In breast cancer metastasis, increased relative abundances of various fatty acids and specific glycerophospholipids were seen. Trends in the alterations in fatty acyl chain composition of lipid species were also observed through detailed mass spectra evaluation and chemical identification of molecular species. The results obtained demonstrate DESI-MSI as a potential clinical tool for the detection of breast and thyroid cancer metastasis in lymph nodes, although further validation is needed. [Figure not available: see fulltext.

The cellular environment of cancerous human tissue. Interfacial and dangling water as a "hydration fingerprint".

PubMed

Abramczyk, Halina; Brozek-Pluska, Beata; Krzesniak, Marta; Kopec, Monika; Morawiec-Sztandera, Alina

2014-08-14

Despite a large number of publications, the role of water in the cellular environment of biological tissue has not been clarified. Characterizing the biological interface is a key challenge in understanding the interactions of water in the tissue. Although we often assume that the properties of the bulk water can be translated to the crowded biological environment, this approach must be considerably revised when considering the biological interface. To our knowledge, few studies have directly monitored the interactions and accumulation of water in the restricted environments of the biological tissue upon realistic crowding conditions. The present study focuses on a molecular picture of water molecules at the biological interface, or specifically, water molecules adjacent to the hydrophobic and hydrophilic surfaces of normal and cancerous tissues. We recorded and analyzed the IR and Raman spectra of the νs(OH) stretching modes of water at the biological interfaces of the human breast and neck tissues. The results revealed dramatic changes in the water content in the tissue and are potentially relevant to both the fundamental problems of interfacial water modeling and the molecular diagnostics of cancer as a 'hydration fingerprint'. Herein, we will discuss the origin of the vibrational substructures observed for the νs(OH) stretching modes of water, showing that the interfacial water interacting via H-bond with other water molecules and biomolecules at the biological surface and free OH vibration of the dangling water are sensitive indicators of the pathology between the normal (noncancerous) and cancerous tissue and cancer types. Copyright © 2014 Elsevier B.V. All rights reserved.

Evaluation of adenoassociated virus 2 and human papilloma virus 16 and 18 infection in cervical cancer biopsies.

PubMed

Ahn, Woong Shick; Bae, Su Mi; Chung, Jae Eun; Lee, Hyun Kyung; Kim, Byung Kee; Lee, Joon Mo; Namkoong, Sung Eun; Kim, Chong Kook; Sin, Jeong- Im

2003-04-01

Protective roles of adenoassociated virus (AAV) 2 in cervical tumorigenesis are controversial. In an effort to clarify this issue, we tested prevalence of AAV 2 and human papillomavirus (HPV) infection in cervical lesions and adjacent normal tissues. Tissues of cervical intraepithelial neoplasm (CIN) I (20 patients), CIN II (24 patients), CIN III (25 patients), and invasive cancer (23 patients) were investigated by microdissection and PCR using HPV-16-, HVP-18-, and AAV-2-specific primers. AAV 2 was detected in 11 out of 20 CIN I (55%), 21 out of 24 CIN II (84.5%), 13 out of 25 CIN III (52%), and 12 out of 23 invasive cancer cases (52.2%). However, HPV 16 was detected in none out of 20 CIN I, 2 out of 24 CIN II (8.3%), 6 out of 25 CIN III (24%), and 6 out of 23 invasive cancer cases (26.1%). HPV 18 was detected in 1 case in CIN II (4.2%) and 2 cases in CIN III (8%). In 92 perilesional normal tissues, AAV 2 was detected in 53 cases (57.6%), displaying 25% of CIN I, 83.3% of CIN II, 52% of CIN III, and 65.2% of invasive cancer. The differences in AAV 2 prevalence are not significant between CIN and normal tissues. However, differences in HPV 16 are significant in CIN III and invasive cancer, as compared to CIN I, CIN II, and normal, suggesting no significant correlation between AAV 2 and cervical cancer. Thus, these results support the notion that AAV 2 is not associated with cervical tumorigenesis.

Protein regulator of cytokinesis-1 expression: prognostic value in lung squamous cell carcinoma patients

PubMed Central

Zhan, Ping; Xi, Guang-Min; Liu, Hong-Bing; Liu, Ya-Fang; Xu, Wu-Jian; Zhu, Qingqing; Zhou, Ze-Jun; Miao, Ying-Ying; Wang, Xiao-Xia; Jin, Jia-Jia

2017-01-01

Background Protein regulator of cytokinesis-1 (PRC1) has been shown to participate in the completion of cytokinesis, and it is dysregulated in cancer processes. However, its relevance in lung squamous cell carcinoma (SCC) remained largely unknown. We aimed to study the expression pattern of PRC1 and assess its clinical significance in lung SCC. Methods PRC1 protein expression in human lung SCC and adjacent normal lung tissues was detected by immunohistochemistry. PRC1 expression was assessed in association with clinicopathological features and clinical outcomes of lung SCC patients. Results In lung SCC tissues, PRC1 protein expression was significantly higher than those in paired normal lung tissues. The lung SCC patients with PRC1 overexpression had an advanced pathological stage (TNM stage), positive lymph node metastasis, and a shorter overall survival (OS) time more frequently than patients with low PRC1 expression. Additional, PRC1 expression was also shown to be poor as a prognostic factor for OS in patients with lung SCC. Conclusions Our study indicated that aberrant expression of PRC1 may point to biochemical recurrence in lung SCC. This highlights its potential as a valuable prognostic marker for lung SCC. PMID:28840006

Mammary stem cell and macrophage markers are enriched in normal tissue adjacent to inflammatory breast cancer.

PubMed

Reddy, Jay P; Atkinson, Rachel L; Larson, Richard; Burks, Jared K; Smith, Daniel; Debeb, Bisrat G; Ruffell, Brian; Creighton, Chad J; Bambhroliya, Arvind; Reuben, James M; Van Laere, Steven J; Krishnamurthy, Savitri; Symmans, William F; Brewster, Abenaa M; Woodward, Wendy A

2018-06-01

We hypothesized that breast tissue not involved by tumor in inflammatory breast cancer (IBC) patients contains intrinsic differences, including increased mammary stem cells and macrophage infiltration, which may promote the IBC phenotype. Normal breast parenchyma ≥ 5 cm away from primary tumors was obtained from mastectomy specimens. This included an initial cohort of 8 IBC patients and 60 non-IBC patients followed by a validation cohort of 19 IBC patients and 25 non-IBC patients. Samples were immunostained for either CD44 + CD49f + CD133/2 + mammary stem cell markers or the CD68 macrophage marker and correlated with IBC status. Quantitation of positive cells was determined using inForm software from PerkinElmer. We also examined the association between IBC status and previously published tumorigenic stem cell and IBC tumor signatures in the validation cohort samples. 8 of 8 IBC samples expressed isolated CD44 + CD49f + CD133/2 + stem cell marked cells in the initial cohort as opposed to 0/60 non-IBC samples (p = 0.001). Similarly, the median number of CD44 + CD49f + CD133/2 + cells was significantly higher in the IBC validation cohort as opposed to the non-IBC validation cohort (25.7 vs. 14.2, p = 0.007). 7 of 8 IBC samples expressed CD68 + histologically confirmed macrophages in initial cohort as opposed to 12/48 non-IBC samples (p = 0.001). In the validation cohort, the median number of CD68 + cells in IBC was 3.7 versus 1.0 in the non-IBC cohort (p = 0.06). IBC normal tissue was positively associated with a tumorigenic stem cell signature (p = 0.02) and with a 79-gene IBC signature (p < 0.001). Normal tissue from IBC patients is enriched for both mammary stem cells and macrophages and has higher association with both a tumorigenic stem cell signature and IBC-specific tumor signature. Collectively, these data suggest that IBC normal tissue differs from non-IBC tissue. Whether these changes occur before the tumor develops or is induced by tumor warrants further investigation.

Correlation analysis between expression of PCNA, Ki-67 and COX-2 and X-ray features in mammography in breast cancer.

PubMed

Qiu, Xiaoming; Mei, Jixin; Yin, Jianjun; Wang, Hong; Wang, Jinqi; Xie, Ming

2017-09-01

This study investigated expression of proliferating cell nuclear antigen (PCNA), proliferation-associated nuclear antigen (Ki-67) and cyclooxygenase-2 (COX-2) in tissues of breast invasive ductal carcinoma, and analyzed the correlations between these indexes and X-ray features in mammography. A total of 90 patients who were admitted to Huangshi Central Hospital and diagnosed as breast invasive ductal carcinoma from January 2014 to January 2016 were selected. The expression of PCNA, Ki-67 and COX-2 in cancer tissues and cancer-adjacent normal tissues of patients were detected by immunohistochemical staining, and X-ray features in mammography of patients were observed. By using Spearman correlation analysis, the correlations between expression of PCNA, Ki-67 and COX-2 and X-ray features in mammography in breast cancer were investigated. As a result, the positive expression rates of PCNA, Ki-67 and COX-2 in cancer tissues of the patient groups were respectively 42.2, 45.6 and 51.1%, which were significantly higher than those in cancer-adjacent normal tissues of the control group (p<0.05). PCNA, Ki-67 and COX-2 expression in cancer tissues of the patient group was associated with clinical staging and lymphatic metastasis (p<0.05), but had no correlation with age and tumor size (p>0.05). PCNA, Ki-67 and COX-2 expression in cancer tissues of the patient group had no correlation with the existence of lumps and localized density-increased shadows (p>0.05), but were associated with manifestations of architectural distortion, calcification as well as skin and nipple depression (p<0.05). Spearman correlation analysis revealed that there was a significantly positive correlation between the expression of PCNA and COX-2 in cancer tissues of the patient group (r=0.676, p<0.05); there was a significantly positive correlation between the expression of Ki-67 and COX-2 (r=0.724, p<0.05); PCNA expression had no obvious correlation with the expression of Ki-67 (p>0.05). In conclusion, PCNA, Ki-67 and COX-2 expression is of great significance in the occurrence, invasion and metastasis of breast invasive ductal carcinoma. There is a strong correlation between PCNA, Ki-67 and COX-2 expression levels and X-ray features in mammography in breast invasive ductal carcinoma. The application of X-ray features in mammography can evaluate the expression levels of PCNA, Ki-67 and COX-2 in tissues of breast invasive ductal carcinoma, thereby prospectively predicting biological behavior of these cancer cells and patient prognosis.

[Knockdown of NEDD9 inhibits the proliferation, invasion and migration of esophageal carcinoma EC109 cells].

PubMed

Zhang, Wen; Li, Shaojun; Zhao, Yunlong; Guo, Nannan; Li, Yingjie

2016-12-01

Objective To observe the expression of the neural precursor cell expressed, developmentally down-regulated 9 (NEDD9) in esophageal cancer, to investigate the impact of decreased expression of NEDD9 on invasion and migration, and to explicit the function of NEDD9 in EC109 human esophageal cancer cell line. Methods Immunohistochemical staining was used to detect the expression of NEDD9 in human esophageal cancer tissues and paracancerous normal tissues. RNA interfering (RNAi) was used to knockdown NEDD9 in EC109 cells. The interference efficiency was detected by reverse transcription PCR (RT-PCR) and Western blot analysis. Cell proliferation was determined by MTT assay and the invasion and migration abilities of EC109 cells were monitored by Transwell TM assay. The protein levels of proliferating cell nuclear antigen (PCNA), Bax and Bcl-2 were tested by Western blotting. Results The positive expression rate of NEDD9 in esophageal carcinoma tissues was significantly higher compared with that in the paracancerous tissues. After NEDD9 expression was successfully downregulated in EC109 cells by siRNA, the proliferation, invasion and migration rates in transfection group were significantly lower than those in control group; meanwhile, the expression of Bcl-2 was reduced and Bax expression was enhanced. Conclusion The protein expression level of NEDD9 is higher in esophageal carcinoma tissues than that in adjacent normal tissues. Knockdown of NEDD9 expression can restrain the proliferation, invasion and migration of EC109 cells.

Utilization of 5-aminolevulinic acid in the photodynamic therapy of tumors: biochemical and photobiological aspects

NASA Astrophysics Data System (ADS)

Pottier, Roy H.; Kennedy, James C.

1994-03-01

Inherent in both plants and animals is the natural porphyrin, Protoporphyrin IX (Pp). Although Pp does not appear to have any intrinsic biological activity, it is a potent natural photosensitizer. When activated with ultraviolet or visible light, this photosensitizer can induce significant photodynamic effects on tissues, cells, subcellular elements, and macromolecules via the production of singlet oxygen. The biosynthesis of endogenous Pp is under strict enzymatic control. It is possible to bypass a rate controlling step and induce large, transient concentrations of Pp by the addition of exogenous 5-aminolevulinic acid (ALA). ALA may be administered systemically or topically. Much larger amounts of Pp are produced in certain types of tumor tissue than in adjacent normal tissue. Topically applied ALA can be used to treat a variety of skin lesions, including actinic keratosis, basal cell carcinomas and psoriasis.

Histological evaluation of the equine larynx after unilateral laser-assisted ventriculocordectomy.

PubMed

Robinson, P; Williams, K J; Sullins, K E; Arnoczky, S P; Stick, J A; Robinson, N E; de Feijter-Rupp, H; Derksen, F J

2007-05-01

Trans-endoscopic laser surgery, such as unilateral laser-assisted ventriculocordectomy (LVC), has gained popularity in the treatment of RLN because a laryngotomy incision or general anaesthesia are not required. However, removal of the vocal fold and ventricle takes considerable laser energy and could cause collateral tissue damage, including injury to the adjacent laryngeal cartilages. To document the histological effects of laser surgery on laryngeal tissues in horses that have undergone LVC for the treatment of laryngeal hemiplegia (LH). Six horses were used: 4 with experimentally induced LH that had subsequently undergone LVC 6 months prior to euthanasia; and, 2 horses were used as controls. One of the control horses with naturally occurring LH was used to study the effect of neuropathy alone, whereas the other was subjected to euthanasia immediately following LVC to evaluate the acute effect of laser surgery. Using a band saw, each larynx was sectioned transversely at 5 mm intervals and evaluated histologically. Acutely, LVC caused thermal damage to adjacent soft tissues but did not affect the histology of the laryngeal cartilages. Six months after LVC, laryngeal cartilages were histologically normal and there was squamous metaplasia of the repaired laryngeal mucosa, resulting in restitution of the mucosal integrity. Using a diode laser in contact fashion at 20 W, LVC can be used to remove the laryngeal vocal fold and ventricle without causing laryngeal cartilage damage. Laryngeal chondritis is an unlikely consequence of LVC.

Estrogenic activity of tamoxifen on normal mammary parenchyma in the luteal phase of the menstrual cycle.

PubMed

Facina, G; de Lima, G R; Simões, M J; Novo, N F; Gebrim, L H

1997-01-01

Tamoxifen, an anti-estrogenic drug used in the adjuvant treatment of breast cancer, deserves more investigation for the determination of its efficacy as a prophylactic agent against breast cancer in high risk women. Thus, the action of tamoxifen on the human mammary gland was studied by measuring the number of lysosomes in normal mammary epithelium during the administration of tamoxifen. Tamoxifen was administered only during the luteal phase of the menstrual cycle to avoid interference with corpus luteum formation. A fragment of breast tissue adjacent to a fibroadenoma was obtained during surgery from 35 premenopausal women aged 15 to 37 years who had been eumenorrheic for at least 6 months; 18 of these patients were treated with tamoxifen and 17 were used as controls. Lysosome counts were performed under the light microscope on slides submitted to the acid phosphatase cytochemical technique and the data were analyzed statistically by the Mann-Whitney test. The fragments from the group treated with tamoxifen showed a significant decrease in lysosome numbers. Tamoxifen administered after ovulation significantly decreases the number of lysosomes in the cells of normal mammary epithelium, demonstrating the antiestrogenic effect of the drug on this target tissue.

PET/MRI of metabolic activity in osteoarthritis: A feasibility study.

PubMed

Kogan, Feliks; Fan, Audrey P; McWalter, Emily J; Oei, Edwin H G; Quon, Andrew; Gold, Garry E

2017-06-01

To evaluate positron emission tomography / magnetic resonance imaging (PET/MRI) knee imaging to detect and characterize osseous metabolic abnormalities and correlate PET radiotracer uptake with osseous abnormalities and cartilage degeneration observed on MRI. Both knees of 22 subjects with knee pain or injury were scanned at one timepoint, without gadolinium, on a hybrid 3.0T PET-MRI system following injection of 18 F-fluoride or 18 F-fluorodeoxyglucose (FDG). A musculoskeletal radiologist identified volumes of interest (VOIs) around bone abnormalities on MR images and scored bone marrow lesions (BMLs) and osteophytes using a MOAKS scoring system. Cartilage appearance adjacent to bone abnormalities was graded with MRI-modified Outerbridge classifications. On PET standardized uptake values (SUV) maps, VOIs with SUV greater than 5 times the SUV in normal-appearing bone were identified as high-uptake VOI (VOI High ). Differences in 18 F-fluoride uptake between bone abnormalities, BML, and osteophyte grades and adjacent cartilage grades on MRI were identified using Mann-Whitney U-tests. SUV max in all subchondral bone lesions (BML, osteophytes, sclerosis) was significantly higher than that of normal-appearing bone on MRI (P < 0.001 for all). Of the 172 high-uptake regions on 18 F-fluoride PET, 63 (37%) corresponded to normal-appearing subchondral bone on MRI. Furthermore, many small grade 1 osteophytes (40 of 82 [49%]), often described as the earliest signs of osteoarthritis (OA), did not show high uptake. Lastly, PET SUV max in subchondral bone adjacent to grade 0 cartilage was significantly lower compared to that of grades 1-2 (P < 0.05) and grades 3-4 cartilage (P < 0.001). PET/MRI can simultaneously assess multiple early metabolic and morphologic markers of knee OA across multiple tissues in the joint. Our findings suggest that PET/MR may detect metabolic abnormalities in subchondral bone, which appear normal on MRI. 2 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2017;45:1736-1745. © 2016 International Society for Magnetic Resonance in Medicine.

Cytoplasmic mislocalization of overexpressed FOXF1 is associated with the malignancy and metastasis of colorectal adenocarcinomas

PubMed Central

Lo, Pang-Kuo; Lee, Ji Shin; Chen, Hexin; Reisman, David.; Berger, Franklin G.; Sukumar, Saraswati

2012-01-01

Our previous studies have revealed that the human FOXF1 gene, encoding a transcription factor member of the forkhead box (FOX) family, functions as a tumor suppressor and its expression is frequently silenced in breast cancer via DNA hypermethylation. Moreover, we recently reported that FOXF1 expression is preferentially silenced in colorectal cancer cell lines with inactive p53 and knockdown of FOXF1 caused genomic instability in FOXF1-expressing colorectal cancer cells with a defect in the p53-p21WAF1 checkpoint, suggesting that FOXF1 plays a key role in colorectal tumorigenesis. Given that the in vivo role of FOXF1 in colorectal cancer remains unknown, the study here was aimed at delineating the clinical relevance of FOXF1 in colorectal adenocarcinomas. To characterize FOXF1 protein expression in colorectal cancer, designed tissue microarrays, comprising 50 cases of primary colorectal adenocarcinoma paired with matched adjacent normal tissue, were utilized in the immunohistochemistry (IHC) study. The IHC results showed that for adjacent normal colorectal tissue, the FOXF1 protein was only detected in stroma, not in epithelium, with either cytoplasmic staining (70% of total cases) or a mix of cytoplasmic and nuclear staining (6%). In contrast, for colorectal adenocarcinomas, FOXF1 staining was predominately identified in the cytoplasm of tumor epithelial cells (40% of total cases) and tumor-associated stromal cells of some cases (10%) also exhibited FOXF1 positivity in their cytoplasm. Cytoplasmic FOXF1 protein expression in tumor epithelial cells positively correlated with the histologic grade, depth of invasion, stage and lymphatic metastasis of colorectal adenocarcinomas (p < 0.05). Moreover, in silico meta-analysis of Oncomine’s cancer microarray database indicates that FOXF1 mRNA is overexpressed in a significant subset of colorectal adenocarcinoma tumors compared with normal colorectal tissue and other types of cancers. Our findings for the first time have revealed that the FOXF1 protein is overexpressed as well as mislocalized in cancerous epithelial cells and underexpressed/lost in tumor-associated stromal fibroblasts of colorectal adenocarcinomas, and suggest that FOXF1 is a potential prognostic marker due to its association with the malignancy and metastasis of colorectal cancer. PMID:23103611

Total marrow irradiation using Helical TomoTherapy

NASA Astrophysics Data System (ADS)

Garcia-Fernandez, Lourdes Maria

Clinical dose response data of human tumours are limited or restricted to a radiation dose range determined by the level of toxicity to the normal tissues. This is the case for the most common disseminated plasma cell neoplasm, multiple myeloma, where the maximum dose deliverable to the entire bony skeleton using a standard total body irradiation (TBI) technique is limited to about 12 Gy. This study is part of scientific background of a phase I/II dose escalation clinical trial for multiple myeloma using image-guided intensity modulated radiotherapy (IG-IMRT) to deliver high dose to the entire volume of bone marrow with Helical TomoTherapy (HT). This relatively new technology can deliver highly conformal dose distributions to complex target shapes while reducing the dose to critical normal tissues. In this study tools for comparing and predicting the effectiveness of different approaches to total marrow irradiation (TMI) using HT were provided. The expected dose response for plasma cell neoplasms was computed and a radiobiological evaluation of different treatment cohorts in a dose escalating study was performed. Normal tissue complication probability (NTCP) and tumour control probability (TCP) models were applied to an actual TMI treatment plan for a patient and the implications of using different longitudinal field widths were assessed. The optimum dose was ˜39 Gy for which a predicted tumour control of 95% (+/-3%) was obtained, with a predicted 3% (0, 8%) occurrence of radiation pneumonitis. Tissue sparing was seen by using smaller field widths only in the organs of the head. This suggests it would be beneficial to use the small fields in the head only since using small fields for the whole treatment would lead to long treatment times. In TMI it may be necessary to junction two longitudinally adjacent treatment volumes to form a contiguous planning target volume PTV. For instance, this is the case when a different SUP-INF spatial resolution is required or when the PTV length exceeds the bed travel distance. In this work, the dosimetric challenges associated with junctioning longitudinally adjacent PTVs with HT were analyzed and the feasibility of PTV junctioning was demonstrated. The benefits of spatially dividing or splitting the treatment into a few sub-treatments along the longitudinal direction were also investigated.

Cathepsin B expression in colorectal cancer in a Middle East population: Potential value as a tumor biomarker for late disease stages

PubMed Central

Abdulla, Maha-Hamadien; Valli-Mohammed, Mansoor-Ali; Al-Khayal, Khayal; Shkieh, Abdulmalik Al; Zubaidi, Ahmad; Ahmad, Rehan; Al-Saleh, Khalid; Al-Obeed, Omar; McKerrow, James

2017-01-01

Cathepsin B (CTSB), is a cysteine protease belonging to the cathepsin (Clan CA) family. The diagnostic and prognostic significance of increased CTSB in the serum of cancer patients have been evaluated for some tumor types. CTSB serum and protein levels have also been reported previously in colorectal cancer (CRC) with contradictory results. The aim of the present study was to investigate CTSB expression in CRC patients and the association of CTSB expression with various tumor stages in a Middle East population. Serum CTSB levels were evaluated in 70 patients and 20 healthy control subjects using enzyme-linked immunosorbant assay (ELISA) technique. CTSB expression was determined in 100 pairs of CRC tumor and adjacent normal colonic tissue using quantitative PCR for mRNA levels. Detection of CTSB protein expression in tissues was carried out using both immunohistochemistry and western blotting techniques. ELISA analysis showed that in sera obtained from CRC patients, the CTSB concentration was significantly higher in late stage patients with lymph node metastases when compared to early stage patients with values of 2.9 and 0.33 ng/ml, respectively (P=0.001). The majority of tumors studied had detectable CTSB protein expression with significant increased positive staining in tumors cells when compared with matched normal colon subjects (P=0.006). The mRNA expression in early stage CRC compared to late stage CRC was 0.04±0.01 and 0.07±0.02, respectively. Increased mRNA expression was more frequently observed in the advanced cancer stages with lymph node metastases when compared with the control (P=0.002). Mann-Whitney test and paired t-test were used to compare serum CTSB and mRNA levels in early and late tumor stage. A subset of four paired tissue extracts were analyzed by western blotting. The result confirmed a consistent increase in the CTSB protein expression level in tumor tissues compared with that noted in the adjacent normal mucosal cells. These findings indicate that CTSB may be an important prognostic biomarker for late stage CRC and cases with lymph node metastases in the Middle Eastern population. Monitoring serum CTSB in CRC patients may predict and/or diagnose cases with lymph node metastases. PMID:28440429

Connective tissue growth factor is activated by gastrin and involved in gastrin-induced migration and invasion.

PubMed

Bhandari, Sabin; Bakke, Ingunn; Kumar, J; Beisvag, Vidar; Sandvik, Arne K; Thommesen, Liv; Varro, Andrea; Nørsett, Kristin G

2016-06-17

Connective tissue growth factor (CTGF) has been reported in gastric adenocarcinoma and in carcinoid tumors. The aim of this study was to explore a possible link between CTGF and gastrin in gastric epithelial cells and to study the role of CTGF in gastrin induced migration and invasion of AGS-GR cells. The effects of gastrin were studied using RT-qPCR, Western blot and assays for migration and invasion. We report an association between serum gastrin concentrations and CTGF abundancy in the gastric corpus mucosa of hypergastrinemic subjects and mice. We found a higher expression of CTGF in gastric mucosa tissue adjacent to tumor compared to normal control tissue. We showed that gastrin induced expression of CTGF in gastric epithelial AGS-GR cells via MEK, PKC and PKB/AKT pathways. CTGF inhibited gastrin induced migration and invasion of AGS-GR cells. We conclude that CTGF expression is stimulated by gastrin and involved in remodeling of the gastric epithelium. Copyright © 2016 Elsevier Inc. All rights reserved.

Nanowired three-dimensional cardiac patches

NASA Astrophysics Data System (ADS)

Dvir, Tal; Timko, Brian P.; Brigham, Mark D.; Naik, Shreesh R.; Karajanagi, Sandeep S.; Levy, Oren; Jin, Hongwei; Parker, Kevin K.; Langer, Robert; Kohane, Daniel S.

2011-11-01

Engineered cardiac patches for treating damaged heart tissues after a heart attack are normally produced by seeding heart cells within three-dimensional porous biomaterial scaffolds. These biomaterials, which are usually made of either biological polymers such as alginate or synthetic polymers such as poly(lactic acid) (PLA), help cells organize into functioning tissues, but poor conductivity of these materials limits the ability of the patch to contract strongly as a unit. Here, we show that incorporating gold nanowires within alginate scaffolds can bridge the electrically resistant pore walls of alginate and improve electrical communication between adjacent cardiac cells. Tissues grown on these composite matrices were thicker and better aligned than those grown on pristine alginate and when electrically stimulated, the cells in these tissues contracted synchronously. Furthermore, higher levels of the proteins involved in muscle contraction and electrical coupling are detected in the composite matrices. It is expected that the integration of conducting nanowires within three-dimensional scaffolds may improve the therapeutic value of current cardiac patches.

Effects of long non-coding RNA HOST2 on cell migration and invasion by regulating MicroRNA let-7b in breast cancer.

PubMed

Lu, Peng-Wei; Li, Lin; Wang, Fang; Gu, Yuan-Ting

2018-06-01

The study intends to investigate the effects of long non-coding RNA HOST2 (lncRNA HOST2) on cell migration and invasion by regulating microRNA let-7b (let-7b) in breast cancer. Breast cancer and adjacent normal tissues were collected from 98 patients with breast cancer. Breast cancer MCF-7 cells were divided into the blank, negative control (NC), pcDNA3-Mock, siHOST2, let-7b inhibitor, pcDNA3-HOST2, let-7b mimic, pcDNA3-HOST2 + let-7b mimic, and siHOST2 + let-7b inhibitor groups. RT-qPCR was used to detect the mRNA expressions of HOST2, let-7b, and c-Myc. Western blotting was conducted to measure the c-Myc expression. Scratch test and Transwell assay were applied to detect the cell motility, migration, and invasion. Xenograft tumor in nude mice was performed to evaluate the effect of different transfection on the tumor growth. Compared with adjacent normal tissues, HOST2 expression was higher but let-7b expression lower in breast cancer tissues. HOST2 expression in breast cancer cells was remarkably increased compared with that in the normal breast epithelial MCF-10A cells. In MCF-7 cells, in comparison with the blank and NC groups, expressions of HOST2 and c-Myc were reduced, but let-7b expression was remarkably elevated in the siHOST2 and let-7b mimic groups; the let-7b inhibitor group exhibited higher expressions of HOST2 and c-Myc but lower let-7b expression. Overexpression of HOST2 could promote cell motility, migration and invasion, thus enhancing the growth of breast cancer tumor. By inhibiting HOST2, opposite trends were found. LncRNA HOST2 promotes cell migration and invasion by inhibiting let-7b in breast cancer patients. © 2017 Wiley Periodicals, Inc.

Epigenomic profiling of DNA methylation in paired prostate cancer versus adjacent benign tissue

PubMed Central

Geybels, Milan S.; Zhao, Shanshan; Wong, Chao-Jen; Bibikova, Marina; Klotzle, Brandy; Wu, Michael; Ostrander, Elaine A.; Fan, Jian-Bing; Feng, Ziding; Stanford, Janet L.

2016-01-01

Background Aberrant DNA methylation may promote prostate carcinogenesis. We investigated epigenome-wide DNA methylation profiles in prostate cancer (PCa) compared to adjacent benign tissue to identify differentially methylated CpG sites. Methods The study included paired PCa and adjacent benign tissue samples from 20 radical prostatectomy patients. Epigenetic profiling was done using the Infinium HumanMethylation450 BeadChip. Linear models that accounted for the paired study design and False Discovery Rate Q-values were used to evaluate differential CpG methylation. mRNA expression levels of the genes with the most differentially methylated CpG sites were analyzed. Results In total, 2,040 differentially methylated CpG sites were identified in PCa versus adjacent benign tissue (Q-value <0.001), the majority of which were hypermethylated (n = 1,946; 95%). DNA methylation profiles accurately distinguished between PCa and benign tissue samples. Twenty-seven top-ranked hypermethylated CpGs had a mean methylation difference of at least 40% between tissue types, which included 25 CpGs in 17 genes. Furthermore, for ten genes over 50% of promoter region CpGs were hypermethylated in PCa versus benign tissue. The top-ranked differentially methylated genes included three genes that were associated with both promoter hypermethylation and reduced gene expression: SCGB3A1, HIF3A, and AOX1. Analysis of The Cancer Genome Atlas (TCGA) data provided confirmatory evidence for our findings. Conclusions This study of PCa versus adjacent benign tissue showed many differentially methylated CpGs and regions in and outside gene promoter regions, which may potentially be used for the development of future epigenetic-based diagnostic tests or as therapeutic targets. PMID:26383847

Epigenomic profiling of DNA methylation in paired prostate cancer versus adjacent benign tissue.

PubMed

Geybels, Milan S; Zhao, Shanshan; Wong, Chao-Jen; Bibikova, Marina; Klotzle, Brandy; Wu, Michael; Ostrander, Elaine A; Fan, Jian-Bing; Feng, Ziding; Stanford, Janet L

2015-12-01

Aberrant DNA methylation may promote prostate carcinogenesis. We investigated epigenome-wide DNA methylation profiles in prostate cancer (PCa) compared to adjacent benign tissue to identify differentially methylated CpG sites. The study included paired PCa and adjacent benign tissue samples from 20 radical prostatectomy patients. Epigenetic profiling was done using the Infinium HumanMethylation450 BeadChip. Linear models that accounted for the paired study design and False Discovery Rate Q-values were used to evaluate differential CpG methylation. mRNA expression levels of the genes with the most differentially methylated CpG sites were analyzed. In total, 2,040 differentially methylated CpG sites were identified in PCa versus adjacent benign tissue (Q-value < 0.001), the majority of which were hypermethylated (n = 1,946; 95%). DNA methylation profiles accurately distinguished between PCa and benign tissue samples. Twenty-seven top-ranked hypermethylated CpGs had a mean methylation difference of at least 40% between tissue types, which included 25 CpGs in 17 genes. Furthermore, for 10 genes over 50% of promoter region CpGs were hypermethylated in PCa versus benign tissue. The top-ranked differentially methylated genes included three genes that were associated with both promoter hypermethylation and reduced gene expression: SCGB3A1, HIF3A, and AOX1. Analysis of The Cancer Genome Atlas (TCGA) data provided confirmatory evidence for our findings. This study of PCa versus adjacent benign tissue showed many differentially methylated CpGs and regions in and outside gene promoter regions, which may potentially be used for the development of future epigenetic-based diagnostic tests or as therapeutic targets. © 2015 Wiley Periodicals, Inc.

GFRA3 promoter methylation may be associated with decreased postoperative survival in gastric cancer.

PubMed

Eftang, Lars Lohne; Klajic, Jovana; Kristensen, Vessela N; Tost, Jörg; Esbensen, Qin Ying; Blom, Gustav Peter; Bukholm, Ida Rashida Khan; Bukholm, Geir

2016-03-16

A large number of epigenetic alterations has been found to be implicated in the etiology of gastric cancer. We have studied the DNA methylation status of 27 500 gene promoter regions in 24 gastric adenocarcinomas from a Norwegian cohort, and aimed at identifying the hypermethylated regions. We have compared our findings to the gene expression in the same tissue, and linked our results to prognosis and survival. Biopsies from gastric adenocarcinomas and adjacent normal gastric mucosa were obtained from 24 patients following surgical resection of the tumor. Genome-wide DNA methylation profiling of the tumor and matched non-cancerous mucosa was performed. The results were compared to whole transcriptome cDNA microarray analysis of the same material. Most of the gene promoter regions in both types of tissue showed a low degree of methylation, however there was a small, but significant hypermethylation of the tumors. Hierarchical clustering showed separate grouping of the tumor and normal tissue. Hypermethylation of the promoter region of the GFRA3 gene showed a strong correlation to post-operative survival and several of the clinicopathological parameters, however no difference was found between the two main histological types of gastric cancer. There was only a modest correlation between the DNA methylation status and gene expression. The different DNA methylation clusters of the tumors and normal tissue indicate that aberrant DNA methylation is a distinct feature of gastric cancer, although there is little difference in the overall, and low, methylation levels between the two tissue types. The GFRA3 promoter region showed marked hypermethylation in almost all tumors, and its correlation with survival and other clinicopathological parameters may have important prognostic significance.

Methylation signature of lymph node metastases in breast cancer patients

PubMed Central

2012-01-01

Background Invasion and metastasis are two important hallmarks of malignant tumors caused by complex genetic and epigenetic alterations. The present study investigated the contribution of aberrant methylation profiles of cancer related genes, APC, BIN1, BMP6, BRCA1, CST6, ESR-b, GSTP1, P14 (ARF), P16 (CDKN2A), P21 (CDKN1A), PTEN, and TIMP3, in the matched axillary lymph node metastasis in comparison to the primary tumor tissue and the adjacent normal tissue from the same breast cancer patients to identify the potential of candidate genes methylation as metastatic markers. Methods The quantitative methylation analysis was performed using the SEQUENOM’s EpiTYPER™ assay which relies on matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Results The quantitative DNA methylation analysis of the candidate genes showed higher methylation proportion in the primary tumor tissue than that of the matched normal tissue and the differences were significant for the APC, BIN1, BMP6, BRCA1, CST6, ESR-b, P16, PTEN and TIMP3 promoter regions (P<0.05). Among those candidate methylated genes, APC, BMP6, BRCA1 and P16 displayed higher methylation proportion in the matched lymph node metastasis than that found in the normal tissue (P<0.05). The pathway analysis revealed that BMP6, BRCA1 and P16 have a role in prevention of neoplasm metastasis. Conclusions The results of the present study showed methylation heterogeneity between primary tumors and metastatic lesion. The contribution of aberrant methylation alterations of BMP6, BRCA1 and P16 genes in lymph node metastasis might provide a further clue to establish useful biomarkers for screening metastasis. PMID:22695536

Circular RNA hsa_circ_0000745 may serve as a diagnostic marker for gastric cancer.

PubMed

Huang, Mei; He, Yi-Ren; Liang, Li-Chuan; Huang, Qiang; Zhu, Zhi-Qiang

2017-09-14

To determine whether circular RNAs (circRNAs) are involved in pathological processes of gastric cancer (GC). Three circRNAs with differential expression in GC and colorectal cancer were randomly selected for validation by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), using 20 pairs of gastric tissues and normal tissues. Based on the predicted circRNA-miRNA network, we then focused on hsa_circ_0000745, which was found to be down-regulated in 20 GC tissues compared with normal tissues. The hsa_circ_0000745 levels were further analyzed by qRT-PCR in 60 GC tissues and paired adjacent non-tumor tissues, as well as 60 plasma samples from GC patients and 60 plasma samples from healthy controls. The associations between the levels of hsa_circ_0000745 and the clinicopathological features of GC patients were statistically assessed. A receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value of hsa_circ_0000745 in GC. Hsa_circ_0000745 was down-regulated in GC tissues vs non-tumorous tissues ( P < 0.001) and in plasma samples from patients with GC vs healthy controls ( P < 0.001). The expression level of hsa_circ_0000745 in GC tissues correlated with tumor differentiation, while the expression level in plasma correlated with tumor-node-metastasis stage. The area under the ROC curve (AUC) of hsa_circ_0000745 in plasma was 0.683, suggesting good diagnostic value. Plasma hsa_circ_0000745 level combined with carcinoembryogenic antigen (CEA) level increased the AUC to 0.775. Hsa_circ_0000745 plays an important role in GC and its expression level in plasma in combination with CEA level is a promising diagnostic marker for this malignancy.

Tissue-engineered cartilaginous constructs for the treatment of caprine cartilage defects, including distribution of laminin and type IV collagen.

PubMed

Jeng, Lily; Hsu, Hu-Ping; Spector, Myron

2013-10-01

The purpose of this study was the immunohistochemical evaluation of (1) cartilage tissue-engineered constructs; and (2) the tissue filling cartilage defects in a goat model into which the constructs were implanted, particularly for the presence of the basement membrane molecules, laminin and type IV collagen. Basement membrane molecules are localized to the pericellular matrix in normal adult articular cartilage, but have not been examined in tissue-engineered constructs cultured in vitro or in tissue filling cartilage defects into which the constructs were implanted. Cartilaginous constructs were engineered in vitro using caprine chondrocyte-seeded type II collagen scaffolds. Autologous constructs were implanted into 4-mm-diameter defects created to the tidemark in the trochlear groove in the knee joints of skeletally mature goats. Eight weeks after implantation, the animals were sacrificed. Constructs underwent immunohistochemical and histomorphometric evaluation. Widespread staining for the two basement membrane molecules was observed throughout the extracellular matrix of in vitro and in vivo samples in a distribution unlike that previously reported for cartilage. At sacrifice, 70% of the defect site was filled with reparative tissue, which consisted largely of fibrous tissue and some fibrocartilage, with over 70% of the reparative tissue bonded to the adjacent host tissue. A novel finding of this study was the observation of laminin and type IV collagen in in vitro engineered cartilaginous constructs and in vivo cartilage repair samples from defects into which the constructs were implanted, as well as in normal caprine articular cartilage. Future work is needed to elucidate the role of basement membrane molecules during cartilage repair and regeneration.

Tissue-Engineered Cartilaginous Constructs for the Treatment of Caprine Cartilage Defects, Including Distribution of Laminin and Type IV Collagen

PubMed Central

Jeng, Lily; Hsu, Hu-Ping

2013-01-01

The purpose of this study was the immunohistochemical evaluation of (1) cartilage tissue-engineered constructs; and (2) the tissue filling cartilage defects in a goat model into which the constructs were implanted, particularly for the presence of the basement membrane molecules, laminin and type IV collagen. Basement membrane molecules are localized to the pericellular matrix in normal adult articular cartilage, but have not been examined in tissue-engineered constructs cultured in vitro or in tissue filling cartilage defects into which the constructs were implanted. Cartilaginous constructs were engineered in vitro using caprine chondrocyte-seeded type II collagen scaffolds. Autologous constructs were implanted into 4-mm-diameter defects created to the tidemark in the trochlear groove in the knee joints of skeletally mature goats. Eight weeks after implantation, the animals were sacrificed. Constructs underwent immunohistochemical and histomorphometric evaluation. Widespread staining for the two basement membrane molecules was observed throughout the extracellular matrix of in vitro and in vivo samples in a distribution unlike that previously reported for cartilage. At sacrifice, 70% of the defect site was filled with reparative tissue, which consisted largely of fibrous tissue and some fibrocartilage, with over 70% of the reparative tissue bonded to the adjacent host tissue. A novel finding of this study was the observation of laminin and type IV collagen in in vitro engineered cartilaginous constructs and in vivo cartilage repair samples from defects into which the constructs were implanted, as well as in normal caprine articular cartilage. Future work is needed to elucidate the role of basement membrane molecules during cartilage repair and regeneration. PMID:23672504

Prostate cancer outcome and tissue levels of metal ions

USGS Publications Warehouse

Sarafanov, A.G.; Todorov, T.I.; Centeno, J.A.; MacIas, V.; Gao, W.; Liang, W.-M.; Beam, C.; Gray, Marion A.; Kajdacsy-Balla, A.

2011-01-01

BACKGROUNDThere are several studies examining prostate cancer and exposure to cadmium, iron, selenium, and zinc. Less data are available on the possible influence of these metal ions on prostate cancer outcome. This study measured levels of these ions in prostatectomy samples in order to examine possible associations between metal concentrations and disease outcome.METHODSWe obtained formalin fixed paraffin embedded tissue blocks of prostatectomy samples of 40 patients with PSA recurrence, matched 1:1 (for year of surgery, race, age, Gleason grading, and pathology TNM classification) with tissue blocks from 40 patients without recurrence (n = 80). Case–control pairs were compared for the levels of metals in areas adjacent to tumors. Inductively coupled plasma-mass spectrometry (ICP-MS) was used for quantification of Cd, Fe, Zn, and Se.RESULTSPatients with biochemical (PSA) recurrence of disease had 12% lower median iron (95 µg/g vs. 111 µg/g; P = 0.04) and 21% lower zinc (279 µg/g vs. 346 µg/g; P = 0.04) concentrations in the normal-appearing tissue immediately adjacent to cancer areas. Differences in cadmium (0.489 µg/g vs. 0.439 µg/g; 4% higher) and selenium (1.68 µg/g vs. 1.58 µg/g; 5% higher) levels were not statistically significant in recurrence cases, when compared to non-recurrences (P = 0.40 and 0.21, respectively).CONCLUSIONSThere is an association between low zinc and low iron prostate tissue levels and biochemical recurrence in prostate cancer. Whether these novel findings are a cause or effect of more aggressive tumors, or whether low zinc and iron prostatic levels raise implications for therapy, remains to be investigated. 

SU-E-T-549: A Combinatorial Optimization Approach to Treatment Planning with Non-Uniform Fractions in Intensity Modulated Proton Therapy

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

Papp, D; Unkelbach, J

2014-06-01

Purpose: Non-uniform fractionation, i.e. delivering distinct dose distributions in two subsequent fractions, can potentially improve outcomes by increasing biological dose to the target without increasing dose to healthy tissues. This is possible if both fractions deliver a similar dose to normal tissues (exploit the fractionation effect) but high single fraction doses to subvolumes of the target (hypofractionation). Optimization of such treatment plans can be formulated using biological equivalent dose (BED), but leads to intractable nonconvex optimization problems. We introduce a novel optimization approach to address this challenge. Methods: We first optimize a reference IMPT plan using standard techniques that deliversmore » a homogeneous target dose in both fractions. The method then divides the pencil beams into two sets, which are assigned to either fraction one or fraction two. The total intensity of each pencil beam, and therefore the physical dose, remains unchanged compared to the reference plan. The objectives are to maximize the mean BED in the target and to minimize the mean BED in normal tissues, which is a quadratic function of the pencil beam weights. The optimal reassignment of pencil beams to one of the two fractions is formulated as a binary quadratic optimization problem. A near-optimal solution to this problem can be obtained by convex relaxation and randomized rounding. Results: The method is demonstrated for a large arteriovenous malformation (AVM) case treated in two fractions. The algorithm yields a treatment plan, which delivers a high dose to parts of the AVM in one of the fractions, but similar doses in both fractions to the normal brain tissue adjacent to the AVM. Using the approach, the mean BED in the target was increased by approximately 10% compared to what would have been possible with a uniform reference plan for the same normal tissue mean BED.« less

Release of metal in vivo from stressed and nonstressed maxillofacial fracture plates and screws.

PubMed

Matthew, I R; Frame, J W

2000-07-01

To analyze the release of metal into the adjacent tissues from stressed and nonstressed titanium and stainless steel miniplates and screws. Two miniplates were inserted into the cranial vaults of 12 beagle dogs while they were under general endotracheal anesthesia. One miniplate was shaped to fit the curvature of the skull (control). Another miniplate, made of the same material, was bent in a curve until the midpoint was raised 3 mm above the ends. Screws were inserted and tightened until the plate conformed to the skull curvature, creating stresses in the system. Four animals (2 each, having titanium or stainless steel plates and screws) were killed after 4, 12, and 24 weeks. Metallosis of adjacent soft tissues was assessed qualitatively. Miniplates and screws were removed, and adjacent soft tissue and bone was excised. Titanium, iron, chromium, nickel, and aluminum levels were assayed by ultraviolet/visible light and atomic absorption spectrophotometry. Nonparametric statistical methods were used for data analysis. There was no clear relationship between pigmentation of soft tissue adjacent to the miniplates and screws and the concentrations of metal present. The data did not demonstrate any consistent differences in the concentrations of metallic elements next to stressed and nonstressed (control) miniplates and screws of either material. Stresses arising through poor contouring of miniplates do not appear to influence the extent of release of metal into the adjacent tissues.

Down-regulation of adenosine monophosphate-activated protein kinase activity: A driver of cancer.

PubMed

He, Xiaoling; Li, Cong; Ke, Rong; Luo, Lingyu; Huang, Deqiang

2017-04-01

Adenosine monophosphate-activated protein kinase (AMPK), a serine/threonine protein kinase, is known as "intracellular energy sensor and regulator." AMPK regulates multiple cellular processes including protein and lipid synthesis, cell proliferation, invasion, migration, and apoptosis. Moreover, AMPK plays a key role in the regulation of "Warburg effect" in cancer cells. AMPK activity is down-regulated in most tumor tissues compared with the corresponding adjacent paracancerous or normal tissues, indicating that the decline in AMPK activity is closely associated with the development and progression of cancer. Therefore, understanding the mechanism of AMPK deactivation during cancer progression is of pivotal importance as it may identify AMPK as a valid therapeutic target for cancer treatment. Here, we review the mechanisms by which AMPK is down-regulated in cancer.

Circular RNA 0000096 affects cell growth and migration in gastric cancer.

PubMed

Li, Peifei; Chen, Huilin; Chen, Shengcan; Mo, Xiaoyan; Li, Tianwen; Xiao, Bingxiu; Yu, Rui; Guo, Junming

2017-02-28

Circular RNAs (circRNAs) are a class of non-coding RNAs broadly expressed in cells of various species. Their role in cancers, especially in gastric cancer, is poorly understood. Circular RNA 0000096 (hsa_circ_0000096) levels in 101 paired gastric cancer tissues and adjacent non-tumorous tissues from patients with gastric cancer were detected by real-time quantitative reverse transcription-polymerase chain reaction. A receiver operating characteristic curve was generated to evaluate the diagnostic value of hsa_circ_0000096. RNA interference was used to manipulate the expression of hsa_circ_0000096. Its biological effects were evaluated by flow cytometry, real-time cell analysis, a wound scratch assay, western blot analysis and xenograft models. Hsa_circ_0000096 was found to be significantly downregulated in gastric cancer tissues and gastric cancer cell lines compared with paired adjacent non-tumorous tissues and normal gastric epithelial cells (P<0.001). Moreover, knockdown of hsa_circ_0000096 significantly inhibited cell proliferation and migration in vitro and in vivo. The results of both immunohistochemical and western blot analyses showed that the protein levels of cyclin D1, cyclin-dependent kinase 6 (CDK6), matrix metalloproteinase-2 and MMP-9 were significantly reduced in vitro and in vivo. A gastric cancer xenograft nude mouse model indicated that Ki67 and VEGF were reduced in a dose-dependent manner following knockdown of hsa_circ_0000096. However, the expression of E-cadherin increased. Hsa_circ_0000096 may be used as a potential novel biomarker for gastric cancer. It affects gastric cancer cell growth and migration by regulating cyclin D1, CDK6, MMP-2 and MMP-9.

Expression analysis of URI/RMP gene in endometrioid adenocarcinoma by tissue microarray immunohistochemistry.

PubMed

Gu, Junxia; Liang, Yuting; Qiao, Longwei; Li, Xiaoyun; Li, Xingang; Lu, Yaojuan; Zheng, Qiping

2013-01-01

Multiple studies have recently demonstrated the oncogenic property of URI (or RMP, a member of the prefoldin family of molecular chaperones) during progression of hepatocellular carcinoma, ovarian cancer, and possibly prostate cancer. Most recently, we have shown that URI/RMP is up-regulated in cervical cancer, another reproductive system tumor beside ovarian and prostate cancers. To investigate if URI/RMP also plays a role in other reproductive system tumors, especially in endometrioid adenocarcinoma, we analyzed URI/RMP expression in a TMA (tissue microarray) containing tissues from 30 cases of endometrioid adenocarcinoma (which covers tumor tissues from Grade I through Grade III) and adjacent endometrium by immunohistochemistry (IHC) and densitometry analysis using image-pro plus 6.0 software. Our results showed that the mean density of URI/RMP expression in cancerous tissue is slightly higher than that of the adjacent endometrial tissue, though not statistically significant (p>0.05). There is no significant difference either between the mean density of Grade III cancerous tissue and that of Grade I and II cancers. Notably, we detected significantly higher signal intensity in cancerous tissue of all 7 Grade III cases than that of their adjacent endometrial tissue (p<0.05), suggesting a correlation of URI/RMP expression with the differentiation and pathological classification of endometrioid adenocarcinoma. Together, our results demonstrate the heterogeneous expression of URI/RMP in endometrioid adenocarcinoma. The higher level of URI/RMP expression in high-grade endometrioid adenocarcinomas compared to tissues of adjacent endometrium or gland suggests a diagnostic and possibly, a prognostic value of URI/RMP in endometrioid adenocarcinoma.

Expression analysis of URI/RMP gene in endometrioid adenocarcinoma by tissue microarray immunohistochemistry

PubMed Central

Gu, Junxia; Liang, Yuting; Qiao, Longwei; Li, Xiaoyun; Li, Xingang; Lu, Yaojuan; Zheng, Qiping

2013-01-01

Multiple studies have recently demonstrated the oncogenic property of URI (or RMP, a member of the prefoldin family of molecular chaperones) during progression of hepatocellular carcinoma, ovarian cancer, and possibly prostate cancer. Most recently, we have shown that URI/RMP is up-regulated in cervical cancer, another reproductive system tumor beside ovarian and prostate cancers. To investigate if URI/RMP also plays a role in other reproductive system tumors, especially in endometrioid adenocarcinoma, we analyzed URI/RMP expression in a TMA (tissue microarray) containing tissues from 30 cases of endometrioid adenocarcinoma (which covers tumor tissues from Grade I through Grade III) and adjacent endometrium by immunohistochemistry (IHC) and densitometry analysis using image-pro plus 6.0 software. Our results showed that the mean density of URI/RMP expression in cancerous tissue is slightly higher than that of the adjacent endometrial tissue, though not statistically significant (p>0.05). There is no significant difference either between the mean density of Grade III cancerous tissue and that of Grade I and II cancers. Notably, we detected significantly higher signal intensity in cancerous tissue of all 7 Grade III cases than that of their adjacent endometrial tissue (p<0.05), suggesting a correlation of URI/RMP expression with the differentiation and pathological classification of endometrioid adenocarcinoma. Together, our results demonstrate the heterogeneous expression of URI/RMP in endometrioid adenocarcinoma. The higher level of URI/RMP expression in high-grade endometrioid adenocarcinomas compared to tissues of adjacent endometrium or gland suggests a diagnostic and possibly, a prognostic value of URI/RMP in endometrioid adenocarcinoma. PMID:24228101

A Presurgical Study of Lecithin Formulation of Green Tea Extract in Women with Early Breast Cancer.

PubMed

Lazzeroni, Matteo; Guerrieri-Gonzaga, Aliana; Gandini, Sara; Johansson, Harriet; Serrano, Davide; Cazzaniga, Massimiliano; Aristarco, Valentina; Macis, Debora; Mora, Serena; Caldarella, Pietro; Pagani, Gianmatteo; Pruneri, Giancarlo; Riva, Antonella; Petrangolini, Giovanna; Morazzoni, Paolo; DeCensi, Andrea; Bonanni, Bernardo

2017-06-01

Epidemiologic data support an inverse association between green tea intake and breast cancer risk. Greenselect Phytosome (GSP) is a lecithin formulation of a caffeine-free green tea catechin extract. The purpose of the study was to determine the tissue distribution of epigallocatechin-3-O-gallate (EGCG) and its effect on cell proliferation and circulating biomarkers in breast cancer patients. Twelve early breast cancer patients received GSP 300 mg, equivalent to 44.9 mg of EGCG, daily for 4 weeks prior to surgery. The EGCG levels were measured before (free) and after (total) enzymatic hydrolysis by HPLC-MS/MS in plasma, urine, breast cancer tissue, and surrounding normal breast tissue. Fasting blood samples were taken at baseline, before the last administration, and 2 hours later. Repeated administration of GSP achieved levels of total EGCG ranging from 17 to 121 ng/mL in plasma. Despite a high between-subject variability, total EGCG was detectable in all tumor tissue samples collected up to 8 ng/g. Median total EGCG concentration was higher in the tumor as compared with the adjacent normal tissue (3.18 ng/g vs. 0 ng/g, P = 0.02). Free EGCG concentrations ranged from 8 to 65.8 ng/mL in plasma ( P between last administration and 2 hours after <0.001). Free EGCG plasma levels showed a significant positive correlation with the Ki-67 decrease in tumor tissue ( P = 0.02). No change in any other biomarkers was noted, except for a slight increase in testosterone levels after treatment. Oral GSP increases bioavailability of EGCG, which is detectable in breast tumor tissue and is associated with antiproliferative effects on breast cancer tissue. Cancer Prev Res; 10(6); 363-9. ©2017 AACR . ©2017 American Association for Cancer Research.

Expression of β-catenin protein in hepatocellular carcinoma and its relationship with alpha-fetoprotein.

PubMed

Ren, Ya-Jun; Huang, Tao; Yu, Hong-Lu; Zhang, Li; He, Qian-Jin; Xiong, Zhi-Fan; Peng, Hua

2016-12-01

This study aimed to investigate the expression of β-catenin in hepatocellular carcinoma (HCC) tissues and its relationship with α-fetoprotein (AFP) in HCC. Immunohistochemistry was used to determine the expression of β-catenin in normal liver tissues (n=10), liver cirrhosis tissues (n=20), and primary HCC tissues (n=60). The relationship between β-catenin expression and clinical parameters of HCC was investigated. Real-time PCR and Western blotting were used to detect the mRNA and protein expression levels of β-catenin in the liver cancer cell line SMMC-7721 transfected with a plasmid encoding AFP, and also the mRNA and protein expression levels of β-catenin were measured in the liver cancer cell line Huh7 before and after the transfection with AFP shRNA plasmids. The results showed that β-catenin was only expressed on the cell membrane in normal liver tissues. Its localization to the cytoplasm and nucleus of cells was observed in a small proportion of cirrhotic tissues or adjacent HCC tissues, and such ectopic expression of β-catenin was predominant in HCC tissues. The abnormal expression of β-catenin was correlated with serum AFP levels, cancer cell differentiation and vascular invasion (P<0.05). Additionally, the increased expression of AFP resulted in the upregulation of β-catenin mRNA and protein levels, while knockdown of AFP with AFP shRNA led to significantly decreased β-catenin mRNA and protein levels (P<0.05). It was suggested that the abnormal expression of β-catenin is implicated in hepatic carcinogenesis and development. AFP can lead to increased expression of β-catenin, which may account for the poor prognosis of AFP-associated HCC patients.

Insulin receptor isoforms A and B as well as insulin receptor substrates-1 and -2 are differentially expressed in prostate cancer.

PubMed

Heni, Martin; Hennenlotter, Jörg; Scharpf, Marcus; Lutz, Stefan Z; Schwentner, Christian; Todenhöfer, Tilman; Schilling, David; Kühs, Ursula; Gerber, Valentina; Machicao, Fausto; Staiger, Harald; Häring, Hans-Ulrich; Stenzl, Arnulf

2012-01-01

In different cancers types, insulin receptor isoform composition or insulin receptor substrate (IRS) isoforms are different to healthy tissue. This may be a molecular link to increased cancer risk in diabetes and obesity. Since this is yet unclear for prostate cancer, we investigated IR isoform composition and IRS balance in prostate cancer compared to benign and tumor adjacent benign prostate tissue and brought this into relation to cell proliferation. We studied 23 benign prostate samples from radical cystectomy or benign prostatic hyperplasia surgery, 30 samples from benign tissue directly adjacent to prostate cancer foci and 35 cancer samples from different patients. RNA expression levels for insulin receptor isoforms A and B, IRS-1, IRS-2, and IGF-1 receptor were assessed by quantitative real-time RT-PCR. In addition, RNA- and protein expression of the cell cycle regulator p27(Kip1) was quantified by real-time RT-PCR and immunohistochemistry. Insulin receptor isoform A to B ratio was significantly higher in cancer as well as in tumor adjacent benign prostate tissue compared to purely benign prostates (p<0.05). IRS-1 to IRS-2 ratios were lower in malignant than in benign prostatic tissue (p<0.05). These altered ratios both in cancer and adjacent tissue were significantly associated with reduced p27(Kip1) content (p<0.02). Interestingly, IGF-1 receptor levels were significantly lower in patients with type 2 diabetes (p = 0.0019). We found significant differences in the insulin signaling cascade between benign prostate tissue and prostate cancer. Histological benign tissue adjacent to cancer showed expression patterns similar to the malignancies. Our findings suggest a role of the insulin signaling pathway in prostate cancer and surrounding tissue and can hence be relevant for both novel diagnostic and therapeutic approaches in this malignancy.

Multi-dimensional TOF-SIMS analysis for effective profiling of disease-related ions from the tissue surface.

PubMed

Park, Ji-Won; Jeong, Hyobin; Kang, Byeongsoo; Kim, Su Jin; Park, Sang Yoon; Kang, Sokbom; Kim, Hark Kyun; Choi, Joon Sig; Hwang, Daehee; Lee, Tae Geol

2015-06-05

Time-of-flight secondary ion mass spectrometry (TOF-SIMS) emerges as a promising tool to identify the ions (small molecules) indicative of disease states from the surface of patient tissues. In TOF-SIMS analysis, an enhanced ionization of surface molecules is critical to increase the number of detected ions. Several methods have been developed to enhance ionization capability. However, how these methods improve identification of disease-related ions has not been systematically explored. Here, we present a multi-dimensional SIMS (MD-SIMS) that combines conventional TOF-SIMS and metal-assisted SIMS (MetA-SIMS). Using this approach, we analyzed cancer and adjacent normal tissues first by TOF-SIMS and subsequently by MetA-SIMS. In total, TOF- and MetA-SIMS detected 632 and 959 ions, respectively. Among them, 426 were commonly detected by both methods, while 206 and 533 were detected uniquely by TOF- and MetA-SIMS, respectively. Of the 426 commonly detected ions, 250 increased in their intensities by MetA-SIMS, whereas 176 decreased. The integrated analysis of the ions detected by the two methods resulted in an increased number of discriminatory ions leading to an enhanced separation between cancer and normal tissues. Therefore, the results show that MD-SIMS can be a useful approach to provide a comprehensive list of discriminatory ions indicative of disease states.

Multi-dimensional TOF-SIMS analysis for effective profiling of disease-related ions from the tissue surface

PubMed Central

Park, Ji-Won; Jeong, Hyobin; Kang, Byeongsoo; Kim, Su Jin; Park, Sang Yoon; Kang, Sokbom; Kim, Hark Kyun; Choi, Joon Sig; Hwang, Daehee; Lee, Tae Geol

2015-01-01

Time-of-flight secondary ion mass spectrometry (TOF-SIMS) emerges as a promising tool to identify the ions (small molecules) indicative of disease states from the surface of patient tissues. In TOF-SIMS analysis, an enhanced ionization of surface molecules is critical to increase the number of detected ions. Several methods have been developed to enhance ionization capability. However, how these methods improve identification of disease-related ions has not been systematically explored. Here, we present a multi-dimensional SIMS (MD-SIMS) that combines conventional TOF-SIMS and metal-assisted SIMS (MetA-SIMS). Using this approach, we analyzed cancer and adjacent normal tissues first by TOF-SIMS and subsequently by MetA-SIMS. In total, TOF- and MetA-SIMS detected 632 and 959 ions, respectively. Among them, 426 were commonly detected by both methods, while 206 and 533 were detected uniquely by TOF- and MetA-SIMS, respectively. Of the 426 commonly detected ions, 250 increased in their intensities by MetA-SIMS, whereas 176 decreased. The integrated analysis of the ions detected by the two methods resulted in an increased number of discriminatory ions leading to an enhanced separation between cancer and normal tissues. Therefore, the results show that MD-SIMS can be a useful approach to provide a comprehensive list of discriminatory ions indicative of disease states. PMID:26046669

Microvessel density and angiogenesis in primary hepatic malignancies: Differential expression of CD31 and VEGFR-2 in hepatocellular carcinoma and intrahepatic cholangiocarcinoma.

PubMed

Bösmüller, Hans; Pfefferle, Vanessa; Bittar, Zeid; Scheble, Veit; Horger, Marius; Sipos, Bence; Fend, Falko

2018-06-19

Microvessel density is an indicator of tumor-driven neoangiogenesis. Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) have distinct vascular patterns, which are also reflected in their imaging characteristics. Since a significant proportion of HCC are treated without biopsy confirmation, it is essential to discriminate HCC and ICC radiologically. The aim of our study was therefore to compare microvessel density and expression of VEGFR-2 in HCC and ICC, since these data may ultimately help us to better understand their imaging characteristics. Whereas CD31 documents vessel density, VEGFR-2 expression is an indicator of tumor-related neoangiogenesis. CD31 and VEGFR-2 expressing microvessels were quantified on tissue microarrays of 95 resection specimens of HCC and 47 cases of ICC. Microvessel density was evaluated by counting immuno-reactive vascular structures both within the tumor and adjacent liver control tissue, respectively. Further 16 cases of ICC were immunostained for CD31 and VEGFR-2 on full sections. The frequency of VEGFR-2 (46.2/HPF; range 0-150) and CD31 (61.2/HPF; range 2.6-140) expressing vascular structures was significantly increased in HCC compared to adjacent liver parenchyma (VEGFR-2 33.3/HPF, range 0-87, CD31 21.4/HPF, range 0-78, both p < 0,001). ICC revealed significantly less VEGFR2-positive microvessels (15.4/HPF; range 2-77) compared to matched control tissue (42.3/HPF; range 4.6-109), whereas microvessel density with CD31 was comparable between ICC and adjacent liver (32.1/HPF; range 5.3-78 versus 28.0/HPF; range 5.3-57; p = 0.89). In ICC, the tumor-to-normal microvessel density ratio was 0.38 for VEGFR-2 and 1.24 for CD31. These ratios were nearly identical (VEGFR: 0.38; CD31: 0,97) for the 16 cases of ICC studied on whole sections, confirming the validity of the TMA approach. In contrast, ratios of VEGFR-2 and CD31 in HCC vs. adjacent liver were significantly higher (VEGFR: 2.23; CD31: 6.57). Expression of VEGFR-2 by tumor cells was not observed in any of the cases. HCC and ICC differ significantly in their microvessel density, confirming the hypovascular nature of ICC as compared to the hypervascularity of HCC. Of note, inverse tumor-to-normal ratios of microvascular VEGFR-2 expression between the two neoplasms indicate distinct features of neoangiogenesis. Whether these differences can be exploited for improvements in imaging of hepatic tumors and may play a role for anti-angiogenic treatment strategies requires further studies. Copyright © 2018 Elsevier GmbH. All rights reserved.

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

PubMed Central

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

2017-01-01

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

[Expression and Significance of PI-PLCε1 in Colon Cancer].

PubMed

Li, Xiao-Ran; Yang, Kun; Huang, Xiao-Li

2017-11-01

To study the expression and clinical significance of phosphoinositide-specific phospholipase Cε1 (PI-PLCε1) in the pathogenesis of colon cancer. qRT-PCR and immunohistochemistry were used to detect the expression of PI-PLCε1 in the 42 cases of colon cancer tissues and their corresponding adjacent tissues. And the effects of tumor differentiation and tumor site on the expression PI-PLCε1 of colon cancer tissues were compared. The results of qRT-PCR showed that the expression of PI-PLCε1 in colon cancer tissue significantly lower than that in the adjacent tissue ( P <0.05). The expression of PI-PLCε1 gene of colon cancer tissue was not effected by tumor differentiation and tumor site ( P >0.05). The results of immuno-histochemistry showed that the positive expression rate of PI-PLCε1 protein in colon cancer tissue was significantly lower than that in the adjacent tissue ( P <0.05). The positive expression rate of PI-PLCε1 protein was not effected by tumor differentiation ( P >0.05),but the expression was different in tumor site ( P <0.05). Expression of PI-PLCε1 was reduced in colon tissue and barely to tumor differentiation.

Synthesis and Preliminary Evaluation of Phenyl 4-123I-Iodophenylcarbamate for Visualization of Cholinesterases Associated with Alzheimer Disease Pathology.

PubMed

Macdonald, Ian R; Reid, G Andrew; Pottie, Ian R; Martin, Earl; Darvesh, Sultan

2016-02-01

Acetylcholinesterase and butyrylcholinesterase accumulate with brain β-amyloid (Aβ) plaques in Alzheimer disease (AD). The overall activity of acetylcholinesterase is found to decline in AD, whereas butyrylcholinesterase has been found to either increase or remain the same. Although some cognitively normal older adults also have Aβ plaques within the brain, cholinesterase-associated plaques are generally less abundant in such individuals. Thus, brain imaging of cholinesterase activity associated with Aβ plaques has the potential to distinguish AD from cognitively normal older adults, with or without Aβ accumulation, during life. Current Aβ imaging agents are not able to provide this distinction. To address this unmet need, synthesis and evaluation of a cholinesterase-binding ligand, phenyl 4-(123)I-iodophenylcarbamate ((123)I-PIP), is described. Phenyl 4-iodophenylcarbamate was synthesized and evaluated for binding potency toward acetylcholinesterase and butyrylcholinesterase using enzyme kinetic analysis. This compound was subsequently rapidly radiolabeled with (123)I and purified by high-performance liquid chromatography. Autoradiographic analyses were performed with (123)I-PIP using postmortem orbitofrontal cortex from cognitively normal and AD human brains. Comparisons were made with an Aβ imaging agent, 2-(4'-dimethylaminophenyl)-6-(123)I-iodo-imidazo[1,2-a]pyridine ((123)I-IMPY), in adjacent brain sections. Tissues were also stained for Aβ and cholinesterase activity to visualize Aβ plaque load for comparison with radioligand uptake. Synthesized and purified PIP exhibited binding to cholinesterases. (123)I was successfully incorporated into this ligand. (123)I-PIP autoradiography with human tissue revealed accumulation of radioactivity only in AD brain tissues in which Aβ plaques had cholinesterase activity. (123)I-IMPY accumulated in brain tissues with Aβ plaques from both AD and cognitively normal individuals. Radiolabeled ligands specific for cholinesterases have potential for use in neuroimaging AD plaques during life. The compound herein described, (123)I-PIP, can detect cholinesterases associated with Aβ plaques and can distinguish AD brain tissues from those of cognitively normal older adults with Aβ plaques. Imaging cholinesterase activity associated with Aβ plaques in the living brain may contribute to the definitive diagnosis of AD during life. © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Overexpression of p42.3 promotes cell growth and tumorigenicity in hepatocellular carcinoma

PubMed Central

Sun, Wei; Dong, Wei-Wei; Mao, Lin-Lin; Li, Wen-Mei; Cui, Jian-Tao; Xing, Rui; Lu, You-Yong

2013-01-01

AIM: To investigate the association of p42.3 expression with clinicopathological characteristics and the biological function of p42.3 in human hepatocellular carcinoma (HCC). METHODS: We used reverse transcription-polymerase chain reaction (RT-PCR), quantitative real-time RT-PCR and western blotting to detect p42.3 mRNA and protein expression in hepatic cell lines. We examined primary HCC samples and matched adjacent normal tissue by immunohistochemistry to investigate the correlation between p42.3 expression and clinicopathological features. HepG2 cells were transfected with a pIRES2-EGFP-p42.3 expression vector to examine the function of the p42.3 gene. Transfected cells were analyzed for their viability and malignant transformation abilities by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, colony formation assay, and tumorigenicity assay in nude mice. RESULTS: p42.3 is differentially expressed in primary HCC tumors and cell lines. Approximately 69.6% (96/138) of cells were p42.3-positive in hepatic tumor tissues, while 30.7% (35/114) were p42.3-positive in tumor-adjacent normal tissues. Clinicopathological characteristics of the HCC specimens revealed a significant correlation between p42.3 expression and tumor differentiation (P = 0.031). However, p42.3 positivity was not related to tumor tumor-node-metastasis classification, hepatitis B virus status, or hepatoma type. Regarding p42.3 overexpression in stably transfected HepG2 cells, we discovered significant enhancement of cancer cell growth and colony formation in vitro, and significantly enhanced tumorigenicity in nude mice. Western blot analysis of cell cycle proteins revealed that enhanced p42.3 levels promote upregulation of proliferating cell nuclear antigen, cyclin B1 and mitotic arrest deficient 2. CONCLUSION: p42.3 promotes tumorigenicity and tumor growth in HCC and may be a potential target for future clinical cancer therapeutics. PMID:23704824

SU-C-207B-03: A Geometrical Constrained Chan-Vese Based Tumor Segmentation Scheme for PET

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

Chen, L; Zhou, Z; Wang, J

Purpose: Accurate segmentation of tumor in PET is challenging when part of tumor is connected with normal organs/tissues with no difference in intensity. Conventional segmentation methods, such as thresholding or region growing, cannot generate satisfactory results in this case. We proposed a geometrical constrained Chan-Vese based scheme to segment tumor in PET for this special case by considering the similarity between two adjacent slices. Methods: The proposed scheme performs segmentation in a slice-by-slice fashion where an accurate segmentation of one slice is used as the guidance for segmentation of rest slices. For a slice that the tumor is not directlymore » connected to organs/tissues with similar intensity values, a conventional clustering-based segmentation method under user’s guidance is used to obtain an exact tumor contour. This is set as the initial contour and the Chan-Vese algorithm is applied for segmenting the tumor in the next adjacent slice by adding constraints of tumor size, position and shape information. This procedure is repeated until the last slice of PET containing tumor. The proposed geometrical constrained Chan-Vese based algorithm was implemented in Matlab and its performance was tested on several cervical cancer patients where cervix and bladder are connected with similar activity values. The positive predictive values (PPV) are calculated to characterize the segmentation accuracy of the proposed scheme. Results: Tumors were accurately segmented by the proposed method even when they are connected with bladder in the image with no difference in intensity. The average PPVs were 0.9571±0.0355 and 0.9894±0.0271 for 17 slices and 11 slices of PET from two patients, respectively. Conclusion: We have developed a new scheme to segment tumor in PET images for the special case that the tumor is quite similar to or connected to normal organs/tissues in the image. The proposed scheme can provide a reliable way for segmenting tumors.« less

Imaging in gynecological disease (9): clinical and ultrasound characteristics of tubal cancer.

PubMed

Ludovisi, M; De Blasis, I; Virgilio, B; Fischerova, D; Franchi, D; Pascual, M A; Savelli, L; Epstein, E; Van Holsbeke, C; Guerriero, S; Czekierdowski, A; Zannoni, G; Scambia, G; Jurkovic, D; Rossi, A; Timmerman, D; Valentin, L; Testa, A C

2014-03-01

To describe clinical history and ultrasound findings in patients with tubal carcinoma. Patients with a histological diagnosis of tubal cancer who had undergone preoperative ultrasound examination were identified from the databases of 13 ultrasound centers. The tumors were described by the principal investigator at each contributing center on the basis of ultrasound images, ultrasound reports and research protocols (when applicable) using the terms and definitions of the International Ovarian Tumor Analysis (IOTA) group. In addition, three authors reviewed together all available digital ultrasound images and described them using subjective evaluation of gray-scale and color Doppler ultrasound findings. We identified 79 women with a histological diagnosis of primary tubal cancer, 70 of whom (89%) had serous carcinomas and 46 (58%) of whom presented at FIGO stage III. Forty-nine (62%) women were asymptomatic (incidental finding), whilst the remaining 30 complained of abdominal bloating or pain. Fifty-three (67%) tumors were described as solid at ultrasound examination, 14 (18%) as multilocular solid, 10 (13%) as unilocular solid and two (3%) as unilocular. No tumor was described as a multilocular mass. Most tumors (70/79, 89%) were moderately or very well vascularized on color or power Doppler ultrasound. Normal ovarian tissue was identified adjacent to the tumor in 51% (39/77) of cases. Three types of ultrasound appearance were identified as being typical of tubal carcinoma using pattern recognition: a sausage-shaped cystic structure with solid tissue protruding into it like a papillary projection (11/62, 18%); a sausage-shaped cystic structure with a large solid component filling part of the cyst cavity (13/62, 21%); an ovoid or oblong completely solid mass (36/62, 58%). A well vascularized ovoid or sausage-shaped structure, either completely solid or with large solid component(s) in the pelvis, should raise the suspicion of tubal cancer, especially if normal ovarian tissue is seen adjacent to it. Copyright © 2013 ISUOG. Published by John Wiley & Sons Ltd.

Aberrant methylation of the MSH3 promoter and distal enhancer in esophageal cancer patients exposed to first-hand tobacco smoke.

PubMed

Vogelsang, Matjaz; Paccez, Juliano D; Schäfer, Georgia; Dzobo, Kevin; Zerbini, Luiz F; Parker, M Iqbal

2014-11-01

Polymorphisms in MSH3 gene confer risk of esophageal cancer when in combination with tobacco smoke exposure. The purpose of this study was to investigate the methylation status of MSH3 gene in esophageal cancer patients in order to further elucidate possible role of MSH3 in esophageal tumorigenesis. We applied nested methylation-specific polymerase chain reaction to investigate the methylation status of the MSH3 promoter in tumors and matching adjacent normal-looking tissues of 84 esophageal cancer patients from a high-risk South African population. The Cancer Genome Atlas data were used to examine DNA methylation profiles at 17 CpG sites located in the MSH3 locus. Overall, promoter methylation was detected in 91.9 % of tumors, which was significantly higher compared to 76.0 % in adjacent normal-looking esophageal tissues (P = 0.008). When samples were grouped according to different demographics (including age, gender and ethnicity) and smoking status of patients, methylation frequencies were found to be significantly higher in tumor tissues of Black subjects (P = 0.024), patients of 55-65 years of age (P = 0.032), males (P = 0.037) and tobacco smokers (P = 0.015). Furthermore, methylation of the MSH3 promoter was significantly more frequent in tumor samples from smokers compared to tumor samples from non-smokers [odds ratio (OR) = 31.9, P = 0.031]. The TCGA data confirmed significantly higher DNA methylation level at the MSH3 promoter region in tumors (P = 0.0024). In addition, we found evidence of an aberrantly methylated putative MSH3-associated distal enhancer element. Our results suggest that methylation of MSH3 together with exposure to tobacco smoke is involved in esophageal carcinogenesis. Due to the active role of the MSH3 protein in modulating chemosensitivity of cells, methylation of MSH3 should further be examined in association with the outcome of esophageal cancer treatment using anticancer drugs.

Safety and efficacy of targeted hyperthermia treatment utilizing gold nanorod therapy in spontaneous canine neoplasia.

PubMed

Schuh, Elizabeth M; Portela, Roberta; Gardner, Heather L; Schoen, Christian; London, Cheryl A

2017-10-02

Hyperthermia is an established anti-cancer treatment but is limited by tolerance of adjacent normal tissues. Parenteral administration of gold nanorods (NRs) as a photosensitizer amplifies the effects of hyperthermia treatment while sparing normal tissues. This therapy is well tolerated and has demonstrated anti-tumor effects in mouse models. The purpose of this phase 1 study was to establish the safety and observe the anti-tumor impact of gold NR enhanced (plasmonic) photothermal therapy (PPTT) in client owned canine patients diagnosed with spontaneous neoplasia. Seven dogs underwent gold NR administration and subsequent NIR PPTT. Side effects were mild and limited to local reactions to NIR laser. All of the dogs enrolled in the study experienced stable disease, partial remission or complete remission. The overall response rate (ORR) was 28.6% with partial or complete remission of tumors at study end. PPTT utilizing gold nanorod therapy can be safely administered to canine patients. Further studies are needed to determine the true efficacy in a larger population of canine cancer patients and to and identify those patients most likely to benefit from this therapy.

Long Noncoding RNA LINC00958 Accelerates Gliomagenesis Through Regulating miR-203/CDK2.

PubMed

Guo, Erkun; Liang, Chaohui; He, Xin; Song, Guozhi; Liu, Hongjiang; Lv, Zhongqiang; Guan, Jianchao; Yang, Dezhen; Zheng, Jiapeng

2018-05-01

Increasing evidence has indicated that long noncoding RNAs (lncRNAs) play crucial roles in various biological processes, including glioma. However, the underlying mechanism of lncRNAs in gliomagenesis is still ambiguous. In this study, we aim to investigate the role of long intergenic noncoding RNA 00958 (LINC00958) in the tumorigenesis of glioma. Results revealed that LINC00958 was significantly upregulated in glioma tissues and cell lines compared with that of adjacent normal brain tissues and normal human astrocytes. Moreover, the ectopic overexpression of LINC00958 was correlated with poor prognosis of glioma patients. Loss-of-function experiments indicated that LINC00958 knockdown suppressed glioma cell proliferation, invasion, and induced cycle arrest at G0/G1 phase in vitro, and inhibited tumor growth in vivo. Bioinformatics programs and luciferase reporter assay revealed that miR-203 shared complementary binding sites with both 3'-untranslated region of LINC00958 and CDK2. In summary, our study concludes that LINC00958 acts as an oncogenic gene in the gliomagenesis through miR-203-CDK2 regulation, providing a novel insight into glioma tumorigenesis.

Anti-EGFRvIII Chimeric Antigen Receptor-Modified T Cells for Adoptive Cell Therapy of Glioblastoma.

PubMed

Ren, Pei-Pei; Li, Ming; Li, Tian-Fang; Han, Shuang-Yin

2017-01-01

Glioblastoma (GBM) is one of the most devastating brain tumors with poor prognosis and high mortality. Although radical surgical treatment with subsequent radiation and chemotherapy can improve the survival, the efficacy of such regimens is insufficient because the GBM cells can spread and destroy normal brain structures. Moreover, these non-specific treatments may damage adjacent healthy brain tissue. It is thus imperative to develop novel therapies to precisely target invasive tumor cells without damaging normal tissues. Immunotherapy is a promising approach due to its capability to suppress the growth of various tumors in preclinical model and clinical trials. Adoptive cell therapy (ACT) using T cells engineered with chimeric antigen receptor (CAR) targeting an ideal molecular marker in GBM, e.g. epidermal growth factor receptor type III (EGFRvIII) has demonstrated a satisfactory efficacy in treating malignant brain tumors. Here we summarize the recent progresses in immunotherapeutic strategy using CAR-modified T cells oriented to EGFRvIII against GBM. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Circular RNA hsa_circ_0008344 regulates glioblastoma cell proliferation, migration, invasion, and apoptosis.

PubMed

Zhou, Jinxu; Wang, Hongxiang; Chu, Junsheng; Huang, Qilin; Li, Guangxu; Yan, Yong; Xu, Tao; Chen, Juxiang; Wang, Yuhai

2018-04-24

Recent studies have found circular RNAs (circRNAs) involved in the biological process of cancers. However, little is known about their functional roles in glioblastoma. Human circRNA microarray analysis was performed to screen the expression profile of circRNAs in IDH1 wild-type glioblastoma tissue. The expression of hsa_circ_0008344 in glioblastoma and normal brain samples was quantified by qRT-PCR. Functional experiments were performed to investigate the biological functions of hsa_circ_0008344, including MTT assay, colony formation assay, transwell assay, and cell apoptosis assay. CircRNA microarray revealed a total of 417 abnormally expressed circRNAs (>1.5-fold, P < .05) in glioblastoma tissue compared with the adjacent normal brain. Hsa_circ_0008344, among the top differentially expressed circRNAs, was significantly upregulated in IDH1 wild-type glioblastoma. Further in vitro studies showed that knockdown of hsa_circ_0008344 suppressed glioblastoma cell proliferation, colony formation, migration, and invasion, but increased cell apoptotic rate. Hsa_circ_0008344 is upregulated in glioblastoma and may contribute to the progression of this malignancy. © 2018 Wiley Periodicals, Inc.

Ski protein levels increase during in vitro progression of HPV16-immortalized human keratinocytes and in cervical cancer

PubMed Central

Chen, Yi; Pirisi, Lucia; Creek, Kim E.

2013-01-01

We compared the levels of the Ski oncoprotein, an inhibitor of transforming growth factor-beta (TGF-β) signaling, in normal human keratinocytes (HKc), HPV16 immortalized HKc (HKc/HPV16), and differentiation resistant HKc/HPV16 (HKc/DR) in the absence and presence of TGF-β. Steady-state Ski protein levels increased in HKc/HPV16 and even further in HKc/DR, compared to HKc. TGF-β treatment of HKc, HKc/HPV16, and HKc/DR dramatically decreased Ski. TGF-β-induced Ski degradation was delayed in HKc/DR. Ski and phospho-Ski protein levels are cell cycle dependent with maximal Ski expression and localization to centrosomes and mitotic spindles during G2/M. ShRNA knock down of Ski in HKc/DR inhibited cell proliferation. More intense nuclear and cytoplasmic Ski staining and altered Ski localization were found in cervical cancer samples compared to adjacent normal tissue in a cervical cancer tissue array. Overall, these studies demonstrate altered Ski protein levels, degradation and localization in HPV16-transformed human keratinocytes and in cervical cancer. PMID:23809940

Overexpression of long intergenic noncoding RNA LINC00312 inhibits the invasion and migration of thyroid cancer cells by down-regulating microRNA-197-3p.

PubMed

Liu, Kai; Huang, Wen; Yan, Dan-Qing; Luo, Qing; Min, Xiang

2017-08-31

The study evaluated the ability of long intergenic noncoding RNA LINC00312 (LINC00312) to influence the proliferation, invasion, and migration of thyroid cancer (TC) cells by regulating miRNA-197-3p. TC tissues and adjacent normal tissues were collected from 211 TC patients. K1 (papillary TC), SW579 (squamous TC), and 8505C (anaplastic TC) cell lines were assigned into a blank, negative control (NC), LINC00312 overexpression, miR-197-3p inhibitors, and LINC00312 overexpression + miR-197-3p mimics group. The expression of LINC00312, miR-197-3p , and p120 were measured using quantitative real-time PCR (qRT-PCR) and Western blotting. Cell proliferation was assessed via CCK8 assay, cell invasion through the scratch test, and cell migration via Transwell assay. In comparison with adjacent normal tissues, the expression of LINC00312 is down-regulated and the expression of miR-197-3p is up-regulated in TC tissues. The dual luciferase reporter gene assay confirmed that P120 is a target of miR-197-3p The expression of LINC00312 and p120 was higher in the LINC00312 overexpression group than in the blank and NV groups. However, the expression of miR-197-3p was lower in the LINC00312 overexpression group than in the blank and NC groups. The miR-197-3p inhibitors group had a higher expression of miR-197-3p , but a lower expression of p120 than the blank and NC groups. The LINC00312 overexpression and miR-197-3p inhibitor groups had reduced cell proliferation, invasion and migration than the blank and NC groups. These results indicate that a LINC00312 overexpression inhibits the proliferation, invasion, and migration of TC cells and that this can be achieved by down-regulating miR-197-3p . © 2017 The Author(s).

IκB kinase b Mediating the Downregulation of p53 and p21 by Lipopolysaccharide in Human Papillomavirus 16+ Cervical Cancer Cells.

PubMed

Tan, Zhi-Hui; Zhang, Yu; Tian, Yan; Tan, Wei; Li, Ying-Hua

2016-11-20

Cervical cancer is the second most common cancer of woman in the world, and human papillomavirus (HPV) infection plays an important role in the development of most of the cases. IκB kinase β (IKKβ) is a kinase-mediating nuclear factor kappa B (NF-κB) activation by phosphorylating the inhibitor of NF-κB (IκB) and is related by some diseases caused by virus infection. However, there is little known about the correlation between IKKβ and HPV infection in cervical cancer. This study aimed to investigate the expression of IKKβ protein in cervical cancer tissues and effects of inflammation on HPV positive or negative cervical cancer cells through detecting the expression of IKKβ, IκBα, p53, and p21 proteins after treated with lipopolysaccharide (LPS) to mimic bacterial infection. We also examined the effects of LPS on cervical cancer cells after blocking IKKβ with pharmacological inhibitor. Thirty-six matched specimens of cervical cancer and adjacent normal tissues were collected and analyzed in the study. The expression of IKKβ in the tissue specimens was determined by immunohistochemical staining. In addition, Western blot was used to detect the expression level changes of IKKβ, IκBα, p53, and p21 after LPS stimulated in the HPV16+ (SiHa) and HPV16- (C33A) cervical cancer cell lines. Furthermore, the effects of IKKβ inhibitor SC-514 on LPS-induced expression change of these proteins were investigated. The expression of IKKβ was higher in cervical cancer than adjacent normal tissues, and there was no significant difference between tumor differentiation, size, and invasive depth with IKKβ expression. The LPS, which increased the expression level of IKKβ protein but decreased in the IκBα, p53 and p21 proteins, was illustrated in HPV16+ (SiHa) but not in HPV16- (C33A) cells. Moreover, IKKβ inhibitor SC-514 totally reversed the upregulation of IKKβ and downregulation of p53 and p21 by LPS in SiHa cells. IKKβ may mediate the downregulation of p53 and p21 by LPS in HPV16+ cervical cancer cells.

Radioresistance of chordoma cells is associated with the ATM/ATR pathway, in which RAD51 serves as an important downstream effector.

PubMed

Zhang, Chao; Wang, Bing; Li, Lei; Li, Yawei; Li, Pengzhi; Lv, Guohua

2017-09-01

Surgery followed by radiotherapy is the standard treatment for chordomas, which are a rare but low-grade type of bone cancer arising from remnants of the embryonic notochord. However, disease recurrence following radiotherapy is common, most likely due to endogenous DNA repair mechanisms that promote cell survival upon radiation strikes. The ataxia telangiectasia mutated/ataxia telangiectasia mutated and Rad3 related (ATM/ATR)-mediated pathway has a critical role in DNA repair mechanisms; however, it has rarely been investigated in chordomas. In the present study, the expression of signal molecules related to the ATM/ATR pathway in chordoma tissues and adjacent normal tissues were initially examined using immunohistochemistry and western blot analysis. Chordoma U-CH1 and U-CH2 cells were subsequently used to investigate cell responses to ionizing radiation and the potential protective actions mediated by the ATM/ATR pathway. Phosphorylated (p)-ATM, p-ATR, γ-H2A histone family, member X (H2AX) and RAD51 were significantly upregulated in chordoma tissues relative to adjacent normal tissues (P<0.05). No significant reductions were observed in the viability of U-CH1 and U-CH2 cells following exposure to low-dose (1 and 2 Gy) radiation. Radiation (1 and 2 Gy) triggered a significant upregulation in p-ATM, γ-H2AX and RAD51 expression in U-CH1 cells (P<0.05), as well as a significant upregulation in p-ATM, p-ATR and RAD51 levels in U-CH2 cells (P<0.05). RAD51 knockdown increased the responses of both U-CH1 and U-CH2 cells to 1 Gy radiation, as evidenced by the significantly decreased cell viability and increased apoptosis rate (P<0.05). Collectively, the results of the present study indicated that radioresistance of chordoma cells is associated with the ATM/ATR pathway, in which RAD51 serves as an important downstream effector. Thus, RAD51 presents a promising therapeutic target for improving the outcome of radiotherapy treatment in chordomas.

Characterization and Management of Mandibular Fractures: Lessons Learned from Iraq and Afghanistan

DTIC Science & Technology

2013-03-01

Anatomic reduction is the goal. In complex fractures, maintain large segments of bone and obtain soft tissue coverage. Atlas Oral Maxillofacial Surg...conflicts of Iraq and Afghanistan. J Oral Maxillofac Surg 2010;68(1):3e7; with permission.) Fig. 2 Complex facial injury with avulsive tissue loss...a point distant from the site of injury Complicated (complex)dfracture with considerable injury to the adjacent soft tissue or adjacent parts, may

Impact of IGF-1, IGF-1R, and IGFBP-3 promoter methylation on the risk and prognosis of esophageal carcinoma.

PubMed

Ye, Peng; Qu, Chang-Fa; Hu, Xue-Lin

2016-05-01

The aim of this study is to investigate IGF-1, IGF-1R, and IGFBP-3 methylations in esophageal carcinoma (EC) patients and their relationship with the development and prognosis of EC. This study population consisted of 264 patients (case group) whom EC radical resection was performed and 283 healthy individuals (control group). Methylation-specific PCR (MSP) detected the methylation status of IGF-1, IGF-1R, and IGFBP-3 in the peripheral blood in both groups. The expressions of IGF-1, IGF-1R, and IGFBP-3 in EC and adjacent normal tissues were detected by immunohistochemistry (IHC). The methylation rates of IGF-1, IGF-1R, IGFBP3, and IGF-1 + IGF1R + IGFBP3 in the case group were higher than those in the control group (all P < 0.05). Additionally, there were statistical significances for the methylation rates of IGF-1, IGF-1R, IGFBP3, and IGF-1 + IGF1R + IGFBP3 IGF-1 among patients of different clinicopathological features (all P < 0.05). The positive expression rates of IGF-1 and IGF-1R in EC were significantly higher than those in adjacent normal tissues (both P < 0.001), and the rate of IGFBP-3 in EC was significantly lower than that in adjacent normal tissues (P < 0.05). Correlation analysis showed that IGF-1 and IGF1R gene promoter methylation was positively correlated with the positive expressions of IGF-1 (r = 0.139, P = 0.024) and IGF-1R (r = 0.135, P = 0.028), while the IGFBP3 methylation was negatively correlated with the positive expression of IGFBP3 (r = -0.133, P = 0.031). The positive expressions of IGF-1, IGF-1R, and IGFBP-3 were related to different clinicopathological features (all P < 0.05). Cox multivariate analysis results showed that methylation status of IGF-1, IGF-1R, and IGF-1 + IGF1R + IGFBP3 ; expressions of IGF-1 and IGF-1R protein; infiltration depth; and lymph node metastasis (LNM) were independent factors of EC prognosis. Our study demonstrated that methylation of IGF-1, IGF1R, IGFBP3, and IGF-1 + IGF1R + IGFBP3 was closely linked with the occurrence of EC and patients' clinicopathological features. Besides, the methylation status of the target genes and the expressions of IGF-1 and IGF-1R protein were independent factors of EC prognosis, which could provide a direction for the prognosis and treatment of EC.

Colon Cancer Associated Transcript-1 (CCAT1) Expression in Adenocarcinoma of the Stomach

PubMed Central

Mizrahi, Ido; Mazeh, Haggi; Grinbaum, Ronit; Beglaibter, Nahum; Wilschanski, Michael; Pavlov, Vera; Adileh, Muchamad; Stojadinovic, Alexander; Avital, Itzhak; Gure, Ali Osmay; Halle, David; Nissan, Aviram

2015-01-01

Background: Long non-coding RNAs (lncRNAs) have been shown to have functional roles in cancer biology and are dys-regulated in many tumors. Colon Cancer Associated Transcript -1 (CCAT1) is a lncRNA, previously shown to be significantly up-regulated in colon cancer. The aim of this study is to determine expression levels of CCAT1 in gastric carcinoma (GC). Methods: Tissue samples were obtained from patients undergoing resection for gastric carcinoma (n=19). For each patient, tumor tissue and normal appearing gastric mucosa were taken. Normal gastric tissues obtained from morbidly obese patients, undergoing laparoscopic sleeve gastrectomy served as normal controls (n=19). A human gastric carcinoma cell line (AGS) served as positive control. RNA was extracted from all tissue samples and CCAT1 expression was analyzed using quantitative real time-PCR (qRT-PCR). Results: Low expression of CCAT1 was identified in normal gastric mucosa samples obtained from morbidly obese patients [mean Relative Quantity (RQ) = 1.95±0.4]. AGS human gastric carcinoma cell line showed an elevated level of CCAT1 expression (RQ=8.02). Expression levels of CCAT1 were approximately 10.8 fold higher in GC samples than in samples taken from the negative control group (RQ=21.1±5 vs. RQ=1.95±0.4, respectively, p<0.001). Interestingly, CCAT1 expression was significantly overexpressed in adjacent normal tissues when compared to the negative control group (RQ = 15.25±2 vs. RQ=1.95±0.4, respectively, p<0.001). Tissues obtained from recurrent GC cases showed the highest expression levels (RQ = 88.8±31; p<0.001). Expression levels increased with tumor stage (T4- 36.4±15, T3- 16.1±6, T2- 4.7±1), however this did not reach statistical significance (p=0.2). There was no difference in CCAT1 expression between intestinal and diffuse type GC (RQ=22.4±7 vs. 22.4±16, respectively, p=0.9). Within the normal gastric tissue samples, no significant difference in CCAT1 expression was observed in helicobacter pylori negative and positive patients (RQ= 2.4±0.9 vs. 0.93±0.2, respectively, p=0.13). Conclusion: CCAT1 is up-regulated in gastric cancer, and may serve as a potential bio-marker for early detection and surveillance. PMID:25561974

Epstein-Barr Virus and Gastric Cancer Risk: A Meta-analysis With Meta-regression of Case-control Studies.

PubMed

Bae, Jong-Myon; Kim, Eun Hee

2016-03-01

Research on how the risk of gastric cancer increases with Epstein-Barr virus (EBV) infection is lacking. In a systematic review that investigated studies published until September 2014, the authors did not calculate the summary odds ratio (SOR) due to heterogeneity across studies. Therefore, we include here additional studies published until October 2015 and conduct a meta-analysis with meta-regression that controls for the heterogeneity among studies. Using the studies selected in the previously published systematic review, we formulated lists of references, cited articles, and related articles provided by PubMed. From the lists, only case-control studies that detected EBV in tissue samples were selected. In order to control for the heterogeneity among studies, subgroup analysis and meta-regression were performed. In the 33 case-control results with adjacent non-cancer tissue, the total number of test samples in the case and control groups was 5280 and 4962, respectively. In the 14 case-control results with normal tissue, the total number of test samples in case and control groups was 1393 and 945, respectively. Upon meta-regression, the type of control tissue was found to be a statistically significant variable with regard to heterogeneity. When the control tissue was normal tissue of healthy individuals, the SOR was 3.41 (95% CI, 1.78 to 6.51; I-squared, 65.5%). The results of the present study support the argument that EBV infection increases the risk of gastric cancer. In the future, age-matched and sex-matched case-control studies should be conducted.

Aberrant Expression of PIWIL1 and PIWIL2 and Their Clinical Significance in Ductal Breast Carcinoma.

PubMed

Litwin, Monika; Szczepańska-Buda, Anna; Michałowska, Dagmara; Grzegrzółka, Jędrzej; Piotrowska, Aleksandra; Gomułkiewicz, Agnieszka; Wojnar, Andrzej; Dzięgiel, Piotr; Witkiewicz, Wojciech

2018-04-01

P-Element-induced wimpy testis (PIWI) proteins in complex with PIWI-interacting RNA (piRNA) are involved in epigenetic regulation of gene expression in germline cells. Aberrant expression of piRNA and PIWI proteins have been identified in various types of tumour cells. The aim of this study was to evaluate the expression profiles of PIWI-like protein-1, -2 (PIWIL1 and PIWIL2), their immunohistochemical (IHC) characteristics in ductal breast cancer, and determine their correlation with clinicopathological parameters of this type of cancer. Material for IHC studies comprised of 101 invasive ductal carcinoma (IDC) cases and 31 mastopathy tissues. Frozen fragments of paired tissue specimens (tumour and adjacent non-malignant breast tissue) taken from 55 patients with IDC and 18 samples of mastopathy were used for molecular studies using real-time polymerase chain reaction (RT-PCR). A statistically significantly higher level of PIWIL1 and PIWIL2 was found in IDC compared to mastopathy samples (p≤0.0001). Increased expression of PIWIL1 was correlated with increased PIWIL2 expression in breast cancer tissue. Surprisingly, PIWIL1 mRNA was detected only in cancer and mastopathy, but was not found in most normal breast tissues, although it is noteworthy that the PIWIL2 mRNA level was statistically significantly lower in mastopathy and IDC samples compared to normal breast tissues. Our results affirm the hypothesis that reactivation of PIWI expression in various caner types is crucial for cancer development. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

PAQR3 overexpression suppresses the aggressive phenotype of esophageal squamous cell carcinoma cells via inhibition of ERK signaling.

PubMed

Bai, Ge; Chu, Jianhu; Eli, Mayinur; Bao, Yongxing; Wen, Hao

2017-10-01

Progestin and adipoQ receptor family member 3 (PAQR3) has exhibited anticancer activity in multiple malignancies. However, its expression and function in esophageal squamous cell carcinoma (ESCC) is still elusive. In this work, we examined the expression of PAQR3 in 40 surgically resected ESCC specimens and their adjacent normal tissues. The expression of PAQR3 in ESCC cell lines was measured after treatment with the demethylating agent 5-aza-2'-deoxycytidine (5-Aza-CdR). The effects of overexpression of PAQR3 on cell proliferation, colony formation, invasion, and tumorigenesis were investigated. It was found that the PAQR3 mRNA level was significantly lower in ESCC than that in adjacent normal tissues (P=0.0318). Low PAQR3 expression was significantly associated with more advanced TNM stage (P=0.0093) and absent lymph node involvement (P=0.0324). Compared to normal esophageal epithelial cells, ESCC cells had significantly lower levels of PAQR3. 5-Aza-CdR treatment led to an induction of PAQR3 in ESCC cells. Enforced expression of PAQR3 significantly inhibited ESCC cell proliferation, colony formation and invasion. Moreover, PAQR3 overexpression blocked cell cycle transition from G1 to S phase, which was associated with induction of p27 and p21 and reduction of cyclin D1, CDK4, and CDK2. Mechanistically, overexpression of PAQR3 suppressed the phosphorylation of ERK1/2 in ESCC cells. In vivo tumorigenic studies confirmed that PAQR3 overexpression retarded the growth of ECA-109 xenograft tumors and inhibited the activation of ERK signaling. Taken together, PAQR3 is epigenetically silenced in ESCC and restoration of PAQR3 suppresses the aggressive phenotype of ESCC cells. Therefore, PAQR3 may represent a potential target for the treatment of ESCC. Copyright © 2017. Published by Elsevier Masson SAS.

Linking γ-aminobutyric acid A receptor to epidermal growth factor receptor pathways activation in human prostate cancer.

PubMed

Wu, Weijuan; Yang, Qing; Fung, Kar-Ming; Humphreys, Mitchell R; Brame, Lacy S; Cao, Amy; Fang, Yu-Ting; Shih, Pin-Tsen; Kropp, Bradley P; Lin, Hsueh-Kung

2014-03-05

Neuroendocrine (NE) differentiation has been attributed to the progression of castration-resistant prostate cancer (CRPC). Growth factor pathways including the epidermal growth factor receptor (EGFR) signaling have been implicated in the development of NE features and progression to a castration-resistant phenotype. However, upstream molecules that regulate the growth factor pathway remain largely unknown. Using androgen-insensitive bone metastasis PC-3 cells and androgen-sensitive lymph node metastasis LNCaP cells derived from human prostate cancer (PCa) patients, we demonstrated that γ-aminobutyric acid A receptor (GABA(A)R) ligand (GABA) and agonist (isoguvacine) stimulate cell proliferation, enhance EGF family members expression, and activate EGFR and a downstream signaling molecule, Src, in both PC-3 and LNCaP cells. Inclusion of a GABA(A)R antagonist, picrotoxin, or an EGFR tyrosine kinase inhibitor, Gefitinib (ZD1839 or Iressa), blocked isoguvacine and GABA-stimulated cell growth, trans-phospohorylation of EGFR, and tyrosyl phosphorylation of Src in both PCa cell lines. Spatial distributions of GABAAR α₁ and phosphorylated Src (Tyr416) were studied in human prostate tissues by immunohistochemistry. In contrast to extremely low or absence of GABA(A)R α₁-positive immunoreactivity in normal prostate epithelium, elevated GABA(A)R α₁ immunoreactivity was detected in prostate carcinomatous glands. Similarly, immunoreactivity of phospho-Src (Tyr416) was specifically localized and limited to the nucleoli of all invasive prostate carcinoma cells, but negative in normal tissues. Strong GABAAR α₁ immunoreactivity was spatially adjacent to the neoplastic glands where strong phospho-Src (Tyr416)-positive immunoreactivity was demonstrated, but not in adjacent to normal glands. These results suggest that the GABA signaling is linked to the EGFR pathway and may work through autocrine or paracine mechanism to promote CRPC progression. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Visualization of CD44 and CD133 in Normal Pancreas and Pancreatic Ductal Adenocarcinomas

PubMed Central

Immervoll, Heike; Hoem, Dag; Steffensen, Ole Johnny; Miletic, Hrvoje; Molven, Anders

2011-01-01

Tumor-initiating cells of pancreatic ductal adenocarcinoma (PDAC) have been isolated based on expression of either CD133 or CD44. The authors aimed to visualize pancreatic cells simultaneously expressing both these cell surface markers by employing the same antibodies commonly used in cell-sorting studies. Normal and diseased pancreatic tissue, including 51 PDAC cases, were analyzed. CD44 and CD133 expression was determined by immunohistochemical double staining on formalin-fixed material and subcellular protein distribution evaluated by immunofluorescence/confocal microscopy. In the normal pancreas, CD44 and CD133 were coexpressed in the centroacinar regions but in non-overlapping subcellular compartments. As expected, CD44 was found mainly basolaterally, whereas CD133 was present on the apical/endoluminal membrane. This was also the case in chronically inflamed/atrophic pancreatic tissue and in PDAC. In some malignant ducts, CD44 was found at the apical cell membrane adjacent to but never overlapping with CD133 expression. CD44 level was significantly associated with the patient’s lymph node status. In conclusion, a CD44+/CD133+ cell population does exist in the normal and neoplastic pancreas. The preferentially centroacinar localization of the doubly positive cells in the normal parenchyma suggests that this population could be of particular interest in attempts to identify tumor-initiating cells in PDAC. This article contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials. PMID:21411814

Tookad-mediated photodynamic effects on the prostate and its adjacent tissues: in vivo study in canine models

NASA Astrophysics Data System (ADS)

Huang, Zheng; Chen, Qun; Luck, David; Beckers, Jill; Blanc, Dominique; Hetzel, Fred W.

2005-04-01

Photodynamic therapy (PDT) mediated with a vascular acting photosensitizer Tookad (pd-bacteriopheophorbide), was investigated as an alternative treatment modality for prostate cancer. Tookad photodynamic effects on the prostate and its adjacent tissues were evaluated in canine models. Interstitial prostate PDT was performed by irradiating individual lobes with a diode laser (763 nm) and 1-cm cylindrical diffuser fibers at various light doses to activate the IV administered photosensitizer Tookad (1 - 2 mg/kg). The sensitivity of the adjacent tissues to Tookad-PDT was determined by superficially irradiating the surfaces of the bladder, colon, abdominal muscle and pelvic plexus with a microlens fiber at various drug/light doses. PDT effect on the prostatic urethra was evaluated by transurethral irradiation. The prostate and adjacent tissues were harvested one-week after the treatment and subjected to histopathologic examination. At one-week post interstitial prostate PDT, the animals recovered well with little or no urethral complications. PDT induced prostate lesions were characterized by marked hemorrhagic necrosis. The bladder, colon, abdominal muscle and pelvic plexus, appeared to also be sensitive to Tookad-PDT at light dose levels greater than 40 Jcm2. Urethral mucosa appeared less sensitive to Tookad-PDT. In conclusion, Tookad-mediated PDT demonstrates very strong vascular effects and can provide an effective alternative for the treatment of localized prostate cancer. Protection of the adjacent tissues should be taken into consideration in the total prostate ablation process due to their sensitivity to the Tookad-mediated PDT.

RASSF1A promoter methylation in high-grade serous ovarian cancer: A direct comparison study in primary tumors, adjacent morphologically tumor cell-free tissues and paired circulating tumor DNA.

PubMed

Giannopoulou, Lydia; Chebouti, Issam; Pavlakis, Kitty; Kasimir-Bauer, Sabine; Lianidou, Evi S

2017-03-28

The RASSF1A promoter is frequently methylated in high-grade serous ovarian cancer (HGSC). We examined RASSF1A promoter methylation in primary tumors, adjacent morphologically tumor cell-free tissues and corresponding circulating tumor DNA (ctDNA) samples of patients with HGSC, using a real-time methylation specific PCR (real-time MSP) and a methylation-sensitive high-resolution melting analysis (MS-HRMA) assay for the detection and semi-quantitative estimation of methylation, respectively. Two groups of primary HGSC tumor FFPE samples were recruited (Group A n=67 and Group B n=61), along with matched adjacent morphologically tumor cell-free tissues (n=58) and corresponding plasma samples (n=59) for group B. Using both assays, RASSF1A promoter was found highly methylated in primary tumors of both groups, and at lower percentages in the adjacent morphologically tumor cell-free tissues. Interestingly, RASSF1A promoter methylation was also observed in ctDNA by real-time MSP. Overall survival (OS) was significantly associated with RASSF1A promoter methylation in primary tumor samples using MS-HRMA (P=0.023). Our results clearly indicate that RASSF1A promoter is methylated in adjacent tissue surrounding the tumor in HGSC patients. We report for the first time that RASSF1A promoter methylation provides significant prognostic information in HGSC patients.

RASSF1A promoter methylation in high-grade serous ovarian cancer: A direct comparison study in primary tumors, adjacent morphologically tumor cell-free tissues and paired circulating tumor DNA

PubMed Central

Giannopoulou, Lydia; Chebouti, Issam; Pavlakis, Kitty; Kasimir-Bauer, Sabine; Lianidou, Evi S.

2017-01-01

The RASSF1A promoter is frequently methylated in high-grade serous ovarian cancer (HGSC). We examined RASSF1A promoter methylation in primary tumors, adjacent morphologically tumor cell-free tissues and corresponding circulating tumor DNA (ctDNA) samples of patients with HGSC, using a real-time methylation specific PCR (real-time MSP) and a methylation-sensitive high-resolution melting analysis (MS-HRMA) assay for the detection and semi-quantitative estimation of methylation, respectively. Two groups of primary HGSC tumor FFPE samples were recruited (Group A n=67 and Group B n=61), along with matched adjacent morphologically tumor cell-free tissues (n=58) and corresponding plasma samples (n=59) for group B. Using both assays, RASSF1A promoter was found highly methylated in primary tumors of both groups, and at lower percentages in the adjacent morphologically tumor cell-free tissues. Interestingly, RASSF1A promoter methylation was also observed in ctDNA by real-time MSP. Overall survival (OS) was significantly associated with RASSF1A promoter methylation in primary tumor samples using MS-HRMA (P=0.023). Our results clearly indicate that RASSF1A promoter is methylated in adjacent tissue surrounding the tumor in HGSC patients. We report for the first time that RASSF1A promoter methylation provides significant prognostic information in HGSC patients. PMID:28206954

Sucrose-Metabolizing Enzymes in Transport Tissues and Adjacent Sink Structures in Developing Citrus Fruit 1

PubMed Central

Lowell, Cadance A.; Tomlinson, Patricia T.; Koch, Karen E.

1989-01-01

Juice tissues of citrus lack phloem; therefore, photosynthates enroute to juice sacs exit the vascular system on the surface of each segment. Areas of extensive phloem unloading and transport (vascular bundles + segment epidermis) can thus be separated from those of assimilate storage (juice sacs) and adjacent tissues where both processes occur (peel). Sugar composition, dry weight accumulation, and activities of four sucrose-metabolizing enzymes (soluble and cell-wall-bound acid invertase, alkaline invertase, sucrose synthase, and sucrose phosphate synthase) were measured in these transport and sink tissues of grapefruit (Citrus paradisi Macf.) to determine more clearly whether a given enzyme appeared to be more directly associated with assimilate transport versus deposition or utilization. Results were compared at three developmental stages. Activity of sucrose (per gram fresh weight and per milligram protein) extracted from zones of extensive phloem unloading and transport was significantly greater than from adjacent sink tissues during the stages (II and III) when juice sacs grow most rapidly. In stage II fruit, activity of sucrose synthase also significantly surpassed that of all other sucrose-metabolizing enzymes in extracts from the transport tissues (vascular bundles + segment epidermis). In contrast, sucrose phosphate synthase and alkaline invertase at this stage of growth were the most active enzymes from adjacent, rapidly growing, phloem-free sink tissues (juice sacs). Activity of these two enzymes in extracts from juice sacs was significantly greater than that form the transport tissues (vascular bundles + segment epidermis). Soluble acid invertase was the most active enzyme in extracts from all tissues of very young fruit (stage I), including nonvascular regions, but nearly disappeared prior to the onset of juice sac sugar accumulation. The physiological function of high sucrose synthase activity in the transport tissues during rapid sucrose import remains to be determined. PMID:16666942

Tissue-engineered tracheal reconstruction using three-dimensionally printed artificial tracheal graft: preliminary report.

PubMed

Chang, Jae Won; Park, Su A; Park, Ju-Kyeong; Choi, Jae Won; Kim, Yoo-Suk; Shin, Yoo Seob; Kim, Chul-Ho

2014-06-01

Three-dimensional printing has come into the spotlight in the realm of tissue engineering. We intended to evaluate the plausibility of 3D-printed (3DP) scaffold coated with mesenchymal stem cells (MSCs) seeded in fibrin for the repair of partial tracheal defects. MSCs from rabbit bone marrow were expanded and cultured. A half-pipe-shaped 3DP polycaprolactone scaffold was coated with the MSCs seeded in fibrin. The half-pipe tracheal graft was implanted on a 10 × 10-mm artificial tracheal defect in four rabbits. Four and eight weeks after the operation, the reconstructed sites were evaluated bronchoscopically, radiologically, histologically, and functionally. None of the four rabbits showed any sign of respiratory distress. Endoscopic examination and computed tomography showed successful reconstruction of trachea without any collapse or blockage. The replaced tracheas were completely covered with regenerated respiratory mucosa. Histologic analysis showed that the implanted 3DP tracheal grafts were successfully integrated with the adjacent trachea without disruption or granulation tissue formation. Neo-cartilage formation inside the implanted graft was sufficient to maintain the patency of the reconstructed trachea. Scanning electron microscope examination confirmed the regeneration of the cilia, and beating frequency of regenerated cilia was not different from those of the normal adjacent mucosa. The shape and function of reconstructed trachea using 3DP scaffold coated with MSCs seeded in fibrin were restored successfully without any graft rejection. Copyright © 2014 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

Minimally invasive scoliosis treatment with a Ho:YAG laser

NASA Astrophysics Data System (ADS)

Rumpf, Christian G.; Lang, Robert D.; Goetz, Marcus H.

2000-11-01

Today most surgical treatment of spinal deformations is concentrated on invasive mechanical techniques with long operation times and major effects on the patient's mobility. The proposed minimally invasive technique using laser light for tissue ablation offers a possibility of gentle scoliosis treatment. It is thought that an early removal of the epiphysial growth zone on the convex side over several vertebrae results in a straightening of the spine. In a first evaluation, four different laser systems including argon ion, Nd:YAG (Q-switched), Nd:YAG (cw), and Ho:YAG laser were compared with respect to thermal damage to adjacent tissue, ablation rates, efficiency and laser handling. For in-vivo investigation, fresh lamb spine was used. Comparison showed that the Ho:YAG laser is the most appropriate laser for the given goal, providing efficient photoablation with moderate thermal effects on the adjacent tissue. In a second step the proposed minimally invasive operation technique was performed in in-vivo experiments on young foxhounds using 3D- thoracoscopic operation techniques. During these operations temperature mapping was done using fiber-optic fluorescent probes. After 12 months of normal growth the animals were sacrificed and x-ray as well as MRI was performed on the spine. First results show a positive effect of scoliotic growth in two cases. Being able to produce a scoliosis by hemiepiphysiodesis on the vertebra, It is thought that this technique is successful for a straightening of the spine on patients with scoliosis.

Transcriptome profiling reveals miR-9-3p as a novel tumor suppressor in gastric cancer.

PubMed

Meng, Qingshun; Xiang, Longquan; Fu, Jingwei; Chu, Xianqun; Wang, Chunlin; Yan, Bingzheng

2017-06-06

It has been well established that microRNAs (miRNAs) play important roles in biological processes. To comprehensively measure the altered miRNA expression, we presented the miRNA expression profile of gastric cancer using microarray. We identified 33 miRNAs that were significantly differentially regulated in gastric specimens compared to adjacent normal tissues, among which miR-9-3p expression are significantly down-regulated in gastric cancers. Next, a cohort of 100 gastric cancer tissues and matched normal tissues were enrolled. Kaplan-Meier and multivariate Cox survival analyses were applied to evaluate the prognostic value of miR-9-3p expression, and the result showed that patients with lower miR-9-3p expression level have significantly poorer overall survival. The expression level of miR-9-3p has been proved to be an independent prognostic factor for 5-year overall survival. Furthermore, the result indicated that over-expression of miR-9-3p can inhibit gastric cancer cell invasion. Taken together, our results suggested that miR-9-3p plays important role in tumor invasion, and these findings implicated the potential effects of miR-9-3p on prognosis of gastric cancer.

SnoN/SKIL modulates proliferation through control of hsa-miR-720 transcription in esophageal cancer cells

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

Shinozuka, Eriko; Miyashita, Masao; Mizuguchi, Yoshiaki, E-mail: yoshi1224@gmail.com

2013-01-04

Highlights: Black-Right-Pointing-Pointer SnoN modulated miR-720, miR-1274A, and miR-1274B expression levels in TE-1 cells. Black-Right-Pointing-Pointer miR-720 and miR-1274A suppressed the expression of target proteins p63 and ADAM9. Black-Right-Pointing-Pointer Silencing of SnoN significantly upregulated cell proliferation in TE-1 cells. Black-Right-Pointing-Pointer Esophageal cancer tissues have lower SnoN expression levels than normal tissues. Black-Right-Pointing-Pointer Esophageal cancer tissues have higher miR-720 expression levels than normal tissues. -- Abstract: It is now evident that changes in microRNA are involved in cancer progression, but the mechanisms of transcriptional regulation of miRNAs remain unknown. Ski-related novel gene (SnoN/SKIL), a transcription co-factor, acts as a potential key regulator withinmore » a complex network of p53 transcriptional repressors. SnoN has pro- and anti-oncogenic functions in the regulation of cell proliferation, senescence, apoptosis, and differentiation. We characterized the roles of SnoN in miRNA transcriptional regulation and its effects on cell proliferation using esophageal squamous cell carcinoma (ESCC) cells. Silencing of SnoN altered a set of miRNA expression profiles in TE-1cells, and the expression levels of miR-720, miR-1274A, and miR-1274B were modulated by SnoN. The expression of these miRNAs resulted in changes to the target protein p63 and a disintegrin and metalloproteinase domain 9 (ADAM9). Furthermore, silencing of SnoN significantly upregulated cell proliferation in TE-1 cells, indicating a potential anti-oncogenic function. These results support our observation that cancer tissues have lower expression levels of SnoN, miR-720, and miR-1274A compared to adjacent normal tissues from ESCC patients. These data demonstrate a novel mechanism of miRNA regulation, leading to changes in cell proliferation.« less

Tissue Sodium Concentration in Myocardial Infarction in Humans: A Quantitative 23Na MR Imaging Study1

PubMed Central

Ouwerkerk, Ronald; Bottomley, Paul A.; Solaiyappan, Meiyappan; Spooner, Amy E.; Tomaselli, Gordon F.; Wu, Katherine C.; Weiss, Robert G.

2008-01-01

Purpose: To prospectively determine whether the absolute tissue sodium concentration (TSC) increases in myocardial infarctions (MIs) in humans and whether TSC is related to infarct size, infarct age, ventricular dysfunction, and/or electrophysiologic inducibility of ventricular arrhythmias. Materials and Methods: Delayed contrast material–enhanced 1.5-T hydrogen 1 (1H) magnetic resonance (MR) imaging was used to measure the size and location of nonacute MIs in 20 patients (18 men, two women; mean age, 63 years ± 9 [standard deviation]; age range, 48–82 years) examined at least 90 days after MI. End-systolic and end-diastolic volumes, ejection fraction, and left ventricle (LV) mass were measured with cine MR imaging. The TSC in normal, infarcted, and adjacent myocardial tissue was measured on sodium 23 (23Na) MR images coregistered with delayed contrast-enhanced 1H MR images. Programmed electric stimulation to induce monomorphic ventricular tachycardia (MVT) was used to assess arrhythmic potential, and myocardial TSC was compared between the inducible MVT and noninducible MVT patient groups. Results: The mean TSC for MIs (59 μmol/g wet weight ± 10) was 30% higher than that for noninfarcted (remote) LV regions (45 μmol/g wet weight ± 5, P < .001) and that for healthy control subjects, and TSC did not correlate with infarct age or functional and morphologic indices. The mean TSC for tissue adjacent to the MI (50 μmol/g wet weight ± 6) was intermediate between that for the MI and that for remote regions. The elevated TSC measured in the MI at 23Na MR imaging lacked sufficient contrast and spatial resolution for routine visualization of MI. Cardiac TSC did not enable differentiation between patients in whom MVT was inducible and those in whom it was not. Conclusion: Absolute TSC is measurable with 23Na MR imaging and is significantly elevated in human MI; however, TSC increase is not related to infarct age, infarct size, or global ventricular function. In regions adjacent to the MI, TSC is slightly increased but not to levels in the MI. © RSNA, 2008 PMID:18566171

A New Era of Image Guidance with Magnetic Resonance-guided Radiation Therapy for Abdominal and Thoracic Malignancies

PubMed Central

Paliwal, Bhudatt; Hill, Patrick; Bayouth, John E; Geurts, Mark W; Baschnagel, Andrew M; Bradley, Kristin A; Harari, Paul M; Rosenberg, Stephen; Brower, Jeffrey V; Wojcieszynski, Andrzej P; Hullett, Craig; Bayliss, R A; Labby, Zacariah E; Bassetti, Michael F

2018-01-01

Magnetic resonance-guided radiation therapy (MRgRT) offers advantages for image guidance for radiotherapy treatments as compared to conventional computed tomography (CT)-based modalities. The superior soft tissue contrast of magnetic resonance (MR) enables an improved visualization of the gross tumor and adjacent normal tissues in the treatment of abdominal and thoracic malignancies. Online adaptive capabilities, coupled with advanced motion management of real-time tracking of the tumor, directly allow for high-precision inter-/intrafraction localization. The primary aim of this case series is to describe MR-based interventions for localizing targets not well-visualized with conventional image-guided technologies. The abdominal and thoracic sites of the lung, kidney, liver, and gastric targets are described to illustrate the technological advancement of MR-guidance in radiotherapy. PMID:29872602

Enhanced expression of G-protein coupled estrogen receptor (GPER/GPR30) in lung cancer

PubMed Central

2012-01-01

Background G-protein-coupled estrogen receptor (GPER/GPR30) was reported to bind 17β-estradiol (E2), tamoxifen, and ICI 182,780 (fulvestrant) and promotes activation of epidermal growth factor receptor (EGFR)-mediated signaling in breast, endometrial and thyroid cancer cells. Although lung adenocarcinomas express estrogen receptors α and β (ERα and ERβ), the expression of GPER in lung cancer has not been investigated. The purpose of this study was to examine the expression of GPER in lung cancer. Methods The expression patterns of GPER in various lung cancer lines and lung tumors were investigated using standard quantitative real time PCR (at mRNA levels), Western blot and immunohistochemistry (IHC) methods (at protein levels). The expression of GPER was scored and the pairwise comparisons (cancer vs adjacent tissues as well as cancer vs normal lung tissues) were performed. Results Analysis by real-time PCR and Western blotting revealed a significantly higher expression of GPER at both mRNA and protein levels in human non small cell lung cancer cell (NSCLC) lines relative to immortalized normal lung bronchial epithelial cells (HBECs). The virally immortalized human small airway epithelial cell line HPL1D showed higher expression than HBECs and similar expression to NSCLC cells. Immunohistochemical analysis of tissue sections of murine lung adenomas as well as human lung adenocarcinomas, squamous cell carcinomas and non-small cell lung carcinomas showed consistently higher expression of GPER in the tumor relative to the surrounding non-tumor tissue. Conclusion The results from this study demonstrate increased GPER expression in lung cancer cells and tumors compared to normal lung. Further evaluation of the function and regulation of GPER will be necessary to determine if GPER is a marker of lung cancer progression. PMID:23273253

Identification of Differentially Expressed K-Ras Transcript Variants in Patients With Leiomyoma.

PubMed

Zolfaghari, Nooshin; Shahbazi, Shirin; Torfeh, Mahnaz; Khorasani, Maryam; Hashemi, Mehrdad; Mahdian, Reza

2017-10-01

Molecular studies have demonstrated a wide range of gene expression variations in uterine leiomyoma. The rat sarcoma virus/rapidly accelerated fibrosarcoma/mitogen-activated protein kinase (RAS/RAF/MAPK) is the crucial cellular pathway in transmitting external signals into nucleus. Deregulation of this pathway contributes to excessive cell proliferation and tumorigenesis. The present study aims to investigate the expression profile of the K-Ras transcripts in tissue samples from patients with leiomyoma. The patients were leiomyoma cases who had no mutation in mediator complex subunit 12 ( MED12) gene. A quantitative approach has been applied to determine the difference in the expression of the 2 main K-Ras messenger RNA (mRNA) variants. The comparison between gene expression levels in leiomyoma and normal myometrium group was performed using relative expression software tool. The expression of K-Ras4B gene was upregulated in leiomyoma group ( P = .016), suggesting the involvement of K-Ras4B in the disease pathogenesis. Pairwise comparison of the K-Ras4B expression between each leiomyoma tissue and its matched adjacent normal myometrium revealed gene upregulation in 68% of the cases. The expression of K-Ras4A mRNA was relatively upregulated in leiomyoma group ( P = .030). In addition, the mean expression of K-Ras4A gene in leiomyoma tissues relative to normal samples was 4.475 (95% confidence interval: 0.10-20.42; standard error: 0.53-12.67). In total, 58% of the cases showed more than 2-fold increase in K-Ras4A gene expression. Our results demonstrated increased expression of both K-Ras mRNA splicing variants in leiomyoma tissue. However, the ultimate result of KRAS expression on leiomyoma development depends on the overall KRAS isoform balance and, consequently, on activated signaling pathways.

Production of monoclonal antibodies recognising the peptide core of MUC2 intestinal mucin.

PubMed

Durrant, L G; Jacobs, E; Price, M R

1994-01-01

A peptide based on the tandem repeat sequence of MUC2 mucin was used to produce a series of monoclonal antibodies (MAb). The fine specificity of these antibodies and their implications for MUC2 expression are presented. Three of the MAbs, 996/1, 996/7 and 995/25, were specific to the MUC2p and failed to bind to peptides based on the MUC1,3,4 tandem repeat sequences whereas three others, 994/152, 994/91 and 996/36, cross reacted with the MUC2p and the MUC3 tandem repeat peptide but not the MUC1 and MUC4 peptides. An antigen, affinity purified from a colorectal tumour on one of the MUC2p-specific MAbs, 996/1, was shown to be a high molecular weight polydisperse, mucin-like antigen. Two of the MAbs, 996/1 and 994/152, recognised MUC2 in tissue sections, although the fine specificity varied between the two MAbs, with 994/152 strongly staining gastric, ileum and kidney epithelia, and MAb 996/1 intensely staining colon, liver and prostate tissues. These antibodies also stained a colorectal cell line, and MAb 994/152 also stained a gastric and an ovarian cell line. Six of the MAbs were used to stain colorectal tumour and adjacent 'normal' colonic mucosa sections. All six stained normal mucosa, but only two of the MAbs, 996/1 and 994/91, stained tumour tissue. The staining probably reflects exposure of cryptic epitopes due to varying levels of glycosylation in different tissues. These anti-MUC2p MAbs may help in determining the normal role of MUC2 mucin and how it is subverted in malignancy.

Enhanced expression of G-protein coupled estrogen receptor (GPER/GPR30) in lung cancer.

PubMed

Jala, Venkatakrishna Rao; Radde, Brandie N; Haribabu, Bodduluri; Klinge, Carolyn M

2012-12-28

G-protein-coupled estrogen receptor (GPER/GPR30) was reported to bind 17β-estradiol (E2), tamoxifen, and ICI 182,780 (fulvestrant) and promotes activation of epidermal growth factor receptor (EGFR)-mediated signaling in breast, endometrial and thyroid cancer cells. Although lung adenocarcinomas express estrogen receptors α and β (ERα and ERβ), the expression of GPER in lung cancer has not been investigated. The purpose of this study was to examine the expression of GPER in lung cancer. The expression patterns of GPER in various lung cancer lines and lung tumors were investigated using standard quantitative real time PCR (at mRNA levels), Western blot and immunohistochemistry (IHC) methods (at protein levels). The expression of GPER was scored and the pairwise comparisons (cancer vs adjacent tissues as well as cancer vs normal lung tissues) were performed. Analysis by real-time PCR and Western blotting revealed a significantly higher expression of GPER at both mRNA and protein levels in human non small cell lung cancer cell (NSCLC) lines relative to immortalized normal lung bronchial epithelial cells (HBECs). The virally immortalized human small airway epithelial cell line HPL1D showed higher expression than HBECs and similar expression to NSCLC cells. Immunohistochemical analysis of tissue sections of murine lung adenomas as well as human lung adenocarcinomas, squamous cell carcinomas and non-small cell lung carcinomas showed consistently higher expression of GPER in the tumor relative to the surrounding non-tumor tissue. The results from this study demonstrate increased GPER expression in lung cancer cells and tumors compared to normal lung. Further evaluation of the function and regulation of GPER will be necessary to determine if GPER is a marker of lung cancer progression.

Cranial nerve threshold for thermal injury induced by MRI-guided high-intensity focused ultrasound (MRgHIFU): preliminary results on an optic nerve model.

PubMed

Harnof, Sagi; Zibly, Zion; Cohen, Zvi; Shaw, Andrew; Schlaff, Cody; Kassel, Neal F

2013-04-01

Future clinical applications of magnetic resonance imaging-guided high-intensity focused ultrasound (MRgHIFU) are moving toward the management of different intracranial pathologies. We sought to validate the production, safety, and efficacy of thermal injury to cranial nerves generated by MRgHIFU. In this study, five female domestic pigs underwent a standard bifrontal craniectomy under general anesthesia. Treatment was then given using an MRgHIFU system to induce hyperthermic ablative sonication (6 to 10 s; 50 to 2000 J.) Histological analyses were done to confirm nerve damage; temperature measured on the optic nerve was approximately 53.4°C (range: 39°C to 70°C.) Histology demonstrated a clear definition between a necrotic, transitional zone, and normal tissue. MRgHIFU induces targeted thermal injury to nervous tissue within a specific threshold of 50°C to 60°C with the tissue near the sonication center yielding the greatest effect; adjacent tissue showed minimal changes. Additional studies utilizing this technology are required to further establish accurate threshold parameters for optic nerve thermo-ablation.

Prognostic significance of kynurenine 3-monooxygenase and effects on proliferation, migration, and invasion of human hepatocellular carcinoma.

PubMed

Jin, Haojie; Zhang, Yurong; You, Haiyan; Tao, Xuemei; Wang, Cun; Jin, Guangzhi; Wang, Ning; Ruan, Haoyu; Gu, Dishui; Huo, Xisong; Cong, Wenming; Qin, Wenxin

2015-06-23

Kynurenine 3-monooxygenase (KMO) is a pivotal enzyme in the kynurenine pathway of tryptophan degradation and plays a critical role in Huntington's and Alzheimer's diseases. This study aimed to examine the expression of KMO in human hepatocellular carcinoma (HCC) and investigate the relationship between its expression and prognosis of HCC patients. We first analyzed KMO expression in 120 paired HCC samples (HCC tissues vs matched adjacent non-cancerous liver tissues), and 205 clinical HCC specimens using immunohistochemistry (IHC). Kaplan-Meier survival and Cox regression analyses were executed to evaluate the prognosis of HCC. The results of IHC analysis showed that KMO expression was significantly higher in HCC tissues than that in normal liver tissues (all p < 0.05). Survival and recurrence analyses showed that KMO was an independent prognostic factor for overall survival (OS) and time to recurrence (TTR) (both p<0.01). And in vitro studies revealed that KMO positively regulated proliferation, migration, and invasion of HCC cells. These results suggest that KMO exhibits tumor-promoting effects towards HCC and it may serve as a novel prognostic marker in HCC.

Prostate tissue metal levels and prostate cancer recurrence in smokers.

PubMed

Neslund-Dudas, Christine; Kandegedara, Ashoka; Kryvenko, Oleksandr N; Gupta, Nilesh; Rogers, Craig; Rybicki, Benjamin A; Dou, Q Ping; Mitra, Bharati

2014-02-01

Although smoking is not associated with prostate cancer risk overall, smoking is associated with prostate cancer recurrence and mortality. Increased cadmium (Cd) exposure from smoking may play a role in progression of the disease. In this study, inductively coupled plasma mass spectrometry was used to determine Cd, arsenic (As), lead (Pb), and zinc (Zn) levels in formalin-fixed paraffin embedded tumor and tumor-adjacent non-neoplastic tissue of never- and ever-smokers with prostate cancer. In smokers, metal levels were also evaluated with regard to biochemical and distant recurrence of disease. Smokers (N = 25) had significantly higher Cd (median ppb, p = 0.03) and lower Zn (p = 0.002) in non-neoplastic tissue than never-smokers (N = 21). Metal levels were not significantly different in tumor tissue of smokers and non-smokers. Among smokers, Cd level did not differ by recurrence status. However, the ratio of Cd ppb to Pb ppb was significantly higher in both tumor and adjacent tissue of cases with distant recurrence when compared with cases without distant recurrence (tumor tissue Cd/Pb, 6.36 vs. 1.19, p = 0.009, adjacent non-neoplastic tissue Cd/Pb, 6.36 vs. 1.02, p = 0.038). Tissue Zn levels were also higher in smokers with distant recurrence (tumor, p = 0.039 and adjacent non-neoplastic, p = 0.028). These initial findings suggest that prostate tissue metal levels may differ in smokers with and without recurrence. If these findings are confirmed in larger studies, additional work will be needed to determine whether variations in metal levels are drivers of disease progression or are simply passengers of the disease process.

CD163 as a marker of M2 macrophage, contribute to predicte aggressiveness and prognosis of Kazakh esophageal squamous cell carcinoma.

PubMed

Hu, Jian Ming; Liu, Kai; Liu, Ji Hong; Jiang, Xian Li; Wang, Xue Li; Chen, Yun Zhao; Li, Shu Gang; Zou, Hong; Pang, Li Juan; Liu, Chun Xia; Cui, Xiao Bin; Yang, Lan; Zhao, Jin; Shen, Xi Hua; Jiang, Jin Fang; Liang, Wei Hua; Yuan, Xiang Lin; Li, Feng

2017-03-28

M2 macrophages was domesticated by tumor microenvironment to produce some angiogenic molecules and protease, facilitating angiogenesis and matrix breakdown, promoting tumor invasive and metastasis. However, The function of M2 macrophages to progression of eophageal carcinoma, especially Kazakh esophageal carcinoma is still dimness. This study aims to investigate M2 macrophages correlated with matrix metalloproteinase-9 (MMP9) and microvessel density, and the role in the progression of Kazakh esophageal squamous cell carcinoma. CD163 and CD34 as the marker of M2 macrophages and endothelial cells, were used to identify the M2 macrophages density and microvessel density, respectively. Immunohistochemistry staining was evaluated the expression of MMP9. The number of infiltrated CD163-positive M2 macrophages in tumor islets and stroma was significantly higher than in cancer adjacent normal tissues. The increased of M2 macrophages and microvessel density were significantly correlated with more malignant phenotypes including lymph node metastasis and clinical stage progression. Meanwhile, the expression of MMP9 showed much higher level in esophageal squamous cell carcinoma than that in cancer adjacent normal tissues, and high expression of MMP9 in Kazakh esophageal squamous cell carcinoma was significantly associated with age, depth of tumor invasion, lymph node metastasis, and tumor clinical stage. The quantity of M2 macrophages in tumor stroma was positively associated with microvessel density and the expression of MMP9, and as an independent poorly prognostic factor for overall survival time of Kazakh esophageal squamous cell carcinoma. These findings suggest the increased number of M2 macrophages correlated with high expression of MMP9 and high microvessel density may contribute to the tumor aggressiveness and angiogenesis, promoting the progression of Kazakh esophageal squamous cell carcinoma.

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

PubMed

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

2015-01-01

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

Coiled-coil domain-containing protein 8 inhibits the invasiveness and migration of non-small cell lung cancer cells.

PubMed

Jiang, Gui-Yang; Zhang, Xiu-Peng; Zhang, Yong; Xu, Hong-Tao; Wang, Liang; Li, Qing-Chang; Wang, En-Hua

2016-10-01

Lung cancer has always been the leading cause of death among patients with malignant tumors, and the majority of these patients die because of cancer cell invasion and metastasis. Previous studies have implicated coiled-coil domain-containing protein 8 (CCDC8) as a tumor suppressor in several types of cancer, such as breast and prostate cancers. However, the expression levels or functions of CCDC8 in lung cancer have not been elucidated. Here, we used immunohistochemical staining to measure CCDC8 expression in 147 samples from tumors and 30 samples from the adjacent normal lung tissues of patients with non-small cell lung cancer. CCDC8 was shown to be located predominantly in the cytoplasm and partially on the cell membrane, and its expression level was significantly lower in lung cancer samples than that in the adjacent normal lung tissues (P=.001). CCDC8 expression was closely related to tumor differentiation (P=.039), tumor-node-metastasis stage (P=.009), lymph node metastasis (P=.038), and prognosis (P=.043) of lung cancer. Transfection of A549 cells with CCDC8 significantly reduced cell invasion and migration (P<.05), whereas the invasiveness and migration capacity in CCDC8-knockdown A549 cells were significantly increased in comparison with the control cells (P<.05). Furthermore, we demonstrated that CCDC8 can downregulate the expression of Snail and upregulate the expression of E-cadherin by inhibiting p-P38 and p-IκBα. Collectively, CCDC8 may suppress the invasion and metastasis of lung cancer cells, and it may represent a promising therapeutic target for non-small cell lung cancer. Copyright © 2016 Elsevier Inc. All rights reserved.

Technical Note: A treatment plan comparison between dynamic collimation and a fixed aperture during spot scanning proton therapy for brain treatment

PubMed Central

Smith, Blake; Gelover, Edgar; Moignier, Alexandra; Wang, Dongxu; Flynn, Ryan T.; Lin, Liyong; Kirk, Maura; Solberg, Tim; Hyer, Daniel E.

2016-01-01

Purpose: To quantitatively assess the advantages of energy-layer specific dynamic collimation system (DCS) versus a per-field fixed aperture for spot scanning proton therapy (SSPT). Methods: Five brain cancer patients previously planned and treated with SSPT were replanned using an in-house treatment planning system capable of modeling collimated and uncollimated proton beamlets. The uncollimated plans, which served as a baseline for comparison, reproduced the target coverage and organ-at-risk sparing of the clinically delivered plans. The collimator opening for the fixed aperture-based plans was determined from the combined cross sections of the target in the beam’s eye view over all energy layers which included an additional margin equivalent to the maximum beamlet displacement for the respective energy of that energy layer. The DCS-based plans were created by selecting appropriate collimator positions for each row of beam spots during a Raster-style scanning pattern which were optimized to maximize the dose contributions to the target and limited the dose delivered to adjacent normal tissue. Results: The reduction of mean dose to normal tissue adjacent to the target, as defined by a 10 mm ring surrounding the target, averaged 13.65% (range: 11.8%–16.9%) and 5.18% (2.9%–7.1%) for the DCS and fixed aperture plans, respectively. The conformity index, as defined by the ratio of the volume of the 50% isodose line to the target volume, yielded an average improvement of 21.35% (19.4%–22.6%) and 8.38% (4.7%–12.0%) for the DCS and fixed aperture plans, respectively. Conclusions: The ability of the DCS to provide collimation to each energy layer yielded better conformity in comparison to fixed aperture plans. PMID:27487886

Circular BANP, an upregulated circular RNA that modulates cell proliferation in colorectal cancer.

PubMed

Zhu, Mingchen; Xu, Yijun; Chen, Yun; Yan, Feng

2017-04-01

Circular RNAs (circRNAs) are recently identified as widespread and diverse endogenous noncoding RNAs that may harbor vital functions in human and animals. However, the role of circRNAs in the process of tumorigenesis and development of colorectal cancer (CRC) remains vague. Here we characterized the circRNA expression profile from three paired CRC cancerous and adjacent normal tissues by human circRNA array, and identified 136 significantly overexpressed circRNAs and 243 downregulated circRNAs in CRC cancerous tissues (>2-fold changes). We further validated one circRNA generated from Exon 5-11 of BANP gene, termed circ-BANP. In addition, RT-PCR result showed that circ-BANP was overexpressed in 35 CRC cancerous tissues. Knockdown of circ-BANP with siRNA significantly attenuate the proliferation of CRC cells. In summary, our findings demonstrated that dysregulated circ-BANP appears to have an important role in CRC cells and could serve as a prognostic and therapeutic marker for CRC. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

RGC32 induces epithelial-mesenchymal transition by activating the Smad/Sip1 signaling pathway in CRC.

PubMed

Wang, Xiao-Yan; Li, Sheng-Nan; Zhu, Hui-Fang; Hu, Zhi-Yan; Zhong, Yan; Gu, Chuan-Sha; Chen, Shi-You; Liu, Teng-Fei; Li, Zu-Guo

2017-05-04

Response gene to complement 32 (RGC32) is a transcription factor that regulates the expression of multiple genes involved in cell growth, viability and tissue-specific differentiation. However, the role of RGC32 in tumorigenesis and tumor progression in colorectal cancer (CRC) has not been fully elucidated. Here, we showed that the expression of RGC32 was significantly up-regulated in human CRC tissues versus adjacent normal tissues. RGC32 expression was significantly correlated with invasive and aggressive characteristics of tumor cells, as well as poor survival of CRC patients. We also demonstrated that RGC32 overexpression promoted proliferation, migration and tumorigenic growth of human CRC cells in vitro and in vivo. Functionally, RGC32 facilitated epithelial-mesenchymal transition (EMT) in CRC via the Smad/Sip1 signaling pathway, as shown by decreasing E-cadherin expression and increasing vimentin expression. In conclusion, our findings suggested that overexpression of RGC32 facilitates EMT of CRC cells by activating Smad/Sip1 signaling.

High mobility group box-1 and its clinical value in breast cancer

PubMed Central

Sun, Shanping; Zhang, Wei; Cui, Zhaoqing; Chen, Qi; Xie, Panpan; Zhou, Changxin; Liu, Baoguo; Peng, Xiangeng; Zhang, Yang

2015-01-01

Background High mobility group box-1 (HMGB1) is a factor regulating malignant tumorigenesis, proliferation, and metastasis, and is associated with poor clinical pathology in various human cancers. We investigated the differential concentrations of HMGB1 in tissues and sera, and their clinical value for diagnosis in patients with breast cancer, benign breast disease, and healthy individuals. Methods HMGB1 levels in tumor tissues, adjacent normal tissues, and benign breast disease tissues was detected via immunohistochemistry. Serum HMGB1 was measured using an enzyme-linked immunosorbent assay in 56 patients with breast cancer, 25 patients with benign breast disease, and 30 healthy control subjects. The clinicopathological features of the patients were compared. Tissues were evaluated histopathologically by pathologists. Results HMGB1 levels in the tissues and sera of patients with breast cancer were significantly higher than those in patients with benign breast disease or normal individuals. The 56 cancer patients were classified as having high tissue HMGB1 levels (n=41) or low tissue HMGB1 levels (n=15), but the corresponsive serum HMGB1 in these two groups was not significantly different. HMGB1 levels in breast cancer tissues significantly correlated with differentiation grade, lymphatic metastasis, and tumor-node-metastasis stage, but not patient age, tumor size, or HER-2/neu expression; no association between serum HMGB1 levels and these clinicopathological parameters was found. The sensitivity and specificity of tissue HMGB1 levels for the diagnosis of breast cancer were 73.21% and 84.00%, respectively, while positive and negative predictive values were 91.11% and 58.33%. Conclusion HMGB1 might be involved in the development and progression of breast cancer and could be a supportive diagnostic marker for breast cancer. Serum HMGB1 could be a useful serological biomarker for diagnosis and screening of breast cancer. PMID:25709474

[Chymotripsin-like activity and subunit composition of proteasomes in human cancers].

PubMed

Kondakova, I V; Spirina, L V; Koval, V D; Shashova, E E; Choinzonov, E L; Ivanova, E V; Kolomiets, L A; Chernyshova, A L; Slonimskaya, E M; Usynin, E A; Afanasyev, S G

2014-01-01

Activity of the proteasome, polyfunctional enzymatic complex, is known to undergo changes during cancer development. This phenomenon is, probably, caused by the changes in subunit composition of proteasomes. In present work, we studied chymotrypsin-like activity of proteasomes, subunit composition and their association in breast cancer, head and neck squamous cell carcinoma, endometrial cancer, renal cancer, bladder cancer, stomach cancer and colorectal cancer. The increase of proteasome activity was revealed in most cancer tissues compared with adjacent tissues except for the renal cell carcinoma. Changes in proteasome activity in cancer tissues compared with correspondent normal tissues were accompanied by modification of its subunit composition. High proteasome activity was observed in combination with an increased expression of immune subunits and/or proteasome activator PA28, associated with activity of 20S proteasome. In breast cancer, head and neck squamous cell carcinoma, bladder cancer, stomach cancer and colorectal cancer we additionally found higher expression of Rpt6 subunit of 26S proteasome. Correlations between chymotrypsin like proteasome activity and subunit expressions were found in human cancer tissues. In summary, we suggest that proteasome ac- tivation and changes in its subunit composition plays an important role in cancer pathogenesis.

Consumptive hypothyroidism due to a gastrointestinal stromal tumor expressing type 3 iodothyronine deiodinase

PubMed Central

Yan, Lin-Hai; Mo, Xian-Wei; Qin, Yu-Zhou; Wang, Cheng; Chen, Zhi-Ning; Lin, Yuan; Chen, Jian-Si

2015-01-01

Context: Gastrointestinal stromal tumors (GISTs) are responsive to sunitinib (the tyrosine kinase inhibitor), this agent is widely used in prevention relapse of GISTs and neo-adjuvant chemotherapy in GIST patients without operation opportunity. The use of these agents has both advantages and disadvantages. On the one hand, it can improve the outcome for patient. On the other hand, it may lead to consumptive hypothyroidism, a rare syndrome caused by increased catabolism of T4 and T3 by increased type 3 iodothyronine deiodinase (D3) activity. D3 is the major physiologic inactivator of thyroid hormone, this selenoenzyme catalyzes the inner-ring deiodination of T(4) to reverse T(3) and T(3) to 3, 3;-diiodothyronine, both of which are biologically inactive [1]. Increased monitoring and supernormal thyroid hormone supplementation are required for affected patient. Objective: The aim of the study was to report the first case of consumptive hypothyroidism in an athyreotic patient after surgical resection of gastrointestinal stromal tumor. Design, setting, and patient: A 60-year-old athyreotic male was presented and he was euthyroid when receiving a stable therapeutic dose of thyroid hormone which was used to treat consumptive hypothyroidism resulting from the side effects of sunitinib, which is used for treatment of neo-adjuvant chemotherapy in gastrointestinal stromal tumor. With a discovery of large D3-expressing gastrointestinal stromal tumor, this patient suffered from marked Hyperthyrotropinemia, which instantly worsened after surgical resection of the gastrointestinal stromal tumor and then continued for 12 weeks after the surgical resection, in spite of further increases in levothyroxine therapy. The patient also had low serum T3 and elevated serum reverse T3 (rT3). Intervention: The patient’s consumptive hypothyroidism caused by marked overexpression of the thyroid hormone-inactivating D3 within the gastrointestinal stromal tumor and adjacent normal gastrointestinal tissue. Main outcome measures and results: D3 immunostaining of the patient’s gastrointestinal stromal tumor was positive, with no significant immunoreactivity in adjacent normal gastrointestinal tissue. The expression levels of CD34, CD117, and DOG1 in peri-tumor tissue samples was lower than that in tumor tissue. The mRNA expression level of KIT exon17 in peri-tumor tissue was higher than that in tumor tissue. Conclusions: This is the first case report of consumptive hypothyroidism in an adult after surgical partial resection of the gastrointestinal stromal tumor. This case demonstrates that hyperthyrotropinemia may worsen after surgical resection of the gastrointestinal stromal tumor. PMID:26770446

Is photodynamic therapy a selective treatment? Analysis of local complications after endoscopic photodynamic therapy of early stage tumors of gastrointestinal, tracheobronchial, and urinary tracts

NASA Astrophysics Data System (ADS)

Spinelli, Pasquale; Dal Fante, Marco; Mancini, Andrea

1995-03-01

Selectivity is the most emphasized advantage of photodynamic therapy (PDT). However, at drug and light doses used for clinical applications, response from normal tissue surrounding the tumor reduces the real selectivity of the drug-light system and increases the surface of the area responding to the treatment. It is now evident that light irradiation of a sensitized patient produces damage at a various degree not only in the tumor but also in non-neoplastic tissues included in the field of irradiation. We report our experience in endoscopic PDT of early stage tumors in tracheobronchial, gastrointestinal and urinary tracts, describing early and late local complications caused by the damage of normal tissues adjacent to the tumors and included in the field of light irradiation. Among 44 patients treated, local complications, attributable to a poor selectivity of the modality, occurred in 6 patients (14%). In particular, the rate of local complications was 9% in patients treated for esophageal tumors, 14% in patients with gastric tumors, 9% in patients with tracheobronchial tumors, and 67% in bladder cancer patients. Clinical pictures as well as endoscopic findings at various intervals from treatment showed that mucositis is a common event following endoscopic PDT. It causes exudation and significant tissue inflammatory response, whose consequences are different in the various organs treated. Photoradiation must be, as much as possible, limited to the malignant area.

Effects of Local Compression on Peroneal Nerve Function in Humans

NASA Technical Reports Server (NTRS)

Hargens, Alan R.; Botte, Michael J.; Swenson, Michael R.; Gelberman, Richard H.; Rhoades, Charles E.; Akeson, Wayne H.

1993-01-01

A new apparatus was developed to compress the anterior compartment selectively and reproducibly in humans. Thirty-five normal volunteers were studied to determine short-term thresholds of local tissue pressure that produce significant neuromuscular dysfunction. Local tissue fluid pressure adjacent to the deep peroneal nerve was elevated by the compression apparatus and continuously monitored for 2-3 h by the slit catheter technique. Elevation of tissue fluid pressure to within 35-40 mm Hg of diastolic blood pressure (approx. 40 mm Hg of in situ pressure in our subjects) elicited a consistent progression of neuromuscular deterioration including, in order, (a) gradual loss of sensation, as assessed by Semmes-Weinstein monofilaments, (b) subjective complaints, (c) reduced nerve conduction velocity, (d) decreased action potential amplitude of the extensor digitorum brevis muscle, and (e) motor weakness of muscles within the anterior compartment. Generally, higher intracompartment at pressures caused more rapid deterioration of neuromuscular function. In two subjects, when in situ compression levels were 0 and 30 mm Hg, normal neuromuscular function was maintained for 3 h. Threshold pressures for significant dysfunction were not always the same for each functional parameter studied, and the magnitudes of each functional deficit did not always correlate with compression level. This variable tolerance to elevated pressure emphasizes the need to monitor clinical signs and symptoms carefully in the diagnosis of compartment syndromes. The nature of the present studies was short term; longer term compression of myoneural tissues may result in dysfunction at lower pressure thresholds.

Flow-Through Free Fibula Osteocutaneous Flap in Reconstruction of Tibial Bone, Soft Tissue, and Main Artery Segmental Defects.

PubMed

Li, Zonghuan; Yu, Aixi; Qi, Baiwen; Pan, Zhenyu; Ding, Junhui

2017-08-01

The aim of this report was to present the use of flow-through free fibula osteocutaneous flap for the repair of complex tibial bone, soft tissue, and main artery segmental defects. Five patients with bone, soft tissue, and segmental anterior tibial artery defects were included. The lengths of injured tibial bones ranged from 4 to 7 cm. The sizes of impaired soft tissues were between 9 × 4 and 15 × 6 cm. The lengths of defect of anterior tibial artery segments ranged from 6 to 10 cm. Two patients had distal limb perfusion problems. Flow-through free fibula osteocutaneous flap was performed for all 5 patients. Patients were followed for 12 to 18 months. All wounds healed after 1-stage operation, and all flow-through flaps survived. The distal perfusion after vascular repair was normal in all patients. Superficial necrosis of flap edge was noted in 1 case. After the local debridement and partial thickness skin graft, the flap healed uneventfully, and the surgical operation did not increase injury to the donor site. Satisfactory bone union was achieved in all patients in 2 to 4 months postoperation. Enlargement of fibula graft was observed during follow-up from 12 to 18 months. The functions of adjacent joints were recovered, and all patients were able to walk normally. Flow-through free fibula osteocutaneous flap was shown to be an effective and efficient technique for repairing composite tibial bone, soft tissue, and main artery segmental defects. This 1-stage operation should be useful in clinical practice for the treatment of complex bone, soft tissue, and vessel defects.

Genome-Wide Analysis of Long Noncoding RNA (lncRNA) Expression in Hepatoblastoma Tissues

PubMed Central

Xue, Ping; Cui, Ximao; Li, Kai; Zheng, Shan; He, Xianghuo; Dong, Kuiran

2014-01-01

Long noncoding RNAs (lncRNAs) have crucial roles in cancer biology. We performed a genome-wide analysis of lncRNA expression in hepatoblastoma tissues to identify novel targets for further study of hepatoblastoma. Hepatoblastoma and normal liver tissue samples were obtained from hepatoblastoma patients. The genome-wide analysis of lncRNA expression in these tissues was performed using a 4×180 K lncRNA microarray and Sureprint G3 Human lncRNA Chips. Quantitative RT-PCR (qRT-PCR) was performed to confirm these results. The differential expressions of lncRNAs and mRNAs were identified through fold-change filtering. Gene Ontology (GO) and pathway analyses were performed using the standard enrichment computation method. Associations between lncRNAs and adjacent protein-coding genes were determined through complex transcriptional loci analysis. We found that 2736 lncRNAs were differentially expressed in hepatoblastoma tissues. Among these, 1757 lncRNAs were upregulated more than two-fold relative to normal tissues and 979 lncRNAs were downregulated. Moreover, in hepatoblastoma there were 420 matched lncRNA-mRNA pairs for 120 differentially expressed lncRNAs, and 167 differentially expressed mRNAs. The co-expression network analysis predicted 252 network nodes and 420 connections between 120 lncRNAs and 132 coding genes. Within this co-expression network, 369 pairs were positive, and 51 pairs were negative. Lastly, qRT-PCR data verified six upregulated and downregulated lncRNAs in hepatoblastoma, plus endothelial cell-specific molecule 1 (ESM1) mRNA. Our results demonstrated that expression of these aberrant lncRNAs could respond to hepatoblastoma development. Further study of these lncRNAs could provide useful insight into hepatoblastoma biology. PMID:24465615

Effects of spaceflight on trabecular bone in rats

NASA Technical Reports Server (NTRS)

Jee, W. S. S.; Wronski, T. J.; Morey, E. R.; Kimmel, D. B.

1983-01-01

Alterations in trabecular bone were observed in growing male Wistar rats after 18.5 days of orbital flight on the COSMOS 1129 biosatellite. Spaceflight induced a decreased mass of mineralized tissue and an increased fat content of the bone marrow in the proximal tibial and humeral metaphyses. The osteoblast population appeared to decline immediately adjacent to the growth cartilage-metaphyseal junction, but osteoclast numbers were unchanged. These results suggested that bone formation may have been inhibited during spaceflight, but resorption remained constant. With the exception of trabecular bone mass in the proximal tibia, the observed skeletal changes returned to normal during a 29-day postflight period.

MRI of placental adhesive disorder

PubMed Central

Prapaisilp, P; Bangchokdee, S

2014-01-01

Placental adhesive disorder (PAD) is a serious pregnancy complication that occurs when the chorionic villi invade the myometrium. Placenta praevia and prior caesarean section are the two important risk factors. PAD is classified on the basis of the depth of myometrial invasion (placenta accreta, placenta increta and placenta percreta). MRI is the preferred image modality for pre-natal diagnosis of PAD and as complementary technique when ultrasonography is inconclusive. Imaging findings that are helpful for the diagnosis include dark intraplacental bands, direct invasion of adjacent structures by placental tissue, interruption of normal trilayered myometrium and uterine bulging. Clinicians should be aware of imaging features of PAD to facilitate optimal patient management. PMID:25060799

MicroRNA Expression Profile in Penile Cancer Revealed by Next-Generation Small RNA Sequencing

PubMed Central

Zhang, Yuanwei; Xu, Bo; Zhou, Jun; Fan, Song; Hao, Zongyao; Shi, Haoqiang; Zhang, Xiansheng; Kong, Rui; Xu, Lingfan; Gao, Jingjing; Zou, Duohong; Liang, Chaozhao

2015-01-01

Penile cancer (PeCa) is a relatively rare tumor entity but possesses higher morbidity and mortality rates especially in developing countries. To date, the concrete pathogenic signaling pathways and core machineries involved in tumorigenesis and progression of PeCa remain to be elucidated. Several studies suggested miRNAs, which modulate gene expression at posttranscriptional level, were frequently mis-regulated and aberrantly expressed in human cancers. However, the miRNA profile in human PeCa has not been reported before. In this present study, the miRNA profile was obtained from 10 fresh penile cancerous tissues and matched adjacent non-cancerous tissues via next-generation sequencing. As a result, a total of 751 and 806 annotated miRNAs were identified in normal and cancerous penile tissues, respectively. Among which, 56 miRNAs with significantly different expression levels between paired tissues were identified. Subsequently, several annotated miRNAs were selected randomly and validated using quantitative real-time PCR. Compared with the previous publications regarding to the altered miRNAs expression in various cancers and especially genitourinary (prostate, bladder, kidney, testis) cancers, the most majority of deregulated miRNAs showed the similar expression pattern in penile cancer. Moreover, the bioinformatics analyses suggested that the putative target genes of differentially expressed miRNAs between cancerous and matched normal penile tissues were tightly associated with cell junction, proliferation, growth as well as genomic instability and so on, by modulating Wnt, MAPK, p53, PI3K-Akt, Notch and TGF-β signaling pathways, which were all well-established to participate in cancer initiation and progression. Our work presents a global view of the differentially expressed miRNAs and potentially regulatory networks of their target genes for clarifying the pathogenic transformation of normal penis to PeCa, which research resource also provides new insights into future investigations aimed to explore the in-depth mechanisms of miRNAs and other small RNAs including piRNAs in penile carcinogenesis regulation and effective target-specific theragnosis. PMID:26158897

Identification of Carbonic Anhydrase IX as a Novel Target for Endoscopic Molecular Imaging of Human Bladder Cancer.

PubMed

Wang, Jiaqi; Fang, Ruizhe; Wang, Lu; Chen, Guang; Wang, Hongzhi; Wang, Zhichao; Zhao, Danfeng; Pavlov, Valentin N; Kabirov, Ildar; Wang, Ziqi; Guo, Pengyu; Peng, Li; Xu, Wanhai

2018-06-27

Emerging novel optical imaging techniques with cancer-specific molecular imaging agents offer a powerful and promising platform for cancer detection and resection. White-light cystoscopy and random bladder biopsies remain the most appropriate but nonetheless suboptimal diagnostic technique for bladder cancer, which is associated with high morbidity and recurrence. However, white-light cystoscopy has intrinsic shortcomings. Although current optical imaging technologies hold great potential for improved diagnostic accuracy, there are few imaging agents for specific molecular targeting. Carbonic anhydrase IX (CAIX) plays a pivotal role in tumorigenesis and tumor progression with potential value as an imaging target. Here, we investigated the feasibility of CAIX as a target and validated the diagnostic performance and significance of CAIX as an imaging agent. We first analyzed the data from The Cancer Genome Atlas (TCGA). Pairs of samples comprising bladder cancer and adjacent normal tissue were collected. All tissue samples were used for real-time PCR and immunohistochemistry to compare CAIX expression in normal and cancer tissue. Using blue-light cystoscopy, we observed the optical distribution of fluorescently labeled CAIX antibody in freshly excised human bladders and obtained random bladder biopsies to assess sensitivity and specificity. The TCGA data revealed that CAIX expression was significantly higher in bladder cancer specimens than in normal tissue. The outcome was similar in quantitative real-time PCR analysis. In immunohistochemical analysis, bladder cancer specimens classified in four pathological subtypes presented a variety of positive staining intensities, whereas no benign specimens showed CAIX staining. Using blue-light cystoscopy, we distinguished bladder cancers that were mainly papillary, some variants of urothelial carcinoma, and less carcinoma in situ, from benign tissue, despite the presence of suspicious-appearing mucosa. The sensitivity and specificity for CAIX-targeted imaging were 88.00% and 93.75%, respectively. CAIX-targeted molecular imaging could be a feasible and adaptive alternative approach for the accurate diagnosis and complete resection of bladder cancer. © 2018 The Author(s). Published by S. Karger AG, Basel.

Aberrant microRNA-137 promoter methylation is associated with lymph node metastasis and poor clinical outcomes in non-small cell lung cancer

PubMed Central

Min, Lingfeng; Wang, Fang; Hu, Suwei; Chen, Yong; Yang, Junjun; Liang, Sudong; Xu, Xingxiang

2018-01-01

MicroRNA-137 (miR-137) functions as a tumor suppressor and is silenced by aberrant promoter methylation. Previous studies have demonstrated that miR-137 is downregulated in lung cancer. The purpose of the present study was to investigate miR-137 promoter methylation and to assess its prognostic value in non-small cell lung cancer (NSCLC). The expression of miR-137 was analyzed inhuman lung cancer A549 and H1299 cells and normal bronchial epithelial BEAS-2B cells, 10 paired formalin-fixed paraffin-embedded lung cancer and normal tissue samples, and 56 archived paraffin-embedded lung cancer tissues. Quantitative methylation-specific polymerase chain reaction analysis was used to assess the miR-137 methylation status. The associations between miR-137 promoter methylation and the clinicopathological features and prognosis of patients with NSCLC (n=56) were analyzed using analysis of variance. miR-137 was markedly downregulated in lung cancer cells and lung cancer tissue specimens compared with expression in BEAS-2B cells and matched adjacent normal lung tissues. A significant negative correlation between miR-137 expression and miR-137 promoter methylation was observed in human lung cancer tissues (r=−0.343; P=0.01). Smoking, lymph node metastasis and advanced clinical stage were associated with significantly lower expression of miR-137 in variance analysis. High levels of miR-137 promoter methylation were associated with a significantly poorer disease-free survival rate (P=0.034), but were not associated with overall survival, in Kaplan-Meier analysis and univariate analysis. In conclusion, the results of the present study indicated that miR-137 is downregulated and that its promoter is aberrantly methylated in lung cancer, and that high levels of miR-137 promoter methylation may have prognostic value for poor disease-free survival. PMID:29740491

Aluminum concentrations in central and peripheral areas of malignant breast lesions do not differ from those in normal breast tissues

PubMed Central

2013-01-01

Background Aluminum is used in a wide range of applications and is a potential environmental hazard. The known genotoxic effects of aluminum might play a role in the development of breast cancer. However, the data currently available on the subject are not sufficient to establish a causal relationship between aluminum exposure and the augmented risk of developing breast cancer. To achieve maximum sensitivity and specificity in the determination of aluminum levels, we have developed a detection protocol using graphite furnace atomic absorption spectrometry (GFAAS). The objective of the present study was to compare the aluminum levels in the central and peripheral areas of breast carcinomas with those in the adjacent normal breast tissues, and to identify patient and/or tumor characteristics associated with these aluminum levels. Methods A total of 176 patients with breast cancer were included in the study. Samples from the central and peripheral areas of their tumors were obtained, as well as from the surrounding normal breast tissue. Aluminum quantification was performed using GFAAS. Results The average (mean ± SD) aluminum concentrations were as follows: central area, 1.88 ± 3.60 mg/kg; peripheral area, 2.10 ± 5.67 mg/kg; and normal area, 1.68 ± 11.1 mg/kg. Overall and two-by-two comparisons of the aluminum concentrations in these areas indicated no significant differences. We detected a positive relationship between aluminum levels in the peripheral areas of the tumors, age and menopausal status of the patients (P = .02). Conclusions Using a sensitive quantification technique we detected similar aluminum concentrations in the central and peripheral regions of breast tumors, and in normal tissues. In addition, we did not detect significant differences in aluminum concentrations as related to the location of the breast tumor within the breast, or to other relevant tumor features such as stage, size and steroid receptor status. The next logical step is the assessment of whether the aluminum concentration is related to the key genomic abnormalities associated with breast carcinogenesis. PMID:23496847

Aluminum concentrations in central and peripheral areas of malignant breast lesions do not differ from those in normal breast tissues.

PubMed

Rodrigues-Peres, Raquel Mary; Cadore, Solange; Febraio, Stefanny; Heinrich, Juliana Karina; Serra, Katia Piton; Derchain, Sophie F M; Vassallo, Jose; Sarian, Luis Otavio

2013-03-08

Aluminum is used in a wide range of applications and is a potential environmental hazard. The known genotoxic effects of aluminum might play a role in the development of breast cancer. However, the data currently available on the subject are not sufficient to establish a causal relationship between aluminum exposure and the augmented risk of developing breast cancer. To achieve maximum sensitivity and specificity in the determination of aluminum levels, we have developed a detection protocol using graphite furnace atomic absorption spectrometry (GFAAS). The objective of the present study was to compare the aluminum levels in the central and peripheral areas of breast carcinomas with those in the adjacent normal breast tissues, and to identify patient and/or tumor characteristics associated with these aluminum levels. A total of 176 patients with breast cancer were included in the study. Samples from the central and peripheral areas of their tumors were obtained, as well as from the surrounding normal breast tissue. Aluminum quantification was performed using GFAAS. The average (mean ± SD) aluminum concentrations were as follows: central area, 1.88 ± 3.60 mg/kg; peripheral area, 2.10 ± 5.67 mg/kg; and normal area, 1.68 ± 11.1 mg/kg. Overall and two-by-two comparisons of the aluminum concentrations in these areas indicated no significant differences. We detected a positive relationship between aluminum levels in the peripheral areas of the tumors, age and menopausal status of the patients (P = .02). Using a sensitive quantification technique we detected similar aluminum concentrations in the central and peripheral regions of breast tumors, and in normal tissues. In addition, we did not detect significant differences in aluminum concentrations as related to the location of the breast tumor within the breast, or to other relevant tumor features such as stage, size and steroid receptor status. The next logical step is the assessment of whether the aluminum concentration is related to the key genomic abnormalities associated with breast carcinogenesis.

Current status of intratumoral therapy for glioblastoma.

PubMed

Mehta, Ankit I; Linninger, Andreas; Lesniak, Maciej S; Engelhard, Herbert H

2015-10-01

With emerging drug delivery technologies becoming accessible, more options are expected to become available to patients with glioblastoma (GBM) in the near future. It is important for clinicians to be familiar with the underlying mechanisms and limitations of intratumoral drug delivery, and direction of recent research efforts. Tumor-adjacent brain is an extremely complex living matrix that creates challenges with normal tissue intertwining with tumor cells. For convection-enhanced delivery (CED), the role of tissue anisotropy for better predicting the biodistribution of the infusate has recently been studied. Computational predictive methods are now available to better plan CED therapy. Catheter design and placement—in addition to the agent being used—are critical components of any protocol. This paper overviews intratumoral therapies for GBM, highlighting key anatomic and physiologic perspectives, selected agents (especially immunotoxins), and some new developments such as the description of the glymphatic system.

MicroRNA-1 promotes apoptosis of hepatocarcinoma cells by targeting apoptosis inhibitor-5 (API-5).

PubMed

Li, Dong; Liu, Yu; Li, Hua; Peng, Jing-Jing; Tan, Yan; Zou, Qiang; Song, Xiao-Feng; Du, Min; Yang, Zheng-Hui; Tan, Yong; Zhou, Jin-Jun; Xu, Tao; Fu, Zeng-Qiang; Feng, Jian-Qiong; Cheng, Peng; chen, Tao; Wei, Dong; Su, Xiao-Mei; Liu, Huan-Yi; Qi, Zhong-Chun; Tang, Li-Jun; Wang, Tao; Guo, Xin; Hu, Yong-He; Zhang, Tao

2015-01-02

Although microRNA-1 (miR-1) is a known liver cancer suppressor, the role of miR-1 in apoptosis of hepatoma cells has remained largely unknown. Our study shows that ectopic miR-1 overexpression induced apoptosis of liver hepatocellular carcinoma (HepG2) cells. Apoptosis inhibitor 5 (API-5) was found to be a potential regulator of miR-1 induced apoptosis, using a bioinformatics approach. Furthermore, an inverse relationship between miR-1 and API-5 expression was observed in human liver cancer tissues and adjacent normal liver tissues. Negative regulation of API-5 expression by miR-1 was demonstrated to promote apoptosis of HepG2 cells. Our study provides a novel regulatory mechanism of miR-1 in the apoptosis of hepatoma cells. Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Estrogen regulates Hippo signaling via GPER in breast cancer.

PubMed

Zhou, Xin; Wang, Shuyang; Wang, Zhen; Feng, Xu; Liu, Peng; Lv, Xian-Bo; Li, Fulong; Yu, Fa-Xing; Sun, Yiping; Yuan, Haixin; Zhu, Hongguang; Xiong, Yue; Lei, Qun-Ying; Guan, Kun-Liang

2015-05-01

The G protein-coupled estrogen receptor (GPER) mediates both the genomic and nongenomic effects of estrogen and has been implicated in breast cancer development. Here, we compared GPER expression in cancerous tissue and adjacent normal tissue in patients with invasive ductal carcinoma (IDC) of the breast and determined that GPER is highly upregulated in cancerous cells. Additionally, our studies revealed that GPER stimulation activates yes-associated protein 1 (YAP) and transcriptional coactivator with a PDZ-binding domain (TAZ), 2 homologous transcription coactivators and key effectors of the Hippo tumor suppressor pathway, via the Gαq-11, PLCβ/PKC, and Rho/ROCK signaling pathways. TAZ was required for GPER-induced gene transcription, breast cancer cell proliferation and migration, and tumor growth. Moreover, TAZ expression positively correlated with GPER expression in human IDC specimens. Together, our results suggest that the Hippo/YAP/TAZ pathway is a key downstream signaling branch of GPER and plays a critical role in breast tumorigenesis.

Pilot clinical study for quantitative spectral diagnosis of non-melanoma skin cancer.

PubMed

Rajaram, Narasimhan; Reichenberg, Jason S; Migden, Michael R; Nguyen, Tri H; Tunnell, James W

2010-12-01

Several research groups have demonstrated the non-invasive diagnostic potential of diffuse optical spectroscopy (DOS) and laser-induced fluorescence (LIF) techniques for early cancer detection. By combining both modalities, one can simultaneously measure quantitative parameters related to the morphology, function and biochemical composition of tissue and use them to diagnose malignancy. The objective of this study was to use a quantitative reflectance/fluorescence spectroscopic technique to determine the optical properties of normal skin and non-melanoma skin cancers and the ability to accurately classify them. An additional goal was to determine the ability of the technique to differentiate non-melanoma skin cancers from normal skin. The study comprised 48 lesions measured from 40 patients scheduled for a biopsy of suspected non-melanoma skin cancers. White light reflectance and laser-induced fluorescence spectra (wavelength range = 350-700 nm) were collected from each suspected lesion and adjacent clinically normal skin using a custom-built, optical fiber-based clinical instrument. After measurement, the skin sites were biopsied and categorized according to histopathology. Using a quantitative model, we extracted various optical parameters from the measured spectra that could be correlated to the physiological state of tissue. Scattering from cancerous lesions was significantly lower than normal skin for every lesion group, whereas absorption parameters were significantly higher. Using numerical cut-offs for our optical parameters, our clinical instrument could classify basal cell carcinomas with a sensitivity and specificity of 94% and 89%, respectively. Similarly, the instrument classified actinic keratoses and squamous cell carcinomas with a sensitivity of 100% and specificity of 50%. The measured optical properties and fluorophore contributions of normal skin and non-melanoma skin cancers are significantly different from each other and correlate well with tissue pathology. A diagnostic algorithm that combines these extracted properties holds promise for the potential non-invasive diagnosis of skin cancer. Copyright © 2010 Wiley-Liss, Inc.

Circular RNA 0068669 as a new biomarker for hepatocellular carcinoma metastasis.

PubMed

Yao, Ting; Chen, Qingqing; Shao, Zhouwei; Song, Zhihua; Fu, Liyun; Xiao, Bingxiu

2018-05-21

Circular RNAs (circRNAs) play important roles in disease occurrence. However, the roles of circRNAs in the diagnosis of hepatocellular carcinoma (HCC) are largely unknown. The aim of this study is to investigate the clinical diagnostic values of hsa_circ_0068669 (Alias: hsa_circ_103561), one of the representative HCC-associated circRNAs. Hsa_circ_0068669 expression levels in HCC tissues, HCC cell lines, and chronic hepatitis tissues were detected by real-time quantitative reverse transcription-polymerase chain reaction. Its expression levels between HCC tissues and adjacent non-tumorous tissues were analyzed using paired t test. Independent t test and one-way analysis of variance (ANOVA) were performed to analyze the relationships between hsa_circ_0068669 expression levels and clinicopathological factors of patients with HCC. A receiver operating characteristic (ROC) curve was established to estimate the value of hsa_circ_0068669 as a biomarker in HCC. Hsa_circ_0068669 expression was significantly downregulated in HCC tissues and HCC cell lines compared with paired non-tumorous tissues and normal hepatic cell line, respectively. Moreover, hsa_circ_0068669 expression in HCC tissues was decreased comparing with chronic hepatitis tissues. Furthermore, hsa_circ_0068669 expression was correlated with microvascular invasion and TNM stages. Our findings indicate that hsa_circ_0068669 might be served as a novel potential biomarker for HCC metastasis. © 2018 Wiley Periodicals, Inc.

Modeling the Epithelial Morphogenesis of Germ Band Retraction in Three Dimensions

NASA Astrophysics Data System (ADS)

McCleery, W. Tyler; Veldhuis, Jim; Brodland, G. Wayne; Crews, Sarah M.; Hutson, M. Shane

2015-03-01

Embryogenesis of higher-order organisms is driven by an intricate coordination of cellular mechanics. Mechanical analysis of certain developmental events, e.g., dorsal closure in the fruit fly D. melanogaster, has been sufficiently described using two-dimensional models. Here, we present a three-dimensional modeling technique to investigate germ band retraction (GBR) - a whole-embryo, irreducibly 3D morphogenetic event. At the start of GBR, the epithelial tissue known as the germ band is initially wrapped around the posterior end of an ellipsoidal fly embryo. This tissue then retracts as an adjacent epithelial tissue, the amnioserosa, simultaneously contracts. We hypothesize that proper GBR requires maintenance of cell-cell connectivity in the amnioserosa, as well as both cell and tissue topology on the embryo's ellipsoidal surface. The exact interfacial tensions are less important. We test the dynamic interactions between these two tissues on a 3D ellipsoidal last. To speed simulation run times and focus on the relevant tissues, epithelial cells are defined as polygons constrained to lie on the surface of the ellipsoidal last. These cells have adjustable parameters such as edge tensions and cell pressures. Tissue movements are simulated by balancing these dynamic cell-level forces with viscous resistance and allowing cells to exchange neighbors. This modeling approach helps elucidate the multicellular stress fields in normal and aberrant development, providing deeper insight into the mechanical interdependence of developing tissues.

Non-invasive pH determination adjacent to degradable biomaterials in vivo.

PubMed

Bartsch, Ivonne; Willbold, Elmar; Rosenhahn, Bodo; Witte, Frank

2014-01-01

An appropriate pH level is an important prerequisite for the physiologal functioning of cells and tissues. Changes in the extracellular pH often lead to specific cellular reactions and an altered metabolism of cells and tissues influences the extracellular pH range. Thus a method to monitor the extracellular pH is a valuable tool to track specific tissue reactions. In this article we describe a method for the determination of the pH range adjacent to degradable biomaterials using wireless in vivo imaging. Using hairless but immunocompetent mice the fluorophor 5-(6)-carboxy SNARF-1 and the in vivo fluorescence and multispectral acquisition and analysis system Maestro it is possible to track shifts in pH in small living animals over a longer period of time. This method is especially suitable for studies which focus on the interaction of degrading biomaterials with their adjacent tissues. Copyright © 2013 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Collecting lymphatic vessel permeability facilitates adipose tissue inflammation and distribution of antigen to lymph node-homing adipose tissue dendritic cells.

PubMed

Kuan, Emma L; Ivanov, Stoyan; Bridenbaugh, Eric A; Victora, Gabriel; Wang, Wei; Childs, Ed W; Platt, Andrew M; Jakubzick, Claudia V; Mason, Robert J; Gashev, Anatoliy A; Nussenzweig, Michel; Swartz, Melody A; Dustin, Michael L; Zawieja, David C; Randolph, Gwendalyn J

2015-06-01

Collecting lymphatic vessels (CLVs), surrounded by fat and endowed with contractile muscle and valves, transport lymph from tissues after it is absorbed into lymphatic capillaries. CLVs are not known to participate in immune responses. In this study, we observed that the inherent permeability of CLVs allowed broad distribution of lymph components within surrounding fat for uptake by adjacent macrophages and dendritic cells (DCs) that actively interacted with CLVs. Endocytosis of lymph-derived Ags by these cells supported recall T cell responses in the fat and also generated Ag-bearing DCs for emigration into adjacent lymph nodes (LNs). Enhanced recruitment of DCs to inflammation-reactive LNs significantly relied on adipose tissue DCs to maintain sufficient numbers of Ag-bearing DCs as the LN expanded. Thus, CLVs coordinate inflammation and immunity within adipose depots and foster the generation of an unexpected pool of APCs for Ag transport into the adjacent LN. Copyright © 2015 by The American Association of Immunologists, Inc.

SGK2 promotes hepatocellular carcinoma progression and mediates GSK-3β/β-catenin signaling in HCC cells.

PubMed

Liu, Junying; Zhang, Guangdong; Lv, Yanping; Zhang, Xiaoyang; Ying, Cui; Yang, Suocheng; Kong, Xin; Yu, Yanzhang

2017-06-01

The phosphoinositide 3-kinase pathway is one of the most commonly altered pathways in human cancers. The serum/glucocorticoid-regulated kinase (SGK) family of serine/threonine kinases consists of three isoforms, SGK1, SGK2, and SGK3. This family of kinases is highly homologous to the AKT kinase family, sharing similar upstream activators and downstream targets. Few studies have investigated the role of SGK2 in hepatocellular carcinoma. Here, we report that SGK2 expression levels were upregulated in hepatocellular carcinoma tissues and human hepatoma cell lines compared to the adjacent normal liver tissues and a normal hepatocyte line, respectively. We found that downregulated SGK2 inhibits cell migration and invasive potential of hepatocellular carcinoma cell lines (SMMC-7721 and Huh-7).We also found that downregulated SGK2 suppressed the expression level of unphosphorylated (activated) glycogen synthase kinase 3 beta. In addition, SGK2 downregulation decreased the dephosphorylation (activation) of β-catenin by preventing its proteasomal degradation in the hepatocellular carcinoma cell lines. These findings suggest that SGK2 promotes hepatocellular carcinoma progression and mediates glycogen synthase kinase 3 beta/β-catenin signaling in hepatocellular carcinoma cells.

Detection of survivin 2α gene expression in thyroid nodules.

PubMed

Kyani, Keyhaneh; Babaei, Esmaeil; Feizi, Mohammad Ali Hosseinpour; Vandghanooni, Somayeh; Montazeri, Vahid; Halimi, Monireh

2014-01-01

Functional studies of the survivin splice variants have been performed almost exclusively in various types of cancer and produced remarkable advances in our understanding of cancer biology and cancer genetics. To observation the expression of survivin 2α in thyroid nodules and estimate its potential as a new molecular marker in thyroid nodules screening and malignant thyroid, as well. We detected the expression of a splice variant of survivin, survivin 2α, in thyroid nodules. Expression of survivin 2α mRNA was evaluated with specific primers by Hemi-Nested RT-PCR in 77 thyroid nodules including malignant and benign tumors, non-tumoral (goiter and thyroiditis) as well as surgical margin, non-neoplastic normal tissues adjacent to the malignant lesions. Our data revealed for the first time the expression of survivin 2α in thyroid nodules. It was detected in 85.7% of non-neoplastic surgical margin tissues, 71.4% of non tumoral, 63.2% of tumoral samples. Also, the expression of survivin 2α in benign tumor samples (64.2%) is more than malignant groups (62.8%). Survivin 2α expression is the highest in non-neoplastic surgical margin rather than other samples and the lowest expression was that of malignancy. According to the results, it can be concluded that survivin 2α protein may be has a vital protective effect throw survivin quenching due to the high expression in normal tissue compared with lesions.

Clinical Implications of Promoter Hypermethylation in RASSF1A and MGMT in Retinoblastoma1

PubMed Central

Choy, Kwong Wai; Lee, Tom C; Cheung, Kin Fai; Fan, Dorothy S P; Lo, Kwok Wai; Beaverson, Katherine L; Abramson, David H; Lam, Dennis S C; Yu, Christopher B O; Pang, Chi Pui

2005-01-01

Abstract We investigated the epigenetic silencing and genetic changes of the RAS-associated domain family 1A (RASSF1A) gene and the O6-methylguanine-DNA methyltransferase (MGMT) gene in retinoblastoma. We extracted DNA from microdissected tumor and normal retina tissues of the same patient in 68 retinoblastoma cases. Promoter methylation in RASSF1A and MGMT was analyzed by methylation-specific PCR, RASSF1A sequence alterations in all coding exons by direct DNA sequencing, and RASSF1A expression by RT-PCR. Cell cycle staging was analyzed by flow cytometry. We detected RASSF1A promoter hypermethylation in 82% of retinoblastoma, in tumor tissues only but not in adjacent normal retinal tissue cells. There was no expression of RASSF1A transcripts in all hypermethylated samples, but RASSF1A transcripts were restored after 5-aza-2′-deoxycytidine treatment with no changes in cell cycle or apoptosis. No mutation in the RASSF1A sequence was found. MGMT hypermethylation was present in 15% of theretinoblastoma samples, and the absence of MGMT hypermethylation was associated (P = .002) with retinoblastoma at advanced Reese-Ellsworth tumor stage. Our results revealed a high RASSF1A hypermethylation frequency in retinoblastoma. The correlation of MGMT inactivation by promoter hypermethylation with lower-stage diseases indicated that MGMT hypermethylation provides useful prognostic information. Epigenetic mechanism plays an important role in the progression of retinoblastoma. PMID:15799820

MiR-137 and its target TGFA modulate cell growth and tumorigenesis of non-small cell lung cancer.

PubMed

Liu, X; Chen, L; Tian, X-D; Zhang, T

2017-02-01

MiR-137 has been reported to serve as a tumor suppressor in non-small cell lung cancer (NSCLC). However, the potential mechanism remains largely unclear. The present study aimed to explore the potential molecular mechanisms by which miR-137 regulated NSCLC. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to quantify the expression levels of miR-137 in NSCLC tissues and cell lines. Dual-luciferase reporter assay was employed to confirm the specificity of miR-137 target genes. An MTT assay and flow cytometry were used to determine the rates of cell proliferation and cell cycle distribution. Furthermore, the effect of miR-137 up-regulation on TGFA expression was examined by western blot. miR-137 expression levels in NSCLC cell lines or tissue were significantly lower than in a normal human lung cell line or adjacent normal tissues. We further found that upregulation of miR-137 inhibited the proliferation of NSCLC cells, whereas silencing of miR-137 promoted the proliferation of NSCLC. Moreover, we identified TGFA as a direct target gene of miR-137 in NSCLC cell. Finally, Similarly, knockdown of TGFA led to the suppression of NSCLC cell proliferation. Overall, our findings indicated that miR-137 served as a tumor suppressor in NSCLC and its suppressive effect is mediated by repressing TGFA expression.

[Human joint capsule in osteoarthrosis (morpholocical changes) (author's transl)].

PubMed

Dettmer, N; Barz, B

1977-07-29

Morphological investigations of the joint capsules in osteoarthrotic-changed joints have given rise to doubts about the present theory of the causal aetiology of the osteoarthrosis. In every inspected and demonstrated illustration beside the partly normal capsules segments could be found every transition between mild regressive alterations and most massive proliferative changes of the conective tissue and the lining cell layer. It was extraordinary, that the strongly dilated vessels were filled with red blood cells. In another part of the same case was found a massive stricture caused by concentrically deposited substances, which were impregnated with collagenous fibers. Regeneration of the vessels frequently happened adjacent totally obstructed ones. Round-cell infiltrations, granulocytes or other indications of an inflammatory synovitis are found only in a few cases. The intracartilaginous enzymatic reactions, which have been much talked of and which were explained as characteristic of the osteoarthrosis cannot be the cause of the degradation of the cartilage, particularly, because of the normal cell count which is to be found in the synovial fluid. We can answer this problem, if we can prove that the substrates of the chondral metabolism themselves exert a direct or indirect influence on the interstitial connective tissue with induction of the powerful proliferation of the same tissue. The changes in the transit zone would be secondary and their effect on the lining cell layer would increase the progression of the arthrotic events.

Developmental tumors and adjacent cortical dysplasia: single or dual pathology?

PubMed

Palmini, André; Paglioli, Eliseu; Silva, Vinicius Duval

2013-12-01

Developmental tumors often lead to refractory partial seizures and constitute a well-defined, surgically remediable epilepsy syndrome. Dysplastic features are often associated with these tumors, and their significance carries both practical and conceptual relevance. If associated focal cortical dysplasia (FCD) relates to the extent of the epileptogenic tissue, then presurgical evaluation and surgical strategies should target both the tumor and the surrounding dyslaminated cortex. Furthermore, the association has been included in the recently revised classification of FCD and the epileptogenicity of this associated dysplastic tissue is crucial to validate such revision. In addition to the possibility of representing dual pathology, the association of developmental tumors and adjacent dysplasia may instead represent a single developmental lesion with distinct parts distributed along a histopathologic continuum. Moreover, the possibility that this adjacent dyslamination is of minor epileptogenic relevance should also be entertained. Surgical data show that complete resection of the solid tumors and immediately adjacent tissue harboring satellites may disrupt epileptogenic networks and lead to high rates of seizure freedom, challenging the epileptogenic relevance of more extensive adjacent dyslaminated cortex. Whether the latter is a primary or secondary abnormality and whether dyslaminated cortex in the context of a second lesion may produce seizures after complete resection of the main lesion is still to be proven. Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.

Biomechanical performance of rigid compared to dynamic anterior cervical plating: analysis of adjacent upper and lower level compressive forces.

PubMed

Connor, David E; Shamieh, Khader Samer; Ogden, Alan L; Mukherjee, Debi P; Sin, Anthony; Nanda, Anil

2012-12-01

Dynamic anterior cervical plating is well established as a means of enhancing graft loading and subsequent arthrodesis. Current concerns center on the degree of adjacent-level stress induced by these systems. The aim of this study was to evaluate and compare the load transferred to adjacent levels for single-level anterior cervical discectomy and fusion utilizing rigid compared to dynamic anterior plating systems. Nine cadaveric adult human cervical spine specimens were subjected to range-of-motion testing prior to and following C5-C6 anterior cervical discectomy and fusion procedures. Interbody grafting was performed with human fibula tissue. Nondestructive biomechanical testing included flexion/extension and lateral bending loading modes. A constant displacement of 5mm was applied in each direction and the applied load was measured in newtons (N). Specimens were tested in the following order: intact, following discectomy, after rigid plating, then after dynamic plating. Adjacent level (C4-C5 [L(S)] and C6-C7 [L(I)]) compressive forces were measured using low profile load cells inserted into each disc space. The measured load values for plating systems were then normalized using values measured for the intact specimens. Mean loads transferred to L(S) and L(I) during forced flexion in specimens with rigid plating were 23.47 N and 8.76 N, respectively; while the corresponding values in specimens with dynamic plating were 18.55 N and 1.03 N, respectively. Dynamic plating yielded no significant change at L(I) and a 21.0% decrease in load at L(S) when compared with rigid plating, although the difference was not significant. The observed trend suggests that dynamic plating may diminish superior adjacent level compressive stresses. Copyright © 2012 Elsevier Ltd. All rights reserved.

Prostate cancer in native Japanese and Japanese-American men: effects of dietary differences on prostatic tissue.

PubMed

Marks, Leonard S; Kojima, Munekado; Demarzo, Angelo; Heber, David; Bostwick, David G; Qian, Junqi; Dorey, Frederick J; Veltri, Robert W; Mohler, James L; Partin, Alan W

2004-10-01

To investigate the relationship between diet and prostate cancer (CaP) among native Japanese (NJ) and second-generation or third-generation Japanese-American (J-A) men--focusing on the effects of animal fat and soy on prostatic tissues. The subjects were 50 Japanese men undergoing radical prostatectomy, 25 NJ living in Nagoya, Japan and 25 U.S.-born J-A men, living in Los Angeles, California. A priori, the NJ men were believed to be a low-fat, high-soy group and the J-A men, a high-fat, low-soy group. The studies included postoperative measurements of diet (Block questionnaire), body fat (bioimpedance), blood, urine, and prostatic biomarkers in malignant and adjacent normal tissue, using a tissue microarray made from the original paraffin blocks. The NJ and J-A men were similar in age (65 to 70 years old; P <0.05), prostate-specific antigen level (7.1 to 8.6 ng/mL), prostate volume (35 to 38 cm3), and Gleason score (5.6 to 6.6), but their body composition differed. J-A men had more body fat (24% versus 19%), higher serum triglyceride levels (245 versus 106 mg/dL), lower estradiol levels (27 versus 31 ng/mL), and much lower urinary soy-metabolite levels (1:3) than NJ men (P <0.02). In both NJ and J-A groups, expression of numerous tissue biomarkers separated normal from CaP tissue, including markers for apoptosis (Bcl-2, caspase-3), growth factor receptors (epidermal growth factor receptor), racemase, 5-lipoxygenase, kinase inhibition (p27), and cell proliferation (Ki-67; all P <0.02). Furthermore, within both normal and CaP tissues, caspase-3 and 5-lipoxygenase were expressed more in NJ than in J-A men (P <0.01). Nuclear morphometry showed that the chromatin in each of the four groups (normal versus CaP, NJ versus J-A) was different (area under the curve 85% to 94%, P <0.01), despite fundamental genetic homogeneity. NJ and J-A men, products of similar genetics but differing environments, were shown to have differences in body composition that could influence CaP evolution. The CaP specimens from the NJ and J-A men were histologically similar, but tissue biomarker expression, especially of lipoxygenase and the caspase family, suggested differing mechanisms of carcinogenesis. Differences in nuclear morphometry suggested the additional possibility of gene-nutrient interactions.

Serine/arginine rich splicing factor 2 expression and clinic pathological features indicating a prognostic factor in human hepatocellular carcinoma patients.

PubMed

Wang, Pingan; Guo, Lingyu; Li, Kaipeng; Ning, Shanglei; Shi, Weichen; Liu, Zhaochen; Chen, Yuxin

2018-02-14

This research was aimed to study the expression of Serine/arginine rich splicing factor 2 (SRSF2) in tissues of hepatocellular carcinoma, and explore the relationship between the expression and the clinic pathological and prognosis of human hepatocellular carcinoma (HCC). One hundred and fifty-three pairs HCC tissues and adjacent normal tissue were collected from January 2010 to March 2013. The expression of SRSF2 gene was detected by immunohistochemistry, western blotting and real-time quantitative polymerase chain reaction (PCR), and the relationship between the expression and the clinic pathological and prognosis of HCC being analyzed. In 153 cases of hepatocellular carcinoma, SRSF2 was highly expressed in 93 cases, low expression of 60 cases, immunohistochemistry score (6.50 ± 2.82), which was significantly higher than that in adjacent normal tissues (2.94 ± 1.23) (P< 0.05). The expression of SRSF2 in HCC was not associated with gender (χ2= 0.014, P= 0.906), age (χ2= 0.007, P= 0.931), tumor size (χ2= 3.566, P= 0.059) and T stage (χ2= 2.708, P= 0.100), and was significantly correlated with tumor differentiation (χ2= 9.687, P= 0.007), lymph node metastasis (χ2= 4.827, P= 0.028), distal metastasis (χ2= 9.235, P= 0.002), tumor, node, metastasis (TNM) stage (χ2= 3.978, P= 0.046), portal vein invasion and serum alpha-fetoprotein (χ2= 14.919, P= 0.000). The expression of SRSF2 protein in hepatocellular carcinoma was positively correlated (r = 0.704, P< 0.05) with serum alpha-fetoprotein through Pearson analysis. The survival rates of SRSF2 overexpressing hepatocellular carcinoma were 74.19%, 44.09%, 26.88%, 24.73% and 21.51% at 1 year, 2 years, 3 years, 4 years and 5 years respectively, which were lower than those of SRSF2 low expression group (93.33%, 71.67%, 56.67%, 51.67% and 50.00%). SRSF2 is highly expressed in hepatocellular carcinoma and its expression increases with the degree of tumor differentiation and TNM staging. It is related to lymph node metastasis and metastasis of tumor cells, and is positively related to serum alpha fetoprotein content, and affects the postoperative survival time of HCC patients.

Treatment of multiple adjacent Miller Class I and II gingival recessions with collagen matrix and the modified coronally advanced tunnel technique.

PubMed

Molnár, Bálint; Aroca, Sofia; Keglevich, Tibor; Gera, István; Windisch, Péter; Stavropoulos, Andreas; Sculean, Anton

2013-01-01

To clinically evaluate the treatment of Miller Class I and II multiple adjacent gingival recessions using the modified coronally advanced tunnel technique combined with a newly developed bioresorbable collagen matrix of porcine origin. Eight healthy patients exhibiting at least three multiple Miller Class I and II multiple adjacent gingival recessions (a total of 42 recessions) were consecutively treated by means of the modified coronally advanced tunnel technique and collagen matrix. The following clinical parameters were assessed at baseline and 12 months postoperatively: full mouth plaque score (FMPS), full mouth bleeding score (FMBS), probing depth (PD), recession depth (RD), recession width (RW), keratinized tissue thickness (KTT), and keratinized tissue width (KTW). The primary outcome variable was complete root coverage. Neither allergic reactions nor soft tissue irritations or matrix exfoliations occurred. Postoperative pain and discomfort were reported to be low, and patient acceptance was generally high. At 12 months, complete root coverage was obtained in 2 out of the 8 patients and 30 of the 42 recessions (71%). Within their limits, the present results indicate that treatment of Miller Class I and II multiple adjacent gingival recessions by means of the modified coronally advanced tunnel technique and collagen matrix may result in statistically and clinically significant complete root coverage. Further studies are warranted to evaluate the performance of collagen matrix compared with connective tissue grafts and other soft tissue grafts.

CpG-island methylation study of liver fluke-related cholangiocarcinoma

PubMed Central

Sriraksa, R; Zeller, C; El-Bahrawy, M A; Dai, W; Daduang, J; Jearanaikoon, P; Chau-in, S; Brown, R; Limpaiboon, T

2011-01-01

Background: Genetic changes have been widely reported in association with cholangiocarcinoma (CCA), while epigenetic changes are poorly characterised. We aimed to further evaluate CpG-island hypermethylation in CCA at candidate loci, which may have potential as diagnostic or prognostic biomarkers. Methods: We analysed methylation of 26 CpG-islands in 102 liver fluke related-CCA and 29 adjacent normal samples using methylation-specific PCR (MSP). Methylation of interest loci was confirmed using pyrosequencing and/or combined bisulfite restriction analysis, and protein expression by immunohistochemistry. Results: A number of CpG-islands (OPCML, SFRP1, HIC1, PTEN and DcR1) showed frequency of hypermethylation in >28% of CCA, but not adjacent normal tissues. The results showed that 91% of CCA were methylated in at least one CpG-island. The OPCML was the most frequently methylated locus (72.5%) and was more frequently methylated in less differentiated CCA. Patients with methylated DcR1 had significantly longer overall survival (Median; 41.7 vs 21.7 weeks, P=0.027). Low-protein expression was found in >70% of CCA with methylation of OPCML or DcR1. Conclusion: Aberrant hypermethylation of certain loci is a common event in liver fluke-related CCA and may potentially contribute to cholangiocarcinogenesis. The OPCML and DcR1 might serve as methylation biomarkers in CCA that can be readily examined by MSP. PMID:21448164

Preliminary study on decreasing the expression of FOXP3 with miR-155 to inhibit diffuse large B-cell lymphoma

PubMed Central

Zhang, Jincheng; Wei, Bin; Hu, Huixian; Liu, Fanrong; Tu, Yan; Zhao, Minzhe; Wu, Dongmei

2017-01-01

The aim of the present study was to analyze the association between the transcription factor forkhead box P3 (FOXP3) and diffuse large B-cell lymphoma (DLBCL), and investigate the effect of microRNA-155 (miR-155) on the generation and development of FOXP3 in DLBCL. The reverse transcription-quantitative polymerase chain reaction (RT-qPCR) technique was used to determine the expression of FOXP3 in the human DLBCL cell lines Ly1, Ly8 and Ly10, and in normal B cells. An immunohistochemical method was used to determine FOXP3 expression in 60 DLBCL tumor and adjacent tissues, and a retrospective analysis of FOXP3 expression in tumor tissues and clinical data was performed. The lentiviral transfection technique was used to silence the miR-155 gene in mouse A20 cells to analyze the influence of miR-155 on FOXP3 in DLBCL. The A20 cell line with a silenced miR-155 gene was used to perform a tumorigenicity assay in BALB/c mice, and to compare the tumorigenicity rate and the tumor growth rate. The results identified that the expression of the transcription factor FOXP3 in the human DLBCL cell lines was increased compared with normal B cells; FOXP3 in human DLBCL tumor issues was increased compared with the tumor-adjacent tissue, and the increased expression of FOXP3 was identified as an indicator of poor prognosis of patients with DLBCL in the middle and late period; FOXP3 level decreased subsequent to silencing miR-155 in A20 cells; A20 cells with the low-expression miR-155 gene were used to determine the tumorigenicity in BALB/c mice and it was identified that the tumorigenicity of the low-expression miR-155 gene group was decreased compared with the untransfected group. Therefore, miR-155 may be a regulatory factor of FOXP3, and miR-155 may be associated with the metastasis and prognosis of patients with DLBCL. PMID:28789399

Preferential elevation of Prx I and Trx expression in lung cancer cells following hypoxia and in human lung cancer tissues.

PubMed

Kim, H J; Chae, H Z; Kim, Y J; Kim, Y H; Hwangs, T S; Park, E M; Park, Y M

2003-10-01

Transient/chronic microenvironmental hypoxia that exists within a majority of solid tumors has been suggested to have a profound influence on tumor growth and therapeutic outcome. Since the functions of novel antioxidant proteins, peroxiredoxin I (Prx I) and II, have been implicated in regulating cell proliferation, differentiation, and apoptosis, it was of our special interest to probe a possible role of Prx I and II in the context of hypoxic tumor microenvironment. Since both Prx I and II use thioredoxin (Trx) as an electron donor and Trx is a substrate for thioredoxin reductase (TrxR), we investigated the regulation of Trx and TrxR as well as Prx expression following hypoxia. Here we show a dynamic change of glutathione homeostasis in lung cancer A549 cells and an up-regulation of Prx I and Trx following hypoxia. Western blot analysis of 10 human lung cancer and paired normal lung tissues also revealed an elevated expression of Prx I and Trx proteins in lung cancer tissues. Immunohistochemical analysis of the lung cancer tissues confirmed an augmented Prx I and Trx expression in cancer cells with respect to the parenchymal cells in adjacent normal lung tissue. Based on these results, we suggest that the redox changes in lung tumor microenvironment could have acted as a trigger for the up-regulation of Prx I and Trx in lung cancer cells. Although the clinical significance of our finding awaits more rigorous future study, preferential augmentation of the Prx I and Trx in lung cancer cells may well represent an attempt of cancer cells to manipulate a dynamic redox change in tumor microenvironment in a manner that is beneficial for their proliferation and malignant progression.

Gene expression profiling of prostate tissue identifies chromatin regulation as a potential link between obesity and lethal prostate cancer.

PubMed

Ebot, Ericka M; Gerke, Travis; Labbé, David P; Sinnott, Jennifer A; Zadra, Giorgia; Rider, Jennifer R; Tyekucheva, Svitlana; Wilson, Kathryn M; Kelly, Rachel S; Shui, Irene M; Loda, Massimo; Kantoff, Philip W; Finn, Stephen; Vander Heiden, Matthew G; Brown, Myles; Giovannucci, Edward L; Mucci, Lorelei A

2017-11-01

Obese men are at higher risk of advanced prostate cancer and cancer-specific mortality; however, the biology underlying this association remains unclear. This study examined gene expression profiles of prostate tissue to identify biological processes differentially expressed by obesity status and lethal prostate cancer. Gene expression profiling was performed on tumor (n = 402) and adjacent normal (n = 200) prostate tissue from participants in 2 prospective cohorts who had been diagnosed with prostate cancer from 1982 to 2005. Body mass index (BMI) was calculated from the questionnaire immediately preceding cancer diagnosis. Men were followed for metastases or prostate cancer-specific death (lethal disease) through 2011. Gene Ontology biological processes differentially expressed by BMI were identified using gene set enrichment analysis. Pathway scores were computed by averaging the signal intensities of member genes. Odds ratios (ORs) for lethal prostate cancer were estimated with logistic regression. Among 402 men, 48% were healthy weight, 31% were overweight, and 21% were very overweight/obese. Fifteen gene sets were enriched in tumor tissue, but not normal tissue, of very overweight/obese men versus healthy-weight men; 5 of these were related to chromatin modification and remodeling (false-discovery rate < 0.25). Patients with high tumor expression of chromatin-related genes had worse clinical characteristics (Gleason grade > 7, 41% vs 17%; P = 2 × 10 -4 ) and an increased risk of lethal disease that was independent of grade and stage (OR, 5.26; 95% confidence interval, 2.37-12.25). This study improves our understanding of the biology of aggressive prostate cancer and identifies a potential mechanistic link between obesity and prostate cancer death that warrants further study. Cancer 2017;123:4130-4138. © 2017 American Cancer Society. © 2017 American Cancer Society.

NASA SMART Probe: Breast Cancer Application

NASA Technical Reports Server (NTRS)

Mah, Robert W.; Norvig, Peter (Technical Monitor)

2000-01-01

There is evidence in breast cancer and other malignancies that the physiologic environment within a tumor correlates with clinical outcome. We are developing a unique percutaneous Smart Probe to be used at the time of needle biopsy of the breast. The Smart Probe will simultaneously measure multiple physiologic parameters within a breast tumor. Direct and indirect measurements of tissue oxygen levels, blood flow, pH, and tissue fluid pressure will be analyzed in real-time. These parameters will be interpreted individually and collectively by innovative neural network techniques using advanced intelligent software. The goals are 1) develop a pecutaneous Smart Probe with multiple sensor modalities and applying advanced Information Technologies to provide real time diagnostic information of the tissue at tip of the probe, 2) test the percutaneous Smart Probe in women with benign and malignant breast masses who will be undergoing surgical biopsy, 3) correlate probe sensor data with benign and malignant status of breast masses, 4) determine whether the probe can detect physiologic differences within a breast tumor, and its margins, and in adjacent normal breast tissue, 5) correlate probe sensor data with known prognostic factors for breast caner, including tumor size, tumor grade, axillary lymph node metastases, estrogen receptor and progesterone receptor status.

Prognostic significance of kynurenine 3-monooxygenase and effects on proliferation, migration, and invasion of human hepatocellular carcinoma

PubMed Central

Jin, Haojie; Zhang, Yurong; You, Haiyan; Tao, Xuemei; Wang, Cun; Jin, Guangzhi; Wang, Ning; Ruan, Haoyu; Gu, Dishui; Huo, Xisong; Cong, Wenming; Qin, Wenxin

2015-01-01

Kynurenine 3-monooxygenase (KMO) is a pivotal enzyme in the kynurenine pathway of tryptophan degradation and plays a critical role in Huntington’s and Alzheimer’s diseases. This study aimed to examine the expression of KMO in human hepatocellular carcinoma (HCC) and investigate the relationship between its expression and prognosis of HCC patients. We first analyzed KMO expression in 120 paired HCC samples (HCC tissues vs matched adjacent non-cancerous liver tissues), and 205 clinical HCC specimens using immunohistochemistry (IHC). Kaplan-Meier survival and Cox regression analyses were executed to evaluate the prognosis of HCC. The results of IHC analysis showed that KMO expression was significantly higher in HCC tissues than that in normal liver tissues (all p < 0.05). Survival and recurrence analyses showed that KMO was an independent prognostic factor for overall survival (OS) and time to recurrence (TTR) (both p<0.01). And in vitro studies revealed that KMO positively regulated proliferation, migration, and invasion of HCC cells. These results suggest that KMO exhibits tumor-promoting effects towards HCC and it may serve as a novel prognostic marker in HCC. PMID:26099564

Modified nucleoside triphosphates exist in mammals† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c7sc05472f

PubMed Central

Jiang, Han-Peng; Xiong, Jun; Liu, Fei-Long; Ma, Cheng-Jie; Tang, Xing-Lin; Feng, Yu-Qi

2018-01-01

DNA and RNA contain diverse chemical modifications that exert important influences in a variety of cellular processes. In addition to enzyme-mediated modifications of DNA and RNA, previous in vitro studies showed that pre-modified nucleoside triphosphates (NTPs) can be incorporated into DNA and RNA during replication and transcription. Herein, we established a chemical labeling method in combination with liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) analysis for the determination of endogenous NTPs in the mammalian cells and tissues. We synthesized 8-(diazomethyl)quinoline (8-DMQ) that could efficiently react with the phosphate group under mild condition to label NTPs. The developed method allowed sensitive detection of NTPs, with the detection limits improved by 56–137 folds. The results showed that 12 types of endogenous modified NTPs were distinctly determined in the mammalian cells and tissues. In addition, the majority of these modified NTPs exhibited significantly decreased contents in human hepatocellular carcinoma (HCC) tissues compared to tumor-adjacent normal tissues. Taken together, our study revealed the widespread existence of various modified NTPs in eukaryotes. PMID:29780546

Myosin phosphatase Fine-tunes Zebrafish Motoneuron Position during Axonogenesis

PubMed Central

Granato, Michael

2016-01-01

During embryogenesis the spinal cord shifts position along the anterior-posterior axis relative to adjacent tissues. How motor neurons whose cell bodies are located in the spinal cord while their axons reside in adjacent tissues compensate for such tissue shift is not well understood. Using live cell imaging in zebrafish, we show that as motor axons exit from the spinal cord and extend through extracellular matrix produced by adjacent notochord cells, these cells shift several cell diameters caudally. Despite this pronounced shift, individual motoneuron cell bodies stay aligned with their extending axons. We find that this alignment requires myosin phosphatase activity within motoneurons, and that mutations in the myosin phosphatase subunit mypt1 increase myosin phosphorylation causing a displacement between motoneuron cell bodies and their axons. Thus, we demonstrate that spinal motoneurons fine-tune their position during axonogenesis and we identify the myosin II regulatory network as a key regulator. PMID:27855159

Use of a Piezosurgery Technique to Remove a Deeply Impacted Supernumerary Tooth in the Anterior Maxilla

PubMed Central

Sukegawa, Shintaro; Kanno, Takahiro; Kawakami, Kiyokazu; Shibata, Akane; Takahashi, Yuka; Furuki, Yoshihiko

2015-01-01

Deeply impacted supernumerary teeth in the anterior maxillary cannot be generally removed by the conventional labial or palatal surgical approach because of the risk of damaging the surrounding soft tissues and the possibility of injuring the roots of adjacent permanent teeth. In piezosurgery, bony tissues are selectively cut, thereby avoiding the soft tissue damage caused by rotary cutting instruments. We report the case of a 15-year-old Japanese boy from whom a deeply impacted supernumerary tooth in the anterior maxillary was safely removed through the floor of the nasal cavity. The surgical extraction was performed without damaging the nasal mucosa or adjacent structures such as the roots of the adjacent permanent teeth. Considering that piezosurgery limits the extent of surgical invasion, this technique can be practiced as a minimally invasive and safe surgical procedure for treating suitably selected cases with a deeply impacted supernumerary tooth. PMID:26779355

Metallic wear in failed titanium-alloy total hip replacements. A histological and quantitative analysis.

PubMed

Agins, H J; Alcock, N W; Bansal, M; Salvati, E A; Wilson, P D; Pellicci, P M; Bullough, P G

1988-03-01

We conducted extensive histological examination of the tissues that were adjacent to the prosthesis in nine hips that had a failed total arthroplasty. The prostheses were composed of titanium alloy (Ti-6Al-4V) and ultra-high molecular weight polyethylene. The average time that the prosthesis had been in place in the tissue was 33.5 months (range, eleven to fifty-seven months). Seven arthroplasties were revised because of aseptic loosening and two, for infection. In eight hips cement had been used and in one (that had a porous-coated implant for fifty-two months) no cement had been utilized. Intense histiocytic and plasma-cell reaction was noted in the pseudocapsular tissue. There was copious metallic staining of the lining cells. Polyethylene debris and particles of cement with concomitant giant-cell reaction were present in five hips. Atomic absorption spectrophotometry revealed values for titanium of fifty-sic to 3700 micrograms per gram of dry tissue (average, 1047 micrograms per gram; normal, zero microgram per gram), for aluminum of 2.1 to 396 micrograms per gram (average, 115 micrograms per gram; normal, zero micrograms per gram), and for vanadium of 2.9 to 220 micrograms per gram (average, sixty-seven micrograms per gram; normal, 1.2 micrograms per gram). The highest values were found in the hip in which surgical revision was performed at fifty-seven months. The concentrations of the three elements in the soft tissues were similar to those in the metal of the prostheses. The factors to which failure was attributed were: vertical orientation of the acetabular component (five hips), poor cementing technique on the femoral side (three hips), infection (two hips), and separation of a sintered pad made of pure titanium (one hip). A femoral component that is made of titanium alloy can undergo severe wear of the surface and on the stem, where it is loose, with liberation of potentially toxic local concentrations of metal debris into the surrounding tissues. It may contribute to infection and loosening.

Nicotinic cholinergic receptors in esophagus: Early alteration during carcinogenesis and prognostic value

PubMed Central

Chianello Nicolau, Marina; Pinto, Luis Felipe Ribeiro; Nicolau-Neto, Pedro; de Pinho, Paulo Roberto Alves; Rossini, Ana; de Almeida Simão, Tatiana; Soares Lima, Sheila Coelho

2016-01-01

AIM To compare expression of nicotinic cholinergic receptors (CHRNs) in healthy and squamous cell carcinoma-affected esophagus and determine the prognostic value. METHODS We performed RT-qPCR to measure the expression of CHRNs in 44 esophageal samples from healthy individuals and in matched normal surrounding mucosa, and in tumors from 28 patients diagnosed with esophageal squamous cell carcinoma (ESCC). Next, we performed correlation analysis for the detected expression of these receptors with the habits and clinico-pathological characteristics of all study participants. In order to investigate the possible correlations between the expression of the different CHRN subunits in both healthy esophagus and tissues from ESCC patients, correlation matrices were generated. Subsequently, we evaluated whether the detected alterations in expression of the various CHRNs could precede histopathological modifications during the esophageal carcinogenic processes by using receiver operating characteristic curve analysis. Finally, we evaluated the impact of CHRNA5 and CHRNA7 expression on overall survival by using multivariate analysis. RESULTS CHRNA3, CHRNA5, CHRNA7 and CHRNB4, but not CHRNA1, CHRNA4, CHRNA9 or CHRNA10, were found to be expressed in normal (healthy) esophageal mucosa. In ESCC, CHRNA5 and CHRNA7 were overexpressed as compared with patient-matched surrounding non-tumor mucosa (ESCC-adjacent mucosa; P < 0.0001 and P = 0.0091, respectively). Positive correlations were observed between CHRNA3 and CHRNB4 expression in all samples analyzed. Additionally, CHRNB4 was found to be differentially expressed in the healthy esophagus and the normal-appearing ESCC-adjacent mucosa, allowing for distinguishment between these tissues with a sensitivity of 75.86% and a specificity of 78.95% (P = 0.0002). Finally, CHRNA5 expression was identified as an independent prognostic factor in ESCC; patients with high CHRNA5 expression showed an increased overall survival, in comparison with those with low expression. The corresponding age- and tumor stage-adjusted hazard ratio was 0.2684 (95%CI: 0.075-0.97, P = 0.0448). CONCLUSION Expression of CHRNs is homogeneous along healthy esophagus and deregulated in ESCC, suggesting a pathogenic role for these receptors in ESCC development and progression. PMID:27610024

Nicotinic cholinergic receptors in esophagus: Early alteration during carcinogenesis and prognostic value.

PubMed

Chianello Nicolau, Marina; Pinto, Luis Felipe Ribeiro; Nicolau-Neto, Pedro; de Pinho, Paulo Roberto Alves; Rossini, Ana; de Almeida Simão, Tatiana; Soares Lima, Sheila Coelho

2016-08-21

To compare expression of nicotinic cholinergic receptors (CHRNs) in healthy and squamous cell carcinoma-affected esophagus and determine the prognostic value. We performed RT-qPCR to measure the expression of CHRNs in 44 esophageal samples from healthy individuals and in matched normal surrounding mucosa, and in tumors from 28 patients diagnosed with esophageal squamous cell carcinoma (ESCC). Next, we performed correlation analysis for the detected expression of these receptors with the habits and clinico-pathological characteristics of all study participants. In order to investigate the possible correlations between the expression of the different CHRN subunits in both healthy esophagus and tissues from ESCC patients, correlation matrices were generated. Subsequently, we evaluated whether the detected alterations in expression of the various CHRNs could precede histopathological modifications during the esophageal carcinogenic processes by using receiver operating characteristic curve analysis. Finally, we evaluated the impact of CHRNA5 and CHRNA7 expression on overall survival by using multivariate analysis. CHRNA3, CHRNA5, CHRNA7 and CHRNB4, but not CHRNA1, CHRNA4, CHRNA9 or CHRNA10, were found to be expressed in normal (healthy) esophageal mucosa. In ESCC, CHRNA5 and CHRNA7 were overexpressed as compared with patient-matched surrounding non-tumor mucosa (ESCC-adjacent mucosa; P < 0.0001 and P = 0.0091, respectively). Positive correlations were observed between CHRNA3 and CHRNB4 expression in all samples analyzed. Additionally, CHRNB4 was found to be differentially expressed in the healthy esophagus and the normal-appearing ESCC-adjacent mucosa, allowing for distinguishment between these tissues with a sensitivity of 75.86% and a specificity of 78.95% (P = 0.0002). Finally, CHRNA5 expression was identified as an independent prognostic factor in ESCC; patients with high CHRNA5 expression showed an increased overall survival, in comparison with those with low expression. The corresponding age- and tumor stage-adjusted hazard ratio was 0.2684 (95%CI: 0.075-0.97, P = 0.0448). Expression of CHRNs is homogeneous along healthy esophagus and deregulated in ESCC, suggesting a pathogenic role for these receptors in ESCC development and progression.

Neutral endopeptidase: variable expression in human lung, inactivation in lung cancer, and modulation of peptide-induced calcium flux.

PubMed

Cohen, A J; Bunn, P A; Franklin, W; Magill-Solc, C; Hartmann, C; Helfrich, B; Gilman, L; Folkvord, J; Helm, K; Miller, Y E

1996-02-15

Neutral endopeptidase (NEP; CALLA, CD10, EC 3.4.24.11) is a cell surface endopeptidase that hydrolyses bioactive peptides, including the bombesin-like peptides, as well as other neuropeptides. Bombesin-like peptides and other neuropeptides are autocrine growth factors for both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Low expression of NEP has been reported in SCLC and NSCLC cell lines. NEP inhibition has been shown to increase proliferation in one cell line. To date, NEP expression has not been quantitatively evaluated in normal adult lung, SCLC or NSCLC tumors, paired uninvolved lung from the same patient, or in other pulmonary neoplasms such as mesotheliomas and carcinoids. We examined the expression of NEP in these tissues and human cell lines using immunohistochemistry, flow cytometry, enzyme activity, ELISA, Western blot, and reverse transcription (RT)-PCR. Uninvolved lung tissue from different individuals displayed considerable variation in NEP activity and protein. By immunohistochemistry, NEP expression was detectable in alveolar and airway epithelium, fibroblasts of normal lung, and in mesotheliomas, whereas it was undetectable in most SCLC, adenocarcinoma, squamous cell carcinoma, and carcinoid tumors of the lung. NEP activity and protein levels were lower in all SCLC and adenocarcinoma tumors when compared to adjacent uninvolved lung, often at levels consistent with expression derived from contaminating stroma. NEP expression and activity were reduced or undetectable in most SCLC and lung adenocarcinoma cell lines. NEP mRNA by RT-PCR was not expressed or was in low abundance in the majority of lung cancer cell lines. The majority of lung tumors did not express NEP by RT-PCR as compared with normal adjacent lung. In addition, recombinant NEP abolished, whereas an NEP inhibitor potentiated, the calcium flux generated by neuropeptides in some lung cancer cell lines, demonstrating potential physiological significance for low NEP expression. NEP, therefore, is a signal transduction and possibly a growth modulator for both SCLC and NSCLC, emphasizing the role of neuropeptides in the pathogenesis of the major histological forms of lung cancer.

Association of proteasomal activity with metastasis in luminal breast cancer

NASA Astrophysics Data System (ADS)

Shashova, E. E.; Fesik, E. A.; Doroshenko, A. V.

2017-09-01

Chimotrypsin-like (ChTL) and caspase-like (CL) proteasomal activities were investigated in different variants of the tumor progression of luminal breast cancer. Patients with primary luminal breast cancer (n = 123) in stage T1-3N0-2M0 who had not received neoadjuvant treatment were included in this study. Proteasome ChTL and CL activities were determined in the samples of tumor and adjacent tissues. The coefficients of chymotrypsin-like (kChTL) and caspase-like (kCL) proteasome activity were also calculated as the ratio of the corresponding activity in the tumor tissue to activity in the adjacent tissue. ChTL, CL, kChTL and kCL in the tissues of luminal A and B breast cancer with lymphogenic metastasis were compared, and their association with hematogenous metastasis was evaluated. On the one hand, CL activity of proteasomes increased in luminal A breast cancer with extensive lymphogenic metastasis (N2), on the other hand it decreased in the luminal B subtype of cancer. The ratio of proteasomal activity in the tumor and adjacent tissues plays a significant role in the hematogenic pathway of breast cancer progression and is associated with poor metastatic-free survival.

Protons and more: state of the art in radiotherapy.

PubMed

Hoskin, Peter J; Bhattacharya, Indrani S

2014-12-01

The purpose of modern radiotherapy is to deliver a precise high dose of radiation which will result in reproductive death of the cells. Radiation should transverse within the tumour volume whilst minimising damage to surrounding normal tissue. Overall 40% of cancers which are cured will have received radiotherapy. Current state of the art treatment will incorporate cross-sectional imaging and multiple high energy X-ray beams in processes called intensity modulated radiotherapy and image guided radiotherapy. Brachytherapy enables very high radiation doses to be delivered by the direct passage of a radiation source through or within the tumour volume and similar results can be achieved using rotational stereotactic X-ray beam techniques. Protons have the characteristics of particle beams which deposit their energy in a finite fixed peak at depth in tissue with no dose beyond this point - the Bragg peak. This has advantages in certain sites such as the spine adjacent to the spinal cord and particularly in children when the overall volume of tissue receiving radiation can be minimised. © 2014 Royal College of Physicians.

Long telomere length predicts poor clinical outcome in esophageal cancer patients.

PubMed

Lv, Yanyan; Zhang, Yong; Li, Xinru; Ren, Xiaojuan; Wang, Meichen; Tian, Sijia; Hou, Peng; Shi, Bingyin; Yang, Qi

2017-02-01

Abnormal telomere length is widely reported in various human cancers, and it is considered to be an important hallmark of cancer. However, there is remarkably little consensus on the value of telomere length in the prognostic evaluation of esophageal cancers. Here, we attempted to determine the association of variable telomere length with clinical outcome of esophageal cancer patients. Using real-time quantitative PCR, we examined relative telomere lengths (RTL) in a cohort of esophageal cancer and normal esophageal tissues, and statistically investigated the association between RTL and clinical outcomes of esophageal cancer patients. The majority of esophageal cancers in this study had longer RTLs as compared to adjacent non-tumor tissues. Enhanced tumor RTL was associated with smoking habit, poor differentiation, advanced tumor stage, lymph node metastasis and cancer related death. In particular, a close relationship between longer RTL and poor survival was fully demonstrated by using cox regression and Kaplan-Maier survival curves. We found frequent telomere elongation in esophageal cancer tissues, and demonstrated longer RTL may be an independent poor prognostic factor for esophageal cancer patients. Copyright © 2016 Elsevier GmbH. All rights reserved.

miR-204 inhibits angiogenesis and promotes sensitivity to cetuximab in head and neck squamous cell carcinoma cells by blocking JAK2-STAT3 signaling.

PubMed

Wu, Qingwei; Zhao, Yingying; Wang, Peihua

2018-03-01

This study aims to investigate the roles of miR-204 in tumor angiogenesis of head and neck squamous cell carcinoma (HNSCC). Here, we found that miR-204 level was reduced in HNSCC tissues relative to that in normal adjacent tissues. Overexpression of miR-204 promoted tumor angiogenesis in HNSCC cells. Mechanistically, JAK2 was identified as a direct target of miR-204, and miR-204 overexpression blocked JAK2/STAT3 pathway. Moreover, overexpression of JAK2 attenuated the inhibition of miR-204 on tumor angiogenesis of HNSCC. Furthermore, overexpression of miR-204 enhanced sensitivity of cetuximab in HNSCC cells, this effect was attenuated by JAK2 overexpression too. Importantly, JAK2 expression was negatively correlated with miR-204 level in HNSCC tissues. Therefore, miR-204 acts as a tumor suppressor by blocking JAK2/STAT3 pathway in HNSCC cells. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Bacteriome and mycobiome associations in oral tongue cancer.

PubMed

Mukherjee, Pranab K; Wang, Hannah; Retuerto, Mauricio; Zhang, Huan; Burkey, Brian; Ghannoum, Mahmoud A; Eng, Charis

2017-11-14

Squamous cell carcinoma of the oral (mobile) tongue (OMTC), a non-human papilloma virus-associated oral cancer, is rapidly increasing without clear etiology. Poor oral hygiene has been associated with oral cancers, suggesting that oral bacteriome (bacterial community) and mycobiome (fungal community) could play a role. While the bacteriome is increasingly recognized as an active participant in health, the role of the mycobiome has not been studied in OMTC. Tissue DNA was extracted from 39 paired tumor and adjacent normal tissues from patients with OMTC. Microbiome profiling, principal coordinate, and dissimilarity index analyses showed bacterial diversity and richness, and fungal richness, were significantly reduced in tumor tissue (TT) compared to their matched non-tumor tissues (NTT, P <0.006). Firmicutes was the most abundant bacterial phylum, which was significantly increased in TT compared to NTT (48% vs. 40%, respectively; P =0.004). Abundance of Bacteroidetes and Fusobacteria were significantly decreased in TT compared to matched NTT ( P ≤0.003 for both). Abundance of 22 bacterial and 7 fungal genera was significantly different between the TT and NTT, including Streptococcus , which was the most abundant and significantly increased in the tumor group (34% vs. 22%, P <0.001). Abundance of fungal genus Aspergillus in TT correlated negatively with bacteria ( Actinomyces, Prevotella , Streptococcus) , but positively with Aggregatibacter . Patients with high T-stage disease had lower mean differences between TT and NTT compared with patients with low T-stage disease (0.07 vs. 0.21, P =0.04). Our results demonstrate differences in bacteriome and mycobiome between OMTC and their matched normal oral epithelium, and their association with T-stage.

The Prognostic Value of Epithelial Membrane Protein 1 (EMP-1) in Patients with Laryngeal Carcinoma

PubMed Central

Liu, Chang; Wei, Xiaojun; Li, Feng; Wang, Li; Ruan, Xinjian; Jia, Jia; Zhang, Xia

2017-01-01

Background In the present study, we aimed to investigate the prognostic value of epithelial membrane protein 1 (EMP-1) gene in patients diagnosed with laryngeal carcinoma (LC). Material/Methods Patients who were pathologically diagnosed with LC were enrolled in the present study. The expression levels of EMP-1 in tumor tissues and corresponding normal tissues collected from the LC patients were detected by semi-reverse transcriptase polymerase chain reaction (semi-RT-PCR). Chi-square analysis was used to evaluate the relationship between EMP-1 expression level and clinical characteristics. Survival analysis for the study population was analyzed by Kaplan-Meier method with log rank test. Additionally, Cox regression model was applied to evaluate the prognostic value of EMP-1 in LC patients. Results 106 LC patients, including 55 men and 51 women, were enrolled in the present study. Semi-RT-PCR demonstrated that the expression level of EMP-1 was decreased in tumor tissues, compared with adjacent normal tissues (p<0.001). Moreover, the level was significantly associated with lymph node metastasis, histological grade, and clinical stage (p<0.05 for all). In addition, low levels of EMP-1 was significantly correlated with poor survival rate (log rank test, p=0.020). Cox regression analysis indicated that EMP-1 was an independent marker for LC prognosis (HR=2.755, 95% CI=1.123–6.760, p=0.027). Conclusions The abnormal expression of EMP-1 may be associated with progression of LC and the gene may act as a prognostic marker for LC. PMID:28779068

The Prognostic Value of Epithelial Membrane Protein 1 (EMP-1) in Patients with Laryngeal Carcinoma.

PubMed

Liu, Chang; Wei, Xiaojun; Li, Feng; Wang, Li; Ruan, Xinjian; Jia, Jia; Zhang, Xia

2017-08-05

BACKGROUND In the present study, we aimed to investigate the prognostic value of epithelial membrane protein 1 (EMP-1) gene in patients diagnosed with laryngeal carcinoma (LC). MATERIAL AND METHODS Patients who were pathologically diagnosed with LC were enrolled in the present study. The expression levels of EMP-1 in tumor tissues and corresponding normal tissues collected from the LC patients were detected by semi-reverse transcriptase polymerase chain reaction (semi-RT-PCR). Chi-square analysis was used to evaluate the relationship between EMP-1 expression level and clinical characteristics. Survival analysis for the study population was analyzed by Kaplan-Meier method with log rank test. Additionally, Cox regression model was applied to evaluate the prognostic value of EMP-1 in LC patients. RESULTS 106 LC patients, including 55 men and 51 women, were enrolled in the present study. Semi-RT-PCR demonstrated that the expression level of EMP-1 was decreased in tumor tissues, compared with adjacent normal tissues (p<0.001). Moreover, the level was significantly associated with lymph node metastasis, histological grade, and clinical stage (p<0.05 for all). In addition, low levels of EMP-1 was significantly correlated with poor survival rate (log rank test, p=0.020). Cox regression analysis indicated that EMP-1 was an independent marker for LC prognosis (HR=2.755, 95% CI=1.123-6.760, p=0.027). CONCLUSIONS The abnormal expression of EMP-1 may be associated with progression of LC and the gene may act as a prognostic marker for LC.

Modeling and stress analyses of a normal foot-ankle and a prosthetic foot-ankle complex.

PubMed

Ozen, Mustafa; Sayman, Onur; Havitcioglu, Hasan

2013-01-01

Total ankle replacement (TAR) is a relatively new concept and is becoming more popular for treatment of ankle arthritis and fractures. Because of the high costs and difficulties of experimental studies, the developments of TAR prostheses are progressing very slowly. For this reason, the medical imaging techniques such as CT, and MR have become more and more useful. The finite element method (FEM) is a widely used technique to estimate the mechanical behaviors of materials and structures in engineering applications. FEM has also been increasingly applied to biomechanical analyses of human bones, tissues and organs, thanks to the development of both the computing capabilities and the medical imaging techniques. 3-D finite element models of the human foot and ankle from reconstruction of MR and CT images have been investigated by some authors. In this study, data of geometries (used in modeling) of a normal and a prosthetic foot and ankle were obtained from a 3D reconstruction of CT images. The segmentation software, MIMICS was used to generate the 3D images of the bony structures, soft tissues and components of prosthesis of normal and prosthetic ankle-foot complex. Except the spaces between the adjacent surface of the phalanges fused, metatarsals, cuneiforms, cuboid, navicular, talus and calcaneus bones, soft tissues and components of prosthesis were independently developed to form foot and ankle complex. SOLIDWORKS program was used to form the boundary surfaces of all model components and then the solid models were obtained from these boundary surfaces. Finite element analyses software, ABAQUS was used to perform the numerical stress analyses of these models for balanced standing position. Plantar pressure and von Mises stress distributions of the normal and prosthetic ankles were compared with each other. There was a peak pressure increase at the 4th metatarsal, first metatarsal and talus bones and a decrease at the intermediate cuneiform and calcaneus bones, in prosthetic ankle-foot complex compared to normal one. The predicted plantar pressures and von Misses stress distributions for a normal foot were consistent with other FE models given in the literature. The present study is aimed to open new approaches for the development of ankle prosthesis.

Gene profiling, biomarkers and pathways characterizing HCV-related hepatocellular carcinoma

PubMed Central

De Giorgi, Valeria; Monaco, Alessandro; Worchech, Andrea; Tornesello, MariaLina; Izzo, Francesco; Buonaguro, Luigi; Marincola, Francesco M; Wang, Ena; Buonaguro, Franco M

2009-01-01

Background Hepatitis C virus (HCV) infection is a major cause of hepatocellular carcinoma (HCC) worldwide. The molecular mechanisms of HCV-induced hepatocarcinogenesis are not yet fully elucidated. Besides indirect effects as tissue inflammation and regeneration, a more direct oncogenic activity of HCV can be postulated leading to an altered expression of cellular genes by early HCV viral proteins. In the present study, a comparison of gene expression patterns has been performed by microarray analysis on liver biopsies from HCV-positive HCC patients and HCV-negative controls. Methods Gene expression profiling of liver tissues has been performed using a high-density microarray containing 36'000 oligos, representing 90% of the human genes. Samples were obtained from 14 patients affected by HCV-related HCC and 7 HCV-negative non-liver-cancer patients, enrolled at INT in Naples. Transcriptional profiles identified in liver biopsies from HCC nodules and paired non-adjacent non-HCC liver tissue of the same HCV-positive patients were compared to those from HCV-negative controls by the Cluster program. The pathway analysis was performed using the BRB-Array- Tools based on the "Ingenuity System Database". Significance threshold of t-test was set at 0.001. Results Significant differences were found between the expression patterns of several genes falling into different metabolic and inflammation/immunity pathways in HCV-related HCC tissues as well as the non-HCC counterpart compared to normal liver tissues. Only few genes were found differentially expressed between HCV-related HCC tissues and paired non-HCC counterpart. Conclusion In this study, informative data on the global gene expression pattern of HCV-related HCC and non-HCC counterpart, as well as on their difference with the one observed in normal liver tissues have been obtained. These results may lead to the identification of specific biomarkers relevant to develop tools for detection, diagnosis, and classification of HCV-related HCC. PMID:19821982

Stereotactic ablative body radiotherapy combined with immunotherapy: present status and future perspectives.

PubMed

Rekers, N H; Troost, E G C; Zegers, C M L; Germeraad, W T V; Dubois, L J; Lambin, P

2014-10-01

Radiotherapy is along with surgery and chemotherapy one of the prime treatment modalities in cancer. It is applied in the primary, neoadjuvant as well as the adjuvant setting. Radiation techniques have rapidly evolved during the past decade enabling the delivery of high radiation doses, reducing side-effects in tumour-adjacent normal tissues. While increasing local tumour control, current and future efforts ought to deal with microscopic disease at a distance of the primary tumour, ultimately responsible for disease-progression. This review explores the possibility of bimodal treatment combining radiotherapy with immunotherapy. Copyright © 2014 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.

Correlation analysis of expressions of PTEN and p53 with the value obtained by magnetic resonance spectroscopy and apparent diffusion coefficient in the tumor and the tumor-adjacent area in magnetic resonance imaging for glioblastoma.

PubMed

Li, Yunyun; Ji, Feng; Jiang, Yuzhi; Zhao, Ting; Xu, Chongfu

2018-01-01

To explore the correlation of the expression levels of phosphate and tension homology deleted on chromosome ten (PTEN) and p53 of glioblastoma multiforme (GBM) with the value obtained by magnetic resonance spectroscopy (MRS) and apparent diffusion coefficient (ADC) in the tumor and the tumor-adjacent area in magnetic resonance imaging (MRI). A total of 38 patients were operated for GBM. All the patients had received diffusion-weighted imaging (DWI) and MRS prior to surgery. ADC of water molecules and values of metabolite indexes of MRS, including n-acetyl aspartate (NAA), choline (Cho) and creatine (Cr), were recorded, and the ratios of Cho/NAA, Cho/Cr and NAA/Cr were calculated. Hematoxylin-eosin (H&E) staining was done to examine the morphology of tumor and of tumor-adjacent tissues; immunohistochemistry (IHC) was performed to examine the expressions of PTEN and p53 in the tumor and the tumor-adjacent area. Finally, the correlations of the expressions of PTEN and p53 with ADC, Cho/NAA, Cho/Cr and NAA/Cr of the tumor and the tumor-adjacent area were analyzed. H&E staining showed that GBM tissues had disordered morphology, different sizes of cells, large cell nuclei and significant cell heterogeneity. IHC indicated that the expression level of p53 protein in the tumor was significantly higher than in the tumor-adjacent tissues (p<0.05). The expression level of PTEN protein was high in the tumor-adjacent tissues, but significantly deficient in the tumor. DWI showed that the signal of DWI in the tumor was significantly increased, but ADC was decreased compared with the tumor-adjacent area. MRS indicated that the wave band of Cho in the tumor was significantly increased, NAA was significantly lowered, and Cr section was decreased compared with the tumor-adjacent area, while NAA/Cr in the tumor was significantly decreased compared with the tumoradjacent area (p<0.05). Correlation analysis indicated that PTEN levels in the tumor and the tumor-adjacent area were positively correlated with ADC in the corresponding area, while p53 in the tumor and the tumor-adjacent area was negatively correlated with ADC in the corresponding area. Cho/NAA and Cho/Cr in the tumor were positively correlated with p53 in the tumor, but negatively correlated with PTEN in the tumor. However, NAA/Cr of the tumor was irrelevant to the levels of PTEN and p53. The test results of DWI and MRS of patients with GBM can accurately reflect the inactivation or mutation of PTEN and p53.

Matrix Stiffness Corresponding to Strictured Bowel Induces a Fibrogenic Response in Human Colonic Fibroblasts

PubMed Central

Johnson, Laura A.; Rodansky, Eva S.; Sauder, Kay L.; Horowitz, Jeffrey C.; Mih, Justin D.; Tschumperlin, Daniel J.; Higgins, Peter D.

2013-01-01

Background Crohn’s disease is characterized by repeated cycles of inflammation and mucosal healing which ultimately progress to intestinal fibrosis. This inexorable progression towards fibrosis suggests that fibrosis becomes inflammation-independent and auto-propagative. We hypothesized that matrix stiffness regulates this auto-propagation of intestinal fibrosis. Methods The stiffness of fresh ex vivo samples from normal human small intestine, Crohn’s disease strictures, and the unaffected margin were measured with a microelastometer. Normal human colonic fibroblasts were cultured on physiologically normal or pathologically stiff matrices corresponding to the physiological stiffness of normal or fibrotic bowel. Cellular response was assayed for changes in cell morphology, α-smooth muscle actin (αSMA) staining, and gene expression. Results Microelastometer measurements revealed a significant increase in colonic tissue stiffness between normal human colon and Crohn’s strictures as well as between the stricture and adjacent tissue margin. In Ccd-18co cells grown on stiff matrices corresponding to Crohn’s strictures, cellular proliferation increased. Pathologic stiffness induced a marked change in cell morphology and increased αSMA protein expression. Growth on a stiff matrix induced fibrogenic gene expression, decreased matrix metalloproteinase and pro-inflammatory gene expression, and was associated with nuclear localization of the transcriptional cofactor MRTF-A. Conclusions Matrix stiffness, representative of the pathological stiffness of Crohn’s strictures, activates human colonic fibroblasts to a fibrogenic phenotype. Matrix stiffness affects multiple pathways suggesting the mechanical properties of the cellular environment are critical to fibroblast function and may contribute to autopropagation of intestinal fibrosis in the absence of inflammation, thereby contributing to the intractable intestinal fibrosis characteristic of Crohn’s disease. PMID:23502354

Gene Expression Profiling of Liver Cancer Stem Cells by RNA-Sequencing

PubMed Central

Lam, Chi Tat; Ng, Michael N. P.; Yu, Wan Ching; Lau, Joyce; Wan, Timothy; Wang, Xiaoqi; Yan, Zhixiang; Liu, Hang; Fan, Sheung Tat

2012-01-01

Background Accumulating evidence supports that tumor growth and cancer relapse are driven by cancer stem cells. Our previous work has demonstrated the existence of CD90+ liver cancer stem cells (CSCs) in hepatocellular carcinoma (HCC). Nevertheless, the characteristics of these cells are still poorly understood. In this study, we employed a more sensitive RNA-sequencing (RNA-Seq) to compare the gene expression profiling of CD90+ cells sorted from tumor (CD90+CSCs) with parallel non-tumorous liver tissues (CD90+NTSCs) and elucidate the roles of putative target genes in hepatocarcinogenesis. Methodology/Principal Findings CD90+ cells were sorted respectively from tumor and adjacent non-tumorous human liver tissues using fluorescence-activated cell sorting. The amplified RNAs of CD90+ cells from 3 HCC patients were subjected to RNA-Seq analysis. A differential gene expression profile was established between CD90+CSCs and CD90+NTSCs, and validated by quantitative real-time PCR (qRT-PCR) on the same set of amplified RNAs, and further confirmed in an independent cohort of 12 HCC patients. Five hundred genes were differentially expressed (119 up-regulated and 381 down-regulated genes) between CD90+CSCs and CD90+NTSCs. Gene ontology analysis indicated that the over-expressed genes in CD90+CSCs were associated with inflammation, drug resistance and lipid metabolism. Among the differentially expressed genes, glypican-3 (GPC3), a member of glypican family, was markedly elevated in CD90+CSCs compared to CD90+NTSCs. Immunohistochemistry demonstrated that GPC3 was highly expressed in forty-two human liver tumor tissues but absent in adjacent non-tumorous liver tissues. Flow cytometry indicated that GPC3 was highly expressed in liver CD90+CSCs and mature cancer cells in liver cancer cell lines and human liver tumor tissues. Furthermore, GPC3 expression was positively correlated with the number of CD90+CSCs in liver tumor tissues. Conclusions/Significance The identified genes, such as GPC3 that are distinctly expressed in liver CD90+CSCs, may be promising gene candidates for HCC therapy without inducing damages to normal liver stem cells. PMID:22606345

The regulatory role of SLP-2 and mechanism on CCBE1 gene expression in rectal carcinoma and adjacent lymphatic tube tissues.

PubMed

Guo, R-L; Wang, X-R; Wang, Q-G; Li, Z; Lu, X; Miao, R-Z; Chang, H

2018-01-01

  The incidence of rectal carcinoma (RC) has been increasing recently, and becomes the second most common digestive tumors besides gastric cancer, with a rise in the incidence of RC in younger populations. The early diagnosis and treatment are thus critical for the improvement of survival rate and life quality of patients. Stomatin-like protein 2 (SLP-2) is a type of membrane factor, which is generally found highly expressed in various tumors. Collagen and calcium-binding EGF domain (CCBE1) belongs to lymphatic tube genesis factor. The regulatory role of SLP-2 gene on CCBE1 expression in RC tumor and adjacent lymphatic tube tissues, however, has not been studied. 52 RC patients were recruited, and tumor and adjacent lymphatic tube tissues were collected. Real-time PCR, western blotting and immunohistochemistry (IHC) staining were used to analyze SLP-2 and CCBE1 expressions. Human lymphatic endothelial cells (LECs) were cultured in vitro and were assigned to control, scramble, and SLP-2 siRNA group. MTT assay was used to detect cell proliferation, while caspase 3 activity was detected. SLP-2 and CCBE1 levels were significantly elevated in tumor lymphatic tissues, compared to that in adjacent tissues. Statistically positive correlation between SLP-1 and CCBE2 was found (p<0.05). The downregulation of SLP-2 by siRNA inhibited cell proliferation, elevated caspase3 activity, and decreased CCBE1 expression (p<0.05 compared to control group). SLP-2 is up-regulated in RC lymphatic tissues, and is positively correlated with the level of CCBE1, which provides the academic the basis for the development of medicine targeting SLP-2 in the anti-rectal carcinoma therapy.

Expression of TMPRSS4 in non-small cell lung cancer and its modulation by hypoxia

PubMed Central

NGUYEN, TRI-HUNG; WEBER, WILLIAM; HAVARI, EVIS; CONNORS, TIMOTHY; BAGLEY, REBECCA G.; McLAREN, RAJASHREE; NAMBIAR, PRASHANT R.; MADDEN, STEPHEN L.; TEICHER, BEVERLY A.; ROBERTS, BRUCE; KAPLAN, JOHANNE; SHANKARA, SRINIVAS

2012-01-01

Overexpression of TMPRSS4, a cell surface-associated transmembrane serine protease, has been reported in pancreatic, colorectal and thyroid cancers, and has been implicated in tumor cell migration and metastasis. Few reports have investigated both TMPRSS4 gene expression levels and the protein products. In this study, quantitative RT-PCR and protein staining were used to assess TMPRSS4 expression in primary non-small cell lung carcinoma (NSCLC) tissues and in lung tumor cell lines. At the transcriptional level, TMPRSS4 message was significantly elevated in the majority of human squamous cell and adenocarcinomas compared with normal lung tissues. Staining of over 100 NSCLC primary tumor and normal specimens with rabbit polyclonal anti-TMPRSS4 antibodies confirmed expression at the protein level in both squamous cell and adenocarcinomas with little or no staining in normal lung tissues. Human lung tumor cell lines expressed varying levels of TMPRSS4 mRNA in vitro. Interestingly, tumor cell lines with high levels of TMPRSS4 mRNA failed to show detectable TMPRSS4 protein by either immunoblotting or flow cytometry. However, protein levels were increased under hypoxic culture conditions suggesting that hypoxia within the tumor microenvironment may upregulate TMPRSS4 protein expression in vivo. This was supported by the observation of TMPRSS4 protein in xenograft tumors derived from the cell lines. In addition, staining of human squamous cell carcinoma samples for carbonic anhydrase IX (CAIX), a hypoxia marker, showed TMPRSS4 positive cells adjacent to CAIX positive cells. Overall, these results indicate that the cancer-associated TMPRSS4 protein is overexpressed in NSCLC and may represent a potential therapeutic target. PMID:22692880

Proteomics detection of S100A6 in tumor tissue interstitial fluid and evaluation of its potential as a biomarker of cholangiocarcinoma.

PubMed

Onsurathum, Sudarat; Haonon, Ornuma; Pinlaor, Porntip; Pairojkul, Chawalit; Khuntikeo, Narong; Thanan, Raynoo; Roytrakul, Sittiruk; Pinlaor, Somchai

2018-04-01

Tumor interstitial fluid contains tumor-specific proteins that may be useful biomarkers for cancers. In this study, we identified proteins present in cholangiocarcinoma interstitial fluid. Proteins derived from three samples of tumor interstitial fluid and paired samples of adjacent normal interstitial fluid from cholangiocarcinoma patients were subjected to two-dimensional liquid chromatography with tandem mass spectrometry. Candidate proteins were selected based on a greater than twofold change in expression levels between tumor interstitial fluid and normal interstitial fluid. Upregulation of six proteins in tumor interstitial fluid, including S100 calcium binding protein A6 (S100A6), S100 calcium binding protein A9, aldo-keto reductase family 1 member C4, neuropilin-1, 14-3-3 zeta/delta, and triosephosphate isomerase was assessed by western blot and immunohistochemistry. Their potential as markers was evaluated in human cholangiocarcinoma tissue arrays, and in serum using enzyme-linked immunosorbent assay. Expression of S100A6 was higher in tumor interstitial fluid than in normal interstitial fluid and showed the highest positive rate (98.96%) in cholangiocarcinoma tissues. Serum levels of S100A6 did not differ between cholangitis and cholangiocarcinoma patients, but were significantly higher than in healthy individuals ( p < 0.0001). In cholangiocarcinoma cases, S100A6 level was associated with vascular invasion ( p = 0.007) and could distinguish cholangiocarcinoma patients from healthy individuals as effectively as the carbohydrate antigen 19-9. In addition, potential for drug treatment targeting S100A6 and other candidate proteins was also demonstrated using STITCH analysis. In conclusion, proteomics analysis of tumor interstitial fluid could be a new approach for biomarker discovery, and S100A6 is a potential risk marker for screening of cholangiocarcinoma.

IMP3 expression is associated with poor outcome and epigenetic deregulation in intrahepatic cholangiocarcinoma.

PubMed

Gao, Yuanyuan; Yang, Michelle; Jiang, Zhong; Woda, Bruce A; Mercurio, Arthur M; Qin, Jianjie; Huang, Xinli; Zhang, Feng

2014-06-01

IMP3 is a fetal protein not expressed in normal adult tissues. IMP3 is an oncoprotein and a useful biomarker for a variety of malignancies and is associated with reduced overall survival of a number of them. IMP3 expression and its prognostic value for patients with intrahepatic cholangiocarcinoma (ICC) have not been well investigated. The molecular mechanism underlying IMP3 expression in human cancer cells remains to be elucidated. Here we investigated IMP3 expression in ICC and adjacent nonneoplastic liver in 72 unifocal primary ICCs from a single institute by immunohistochemistry, immunoblotting, and real-time polymerase chain reaction. IMP3 was specifically expressed in cancer cells but not in the surrounding normal tissue, and 59 (82%) of 72 ICCs were IMP3 positive by immunohistochemistry. Among 35 cases with lymphovascular invasion, 26 (74%) showed IMP3 positivity in lymph node metastases. IMP3 expression was significantly correlated with tumor size, pathological grade, metastasis, and clinical stage. Kaplan-Meier analysis demonstrated an inverse correlation between IMP3 expression and overall survival rate. Multivariate analysis revealed that IMP3 was the only risk factor associated with survival. To further explore the mechanism of IMP3 expression in cancers, we identified 2 CpG islands at IMP3 proximal promoter. Interestingly, the IMP3 promoter was almost completely demethylated in ICCs in contrast to densely methylated promoter in normal liver tissues. IMP3 expression is a useful biomarker for ICCs and can provide an independent prognostic value for patients with ICC. To our knoweldge, this is the first direct evidence of epigenetic deregulation of IMP3 in human cancer. Copyright © 2014 The Auhtors. Published by Elsevier Inc. All rights reserved.

Genomic profiling of 766 cancer-related genes in archived esophageal normal and carcinoma tissues.

PubMed

Chen, Jing; Guo, Liping; Peiffer, Daniel A; Zhou, Lixin; Chan, Owen Tsan Mo; Bibikova, Marina; Wickham-Garcia, Eliza; Lu, Shih-Hsin; Zhan, Qimin; Wang-Rodriguez, Jessica; Jiang, Wei; Fan, Jian-Bing

2008-05-15

We employed the BeadArraytrade mark technology to perform a genetic analysis in 33 formalin-fixed, paraffin-embedded (FFPE) human esophageal carcinomas, mostly squamous-cell-carcinoma (ESCC), and their adjacent normal tissues. A total of 1,432 single nucleotide polymorphisms (SNPs) derived from 766 cancer-related genes were genotyped with partially degraded genomic DNAs isolated from these samples. This directly targeted genomic profiling identified not only previously reported somatic gene amplifications (e.g., CCND1) and deletions (e.g., CDKN2A and CDKN2B) but also novel genomic aberrations. Among these novel targets, the most frequently deleted genomic regions were chromosome 3p (including tumor suppressor genes FANCD2 and CTNNB1) and chromosome 5 (including tumor suppressor gene APC). The most frequently amplified genomic region was chromosome 3q (containing DVL3, MLF1, ABCC5, BCL6, AGTR1 and known oncogenes TNK2, TNFSF10, FGF12). The chromosome 3p deletion and 3q amplification occurred coincidently in nearly all of the affected cases, suggesting a molecular mechanism for the generation of somatic chromosomal aberrations. We also detected significant differences in germline allele frequency between the esophageal cohort of our study and normal control samples from the International HapMap Project for 10 genes (CSF1, KIAA1804, IL2, PMS2, IRF7, FLT3, NTRK2, MAP3K9, ERBB2 and PRKAR1A), suggesting that they might play roles in esophageal cancer susceptibility and/or development. Taken together, our results demonstrated the utility of the BeadArray technology for high-throughput genetic analysis in FFPE tumor tissues and provided a detailed genetic profiling of cancer-related genes in human esophageal cancer. (c) 2008 Wiley-Liss, Inc.

Genome-wide DNA methylation measurements in prostate tissues uncovers novel prostate cancer diagnostic biomarkers and transcription factor binding patterns.

PubMed

Kirby, Marie K; Ramaker, Ryne C; Roberts, Brian S; Lasseigne, Brittany N; Gunther, David S; Burwell, Todd C; Davis, Nicholas S; Gulzar, Zulfiqar G; Absher, Devin M; Cooper, Sara J; Brooks, James D; Myers, Richard M

2017-04-17

Current diagnostic tools for prostate cancer lack specificity and sensitivity for detecting very early lesions. DNA methylation is a stable genomic modification that is detectable in peripheral patient fluids such as urine and blood plasma that could serve as a non-invasive diagnostic biomarker for prostate cancer. We measured genome-wide DNA methylation patterns in 73 clinically annotated fresh-frozen prostate cancers and 63 benign-adjacent prostate tissues using the Illumina Infinium HumanMethylation450 BeadChip array. We overlaid the most significantly differentially methylated sites in the genome with transcription factor binding sites measured by the Encyclopedia of DNA Elements consortium. We used logistic regression and receiver operating characteristic curves to assess the performance of candidate diagnostic models. We identified methylation patterns that have a high predictive power for distinguishing malignant prostate tissue from benign-adjacent prostate tissue, and these methylation signatures were validated using data from The Cancer Genome Atlas Project. Furthermore, by overlaying ENCODE transcription factor binding data, we observed an enrichment of enhancer of zeste homolog 2 binding in gene regulatory regions with higher DNA methylation in malignant prostate tissues. DNA methylation patterns are greatly altered in prostate cancer tissue in comparison to benign-adjacent tissue. We have discovered patterns of DNA methylation marks that can distinguish prostate cancers with high specificity and sensitivity in multiple patient tissue cohorts, and we have identified transcription factors binding in these differentially methylated regions that may play important roles in prostate cancer development.

Endothelin-1 stimulates colon cancer adjacent fibroblasts.

PubMed

Knowles, Jonathan P; Shi-Wen, Xu; Haque, Samer-ul; Bhalla, Ashish; Dashwood, Michael R; Yang, Shiyu; Taylor, Irving; Winslet, Marc C; Abraham, David J; Loizidou, Marilena

2012-03-15

Endothelin-1 (ET-1) is produced by and stimulates colorectal cancer cells. Fibroblasts produce tumour stroma required for cancer development. We investigated whether ET-1 stimulated processes involved in tumour stroma production by colonic fibroblasts. Primary human fibroblasts, isolated from normal tissues adjacent to colon cancers, were cultured with or without ET-1 and its antagonists. Cellular proliferation, migration and contraction were measured. Expression of enzymes involved in tumour stroma development and alterations in gene transcription were determined by Western blotting and genome microarrays. ET-1 stimulated proliferation, contraction and migration (p < 0.01 v control) and the expression of matrix degrading enzymes TIMP-1 and MMP-2, but not MMP-3. ET-1 upregulated genes for profibrotic growth factors and receptors, signalling molecules, actin modulators and extracellular matrix components. ET-1 stimulated colonic fibroblast cellular processes in vitro that are involved in developing tumour stroma. Upregulated genes were consistent with these processes. By acting as a strong stimulus for tumour stroma creation, ET-1 is proposed as a target for adjuvant cancer therapy. Copyright © 2011 UICC.

Cuboid oedema due to peroneus longus tendinopathy: a report of four cases.

PubMed

O'Donnell, Paul; Saifuddin, Asif

2005-07-01

To highlight focal bone abnormality in the cuboid due to tendinopathy of the adjacent peroneus longus. A retrospective review was carried out of the relevant clinical and imaging features. Two male and two female patients were studied, mean age 51.5 years (range 32-67 years), referred with foot pain and imaging showing an abnormal cuboid thought to represent either tumour or infection. A long history of foot pain was usual with a maximum of 8 years. Radiographs were normal in two cases and showed erosion in two, one of which exhibited periosteal new bone formation affecting the cuboid. Bone scintigraphy was undertaken in two patients, both of whom showed increased uptake of isotope. MRI, performed in all patients, showed oedema in the cuboid adjacent to the peroneus longus tendon. The tendon and/or paratendinous tissues were abnormal in all cases, but no tendon discontinuity was identified. One patient possessed an os peroneum. Unequivocal evidence of bone erosion was seen using MRI in three patients, but with greater clarity in two cases using CT. Additional findings of tenosynovitis of tibialis posterior, oedema in the adjacent medial malleolus and synovitis of multiple joints in the foot were seen in one patient. Imaging diagnosis was made in all cases avoiding bone biopsy, but surgical exploration of the peroneal tendons was performed in two cases and biopsy of ankle synovium in one. Oedema with erosion of the cuboid bone, simulating a bone lesion (cuboid "pseudotumour"), may be caused by adjacent tendinopathy of peroneus longus. It is vital to be aware of this entity to avoid unnecessary biopsy of the cuboid.

Use of the tunnel technique and an acellular dermal matrix in the treatment of multiple adjacent teeth with gingival recession in the esthetic zone.

PubMed

Mahn, Douglas H

2010-12-01

The proper management of gingival recession is critical to the establishment of a natural-appearing soft tissue architecture. Subepithelial connective tissue grafts have been considered the "gold standard" but are limited by the availability of palatal donor tissue. Tunnel techniques have improved the esthetic results of connective tissue grafting. Acellular dermal matrices have been successful in the treatment of gingival recession and are not limited by the palatal anatomy. The aim of this report is to describe the application of the tunnel technique, with use of an acellular dermal matrix, in the correction of gingival recession affecting multiple adjacent teeth in the esthetic zone.

Improved Cerebral Time-of-Flight Magnetic Resonance Angiography at 7 Tesla – Feasibility Study and Preliminary Results Using Optimized Venous Saturation Pulses

PubMed Central

Wrede, Karsten H.; Johst, Sören; Dammann, Philipp; Özkan, Neriman; Mönninghoff, Christoph; Kraemer, Markus; Maderwald, Stefan; Ladd, Mark E.; Sure, Ulrich; Umutlu, Lale; Schlamann, Marc

2014-01-01

Purpose Conventional saturation pulses cannot be used for 7 Tesla ultra-high-resolution time-of-flight magnetic resonance angiography (TOF MRA) due to specific absorption rate (SAR) limitations. We overcome these limitations by utilizing low flip angle, variable rate selective excitation (VERSE) algorithm saturation pulses. Material and Methods Twenty-five neurosurgical patients (male n = 8, female n = 17; average age 49.64 years; range 26–70 years) with different intracranial vascular pathologies were enrolled in this trial. All patients were examined with a 7 Tesla (Magnetom 7 T, Siemens) whole body scanner system utilizing a dedicated 32-channel head coil. For venous saturation pulses a 35° flip angle was applied. Two neuroradiologists evaluated the delineation of arterial vessels in the Circle of Willis, delineation of vascular pathologies, presence of artifacts, vessel-tissue contrast and overall image quality of TOF MRA scans in consensus on a five-point scale. Normalized signal intensities in the confluence of venous sinuses, M1 segment of left middle cerebral artery and adjacent gray matter were measured and vessel-tissue contrasts were calculated. Results Ratings for the majority of patients ranged between good and excellent for most of the evaluated features. Venous saturation was sufficient for all cases with minor artifacts in arteriovenous malformations and arteriovenous fistulas. Quantitative signal intensity measurements showed high vessel-tissue contrast for confluence of venous sinuses, M1 segment of left middle cerebral artery and adjacent gray matter. Conclusion The use of novel low flip angle VERSE algorithm pulses for saturation of venous vessels can overcome SAR limitations in 7 Tesla ultra-high-resolution TOF MRA. Our protocol is suitable for clinical application with excellent image quality for delineation of various intracranial vascular pathologies. PMID:25232868

L-DOPA decarboxylase mRNA expression is associated with tumor stage and size in head and neck squamous cell carcinoma: a retrospective cohort study

PubMed Central

2012-01-01

Background Head and neck squamous cell carcinoma (HNSCC) represents one of the most commonly diagnosed malignancies worldwide. The DDC gene encodes L-DOPA decarboxylase, an enzyme catalyzing the decarboxylation of L-DOPA to dopamine. We have recently shown that DDC mRNA is a significant predictor of patients’ prognosis in colorectal adenocarcinoma and prostate cancer. The aim of the current study was to analyze the DDC mRNA expression in HNSCC patients. Methods 53 malignant tumors were resected from the larynx, pharynx, tongue, buccal mucosa, parotid glands, and nasal cavity, as well as from 34 adjacent non-cancerous tissues of HNSCC patients, and were homogenized. Total RNA was isolated and converted into first-strand cDNA. An ultrasensitive real-time PCR method based on the SYBR Green chemistry was used for DDC mRNA quantification in head and neck tissue specimens. Relative quantification was performed using the comparative Ct (2-ddCt) method. Results DDC mRNA levels were lower in squamous cell carcinomas (SCCs) of the larynx and tongue than in adjacent non-cancerous tissue specimens. Furthermore, low DDC mRNA expression was noticed in laryngeal and tongue tumors of advanced TNM stage or bigger size, compared to early-stage or smaller tumors, respectively. No statistically significant differences were observed between SCCs resected from pharynx, buccal mucosa, or nasal cavity, and their normal counterparts. Conclusion This is the first study examining the DDC mRNA expression in HNSCC. According to our results, DDC mRNA expression may constitute a potential prognostic biomarker in tongue and/or larynx SCCs, which principally represent the overwhelming majority of HNSCC cases. PMID:23083099

L-DOPA decarboxylase mRNA expression is associated with tumor stage and size in head and neck squamous cell carcinoma: a retrospective cohort study.

PubMed

Geomela, Panagiota-Aikaterini; Kontos, Christos K; Yiotakis, Ioannis; Fragoulis, Emmanuel G; Scorilas, Andreas

2012-10-20

Head and neck squamous cell carcinoma (HNSCC) represents one of the most commonly diagnosed malignancies worldwide. The DDC gene encodes L-DOPA decarboxylase, an enzyme catalyzing the decarboxylation of L-DOPA to dopamine. We have recently shown that DDC mRNA is a significant predictor of patients' prognosis in colorectal adenocarcinoma and prostate cancer. The aim of the current study was to analyze the DDC mRNA expression in HNSCC patients. 53 malignant tumors were resected from the larynx, pharynx, tongue, buccal mucosa, parotid glands, and nasal cavity, as well as from 34 adjacent non-cancerous tissues of HNSCC patients, and were homogenized. Total RNA was isolated and converted into first-strand cDNA. An ultrasensitive real-time PCR method based on the SYBR Green chemistry was used for DDC mRNA quantification in head and neck tissue specimens. Relative quantification was performed using the comparative Ct (2-ddCt) method. DDC mRNA levels were lower in squamous cell carcinomas (SCCs) of the larynx and tongue than in adjacent non-cancerous tissue specimens. Furthermore, low DDC mRNA expression was noticed in laryngeal and tongue tumors of advanced TNM stage or bigger size, compared to early-stage or smaller tumors, respectively. No statistically significant differences were observed between SCCs resected from pharynx, buccal mucosa, or nasal cavity, and their normal counterparts. This is the first study examining the DDC mRNA expression in HNSCC. According to our results, DDC mRNA expression may constitute a potential prognostic biomarker in tongue and/or larynx SCCs, which principally represent the overwhelming majority of HNSCC cases.

High expression of long noncoding RNA NORAD indicates a poor prognosis and promotes clinical progression and metastasis in bladder cancer.

PubMed

Li, Qiaqia; Li, Chao; Chen, Jinbo; Liu, Peihua; Cui, Yu; Zhou, Xinyi; Li, Huihuang; Zu, Xiongbing

2018-06-01

To explore the function of NORAD in bladder cancer (BC), and to verify whether NORAD could be used as a biomarker to determine preoperative presence of progression and lymph node metastasis. To our knowledge, it is the first study investigating NORAD and its implications in BC. BC specimens of 90 patients underwent bladder cystectomy or transurethral resection between January 2012 to December 2016 were tested by fluorescence in situ hybridization. The association between NORAD expression and clinicopathological features and prognosis of the patients was analyzed using Kaplan-Meier survival analysis and Cox regression analysis. Quantitative real-time polymerase chain reaction was performed in 4 BC cell lines and 10 fresh tumor sample together with adjacent tissues. MTT, colony formation assay, and Annexin-V apoptosis detection were performed after knockdown of NORAD using shRNA in TSSCUP cells. Western blot was performed to related proteins extracted from these cells. Fluorescence in situ hybridization indicated that high NORAD expression was associated with more advanced histological grade and clinical stage for patients with BC. Higher NORAD expression resulted in lower overall survival, and was an independent prognostic indicator. Real-time polymerase chain reaction showed that the expression of NORAD in BC tissues was higher than those measured in adjacent normal tissues. MTT and colony formation assay demonstrated that knockdown of NORAD results in lower proliferation in TSSCUP cells, whereas PUM2 expression was upregulated and E2F3 downregulated. High NORAD expression could serve as an independent prognostic factor for overall survival of patients with transitional BC. NORAD could be considered as a promising candidate for novel biomarker and therapeutic target for human BC. Copyright © 2018 Elsevier Inc. All rights reserved.

Long non-coding RNA FEZF1-AS1 is up-regulated and associated with poor prognosis in patients with cervical cancer.

PubMed

Zhang, H-H; Li, A-H

2018-06-01

Long noncoding RNA FEZF1-AS1 (FEZF1-AS1) has been showed to involve in a variety of cancers. However, its function and clinical significance in cervical cancer (CC) have not been investigated. The aim of this study was to explore the prognostic value of FEZF1-AS1 in CC patients. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to determine the expression level of FEZF1-AS1 in CC specimens and adjacent normal cervical tissues. Association between FEZF1-AS1 expression and clinicopathological characteristics was analyzed x2-test. The Kaplan-Meier method was used to estimate survival curves, and the log-rank statistic was used to test the role of FEZF1-AS1 expression. The possibility of FEZF1-AS1 as a prognostic biomarker for CC was examined by Cox proportional hazard regression model. We found that FEZF1-AS1 expression levels were significantly higher in CC tissues compared with adjacent non-cancerous tissues (p < 0.01). High expressions of FEZF1-AS1 were significantly association with poorer histological grade (p = 0.004), positive distant metastasis (p = 0.002) and advanced FIGO stage (p = 0.001). Furthermore, patients with low FEZF1-AS1 expression lived shorter than those with high FEZF1-AS1 expression (Log-rank test, p < 0.0034). Cox regression analysis demonstrated that FEZF1-AS1 expression level was an independent prognostic factor for CC overall survival rates (p = 0.008). We firstly provided clinical evidence that FEZF1-AS1 may be a possible biomarker of poor prognosis in CC.

Global PROTOMAP profiling to search for biomarkers of early-recurrent hepatocellular carcinoma.

PubMed

Taoka, Masato; Morofuji, Noriaki; Yamauchi, Yoshio; Ojima, Hidenori; Kubota, Daisuke; Terukina, Goro; Nobe, Yuko; Nakayama, Hiroshi; Takahashi, Nobuhiro; Kosuge, Tomoo; Isobe, Toshiaki; Kondo, Tadashi

2014-11-07

This study used global protein expression profiling to search for biomarkers to predict early recurrent hepatocellular carcinoma (HCC). HCC tissues surgically resected from patients with or without recurrence within 2 years (early recurrent) after surgery were compared with adjacent nontumor tissue and with normal liver tissue. We used the PROTOMAP strategy for comparative profiling, which integrates denaturing polyacrylamide gel electrophoresis migratory rates and high-resolution, semiquantitative mass-spectrometry-based identification of in-gel-digested tryptic peptides. PROTOMAP allows examination of global changes in the size, topography, and abundance of proteins in complex tissue samples. This approach identified 8438 unique proteins from 45 708 nonredundant peptides and generated a proteome-wide map of changes in expression and proteolytic events potentially induced by intrinsic apoptotic/necrotic pathways. In the early recurrent HCC tissue, 87 proteins were differentially expressed (≥20-fold) relative to the other tissues, 46 of which were up-regulated or specifically proteolyzed and 41 of which were down-regulated. This data set consisted of proteins that fell into various functional categories, including signal transduction and cell organization and, notably, the major catalytic pathways responsible for liver function, such as the urea cycle and detoxification metabolism. We found that aberrant proteolysis appeared to occur frequently during recurrence of HCC in several key signal transducers, including STAT1 and δ-catenin. Further investigation of these proteins will facilitate the development of novel clinical applications.

Expression of CD147 and matrix metalloproteinase-11 in colorectal cancer and their relationship to clinicopathological features.

PubMed

Tian, Xiuyun; Ye, Chunxiang; Yang, Yongyong; Guan, Xiaoya; Dong, Bin; Zhao, Min; Hao, Chunyi

2015-10-27

This study aimed to investigate the expression of CD147 and MMP-11 in human colorectal cancer (CRC) and to evaluate their clinical significance. Real-time polymerase chain reaction was used to evaluate CD147 and MMP-11 mRNA level in 56 pairs of fresh CRC samples matched with adjacent normal mucosa. The protein expression of CD147 and MMP-11 in CRC specimens and corresponding normal colorectal mucosa were evaluated by immunohistochemistry on CRC tissue microarrays. Expression and co-localization of these two proteins in human colorectal cancer tissue were also evaluated by laser scanning confocal microscopy. Furthermore, their correlations with clinicopathological factors and overall survival after surgery were evaluated. Both CD147 and MMP-11 were demonstrated to be over-expressed at mRNA level (P < 0.001, both) and protein level (P < 0.001, both) in CRC tissue than paired normal mucosa. Spearman rank test showed a positive correlation between these two proteins (P = 0.025). Immunofluorescence double staining confirmed the co-localization of CD147 and MMP-11 in paraffin-embedded tissues of CRC patients. Expression of CD147 and MMP-11 were both correlated with CRC lymph node metastasis (P = 0.021 and P = 0.031, respectively), distant metastasis (P < 0.001 and P = 0.013, respectively) and TNM stage (P = 0.006 and P = 0.049, respectively). Univariate survival analysis showed that both CD147 and MMP11 expression was significantly associated with shorter survival time (P = 0.001 and P = 0.009, respectively). Additionally, in multivariate analysis, both CD147 and MMP-11 were proved to be independent prognostic factors (P = 0.009, 0.028, respectively). These results indicated that both CD147 and MMP-11 may be involved in the progression of colorectal cancer, and they are potential prognostic factors and might become new therapeutic targets for CRC patients.

Targeted expression of suicide gene by tissue-specific promoter and microRNA regulation for cancer gene therapy.

PubMed

Danda, Ravikanth; Krishnan, Gopinath; Ganapathy, Kalaivani; Krishnan, Uma Maheswari; Vikas, Khetan; Elchuri, Sailaja; Chatterjee, Nivedita; Krishnakumar, Subramanian

2013-01-01

In order to realise the full potential of cancer suicide gene therapy that allows the precise expression of suicide gene in cancer cells, we used a tissue specific Epithelial cell adhesion molecule (EpCAM) promoter (EGP-2) that directs transgene Herpes simplex virus-thymidine kinase (HSV-TK) expression preferentially in EpCAM over expressing cancer cells. EpCAM levels are considerably higher in retinoblastoma (RB), a childhood eye cancer with limited expression in normal cells. Use of miRNA regulation, adjacent to the use of the tissue-specific promoter, would provide the second layer of control to the transgene expression only in the tumor cells while sparing the normal cells. To test this hypothesis we cloned let-7b miRNA targets in the 3'UTR region of HSV-TK suicide gene driven by EpCAM promoter because let-7 family miRNAs, including let-7b, were found to be down regulated in the RB tumors and cell lines. We used EpCAM over expressing and let-7 down regulated RB cell lines Y79, WERI-Rb1 (EpCAM (+ve)/let-7b(down-regulated)), EpCAM down regulated, let-7 over expressing normal retinal Müller glial cell line MIO-M1(EpCAM (-ve)/let-7b(up-regulated)), and EpCAM up regulated, let-7b up-regulated normal thyroid cell line N-Thy-Ori-3.1(EpCAM (+ve)/let-7b(up-regulated)) in the study. The cell proliferation was measured by MTT assay, apoptosis was measured by probing cleaved Caspase3, EpCAM and TK expression were quantified by Western blot. Our results showed that the EGP2-promoter HSV-TK (EGP2-TK) construct with 2 or 4 copies of let-7b miRNA targets expressed TK gene only in Y79, WERI-Rb-1, while the TK gene did not express in MIO-M1. In summary, we have developed a tissue-specific, miRNA-regulated dual control vector, which selectively expresses the suicide gene in EpCAM over expressing cells.

Signaling pathways effecting crosstalk between cartilage and adjacent tissues: Seminars in cell and developmental biology: The biology and pathology of cartilage.

PubMed

Maes, Christa

2017-02-01

Endochondral ossification, the mechanism responsible for the development of the long bones, is dependent on an extremely stringent coordination between the processes of chondrocyte maturation in the growth plate, vascular expansion in the surrounding tissues, and osteoblast differentiation and osteogenesis in the perichondrium and the developing bone center. The synchronization of these processes occurring in adjacent tissues is regulated through vigorous crosstalk between chondrocytes, endothelial cells and osteoblast lineage cells. Our knowledge about the molecular constituents of these bidirectional communications is undoubtedly incomplete, but certainly some signaling pathways effective in cartilage have been recognized to play key roles in steering vascularization and osteogenesis in the perichondrial tissues. These include hypoxia-driven signaling pathways, governed by the hypoxia-inducible factors (HIFs) and vascular endothelial growth factor (VEGF), which are absolutely essential for the survival and functioning of chondrocytes in the avascular growth plate, at least in part by regulating the oxygenation of developing cartilage through the stimulation of angiogenesis in the surrounding tissues. A second coordinating signal emanating from cartilage and regulating developmental processes in the adjacent perichondrium is Indian Hedgehog (IHH). IHH, produced by pre-hypertrophic and early hypertrophic chondrocytes in the growth plate, induces the differentiation of adjacent perichondrial progenitor cells into osteoblasts, thereby harmonizing the site and time of bone formation with the developmental progression of chondrogenesis. Both signaling pathways represent vital mediators of the tightly organized conversion of avascular cartilage into vascularized and mineralized bone during endochondral ossification. Copyright © 2016. Published by Elsevier Ltd.

The dynamics of spiral tip adjacent to inhomogeneity in cardiac tissue

NASA Astrophysics Data System (ADS)

Zhang, Juan; Tang, Jun; Ma, Jun; Luo, Jin Ming; Yang, Xian Qing

2018-02-01

Rotating spiral waves in cardiac tissue are implicated in life threatening cardiac arrhythmias. Experimental and theoretical evidences suggest the inhomogeneities in cardiac tissue play a significant role in the dynamics of spiral waves. Based on a modified 2D cardiac tissue model, the interaction of inhomogeneity on the nearby rigidly rotating spiral wave is numerically studied. The adjacent area of the inhomogeneity is divided to two areas, when the initial rotating center of the spiral tip is located in the two areas, the spiral tip will be attracted and anchor on the inhomogeneity finally, or be repulsed away. The width of the area is significantly dependent on the intensity and size of the inhomogeneity. Our numerical study sheds some light on the mechanism of the interaction of inhomogeneity on the spiral wave in cardiac tissue.

Association and regulation of protein factors of field effect in prostate tissues

PubMed Central

Gabriel, Kristin N.; Jones, Anna C.; Nguyen, Julie P.T.; Antillon, Kresta S.; Janos, Sara N.; Overton, Heidi N.; Jenkins, Shannon M.; Frisch, Emily H.; Trujillo, Kristina A.; Bisoffi, Marco

2016-01-01

Field effect or field cancerization denotes the presence of molecular aberrations in structurally intact cells residing in histologically normal tissues adjacent to solid tumors. Currently, the etiology of prostate field-effect formation is unknown and there is a prominent lack of knowledge of the underlying cellular and molecular pathways. We have previously identified an upregulated expression of several protein factors representative of prostate field effect, i.e., early growth response-1 (EGR-1), platelet-derived growth factor-A (PDGF-A), macrophage inhibitory cytokine-1 (MIC-1), and fatty acid synthase (FASN) in tissues at a distance of 1 cm from the visible margin of intracapsule prostate adenocarcinomas. We have hypothesized that the transcription factor EGR-1 could be a key regulator of prostate field-effect formation by controlling the expression of PDGF-A, MIC-1, and FASN. Taking advantage of our extensive quantitative immunofluorescence data specific for EGR-1, PDGF-A, MIC-1, and FASN generated in disease-free, tumor-adjacent, and cancerous human prostate tissues, we chose comprehensive correlation as our major approach to test this hypothesis. Despite the static nature and sample heterogeneity of association studies, we show here that sophisticated data generation, such as by spectral image acquisition, linear unmixing, and digital quantitative imaging, can provide meaningful indications of molecular regulations in a physiologically relevant in situ environment. Our data suggest that EGR-1 acts as a key regulator of prostate field effect through induction of pro-proliferative (PDGF-A and FASN), and suppression of pro-apoptotic (MIC-1) factors. These findings were corroborated by computational promoter analyses and cell transfection experiments in non-cancerous prostate epithelial cells with ectopically induced and suppressed EGR-1 expression. Among several clinical applications, a detailed knowledge of pathways of field effect may lead to the development of targeted intervention strategies preventing progression from pre-malignancy to cancer. PMID:27634112

Distinction between the extracellular matrix of the nucleus pulposus and hyaline cartilage: a requisite for tissue engineering of intervertebral disc.

PubMed

Mwale, F; Roughley, P; Antoniou, J

2004-12-15

Tissue engineering of intervertebral discs (IVD) using mesenchymal stem cells (MSCs) induced to differentiate into a disc-cell phenotype has been considered as an alternative treatment for disc degeneration. However, since there is no unique marker characteristic of discs and since hyaline cartilage and immature nucleus pulposus (NP) possess similar macromolecules in their extracellular matrix, it is currently difficult to recognize MSC conversion to a disc cell. This study was performed to compare the proteoglycan to collagen ratio (measured as GAG to hydroxyproline ratio) in the NP of normal disc to that of the hyaline cartilage of the endplate within the same group of individuals and test the hypothesis that this ratio can be used for in vivo studies to distinguish between a normal NP and hyaline cartilage phenotype. Whole human lumbar spine specimens from fresh cadavers, ranging in age from 12 weeks to 79 years, were used to harvest the IVDs and adjacent endplates. The GAG to hydroxyproline ratio within the NP of young adults is approximately 27:1, whereas the ratio within the hyaline cartilage endplate of the same aged individuals is about 2:1. The production of an extracellular matrix with a high proteoglycan to collagen ratio can be used in vivo to distinguish NP cells from chondrocytes, and could help in identifying a NP-like phenotype in vivo as opposed to a chondrocyte when MSCs are induced to differentiate for tissue engineering of a disc.

Big Data Analytics for Prostate Radiotherapy.

PubMed

Coates, James; Souhami, Luis; El Naqa, Issam

2016-01-01

Radiation therapy is a first-line treatment option for localized prostate cancer and radiation-induced normal tissue damage are often the main limiting factor for modern radiotherapy regimens. Conversely, under-dosing of target volumes in an attempt to spare adjacent healthy tissues limits the likelihood of achieving local, long-term control. Thus, the ability to generate personalized data-driven risk profiles for radiotherapy outcomes would provide valuable prognostic information to help guide both clinicians and patients alike. Big data applied to radiation oncology promises to deliver better understanding of outcomes by harvesting and integrating heterogeneous data types, including patient-specific clinical parameters, treatment-related dose-volume metrics, and biological risk factors. When taken together, such variables make up the basis for a multi-dimensional space (the "RadoncSpace") in which the presented modeling techniques search in order to identify significant predictors. Herein, we review outcome modeling and big data-mining techniques for both tumor control and radiotherapy-induced normal tissue effects. We apply many of the presented modeling approaches onto a cohort of hypofractionated prostate cancer patients taking into account different data types and a large heterogeneous mix of physical and biological parameters. Cross-validation techniques are also reviewed for the refinement of the proposed framework architecture and checking individual model performance. We conclude by considering advanced modeling techniques that borrow concepts from big data analytics, such as machine learning and artificial intelligence, before discussing the potential future impact of systems radiobiology approaches.

APE/Ref-1 is increased in nuclear fractions of human thyroid hyperfunctioning nodules.

PubMed

Russo, D; Celano, M; Bulotta, S; Bruno, R; Arturi, F; Giannasio, P; Filetti, S; Damante, G; Tell, G

2002-08-30

Apurinic/apyrimidinic endonuclease APE/Ref-1 is a multifunctional protein provided with DNA repair, transcription-factor regulation and anti-apoptotic activities. We have previously reported that, in thyroid cells, TSH regulates both the synthesis and nuclear translocation of APE/Ref-1. We have also shown that nuclear levels of this protein are reduced both in thyroid carcinoma tissues and cell lines. In the present study, APE/Ref-1 expression and cellular localization were analysed by Western blot in hyperfunctioning thyroid nodules from patients with toxic adenoma and/or toxic multinodular goiter. The total content of APE/Ref-1 protein was increased in the majority of the hyperfunctioning tissues with respect to normal adjacent tissue. There was also an increase in the nuclear levels of APE/Ref-1, suggesting enhanced cytoplasm-to-nucleus translocation of the protein in addition to its increased rate of synthesis. These results demonstrate that the phenomenon of nuclear translocation of APE/Ref-1 hypothesized on the basis of cell culture experiments does actually occur in vivo. Together with previous observations in thyroid carcinomas and tumoral cell lines, our findings suggest a two-stage model of APE/Ref-1 behaviour during malignant thyrocyte transformation: an early stage characterized by simple hyperplasia and upregulation of APE/Ref-1 in the nuclear compartment of the cell and a later stage in which nuclear levels of the protein drop to below-normal levels as the cell becomes progressively undifferentiated.

Overexpression of Amyloid Precursor Protein Promotes the Onset of Seborrhoeic Keratosis and is Related to Skin Ageing.

PubMed

Li, Yuanying; Wang, Yu; Zhang, Wei; Jiang, Leiwei; Zhou, Wenming; Liu, Zhi; Li, Shijun; Lu, Hongguang

2018-02-28

Seborrhoeic keratosis is an age-related skin disease. Amyloid precursor protein (APP) plays an important role in the pathogenesis of age-related Alzheimer's disease. The aim of this study was to elucidate the expression characteristics of APP in seborrhoeic keratosis tissues (n = 50), and explore whether the production of APP is related to the onset of seborrhoeic keratosis and skin ageing, including ultraviolet (UV)-induced ageing, as observed in normal skin (n = 79). The results of immunohistochemistry, Western blotting and quantitative real-time PCR showed that APP and its downstream products (i.e. amyloid-β42) were more highly expressed in seborrhoeic keratosis than in paired adjacent normal skin tissues. In contrast, the expression of its key secretase (i.e. β-secretase1) was generally low. Furthermore, APP expression was higher in UV-exposed than non-exposed skin sites, and expression in the older age group (61-85 years) was greater than that in the younger age group (41-60 years) in seborrhoeic keratosis tissues (p<0.05). APP expression correlated positively with age in epidermis (p<0.05), but not in dermis. These findings suggest that overexpression of APP may promote the onset of seborrhoeic keratosis and is a marker of skin ageing and UV damage. Further research will elucidate whether therapeutic mitigation of increased levels of APP in the skin might delay the onset of seborrhoeic keratosis and skin ageing.

Specific Accumulation of Tumor-Derived Adhesion Factor in Tumor Blood Vessels and in Capillary Tube-Like Structures of Cultured Vascular Endothelial Cells

NASA Astrophysics Data System (ADS)

Akaogi, Kotaro; Okabe, Yukie; Sato, Junji; Nagashima, Yoji; Yasumitsu, Hidetaro; Sugahara, Kazuyuki; Miyazaki, Kaoru

1996-08-01

Tumor-derived adhesion factor (TAF) was previously identified as a cell adhesion molecule secreted by human bladder carcinoma cell line EJ-1. To elucidate the physiological function of TAF, we examined its distribution in human normal and tumor tissues. Immunochemical staining with an anti-TAF monoclonal antibody showed that TAF was specifically accumulated in small blood vessels and capillaries within and adjacent to tumor nests, but not in those in normal tissues. Tumor blood vessel-specific staining of TAF was observed in various human cancers, such as esophagus, brain, lung, and stomach cancers. Double immunofluorescent staining showed apparent colocalization of TAF and type IV collagen in the vascular basement membrane. In vitro experiments demonstrated that TAF preferentially bound to type IV collagen among various extracellular matrix components tested. In cell culture experiments, TAF promoted adhesion of human umbilical vein endothelial cells to type IV collagen substrate and induced their morphological change. Furthermore, when the endothelial cells were induced to form capillary tube-like structures by type I collagen, TAF and type IV collagen were exclusively detected on the tubular structures. The capillary tube formation in vitro was prevented by heparin, which inhibited the binding of TAF to the endothelial cells. These results strongly suggest that TAF contributes to the organization of new capillary vessels in tumor tissues by modulating the interaction of endothelial cells with type IV collagen.

Big Data Analytics for Prostate Radiotherapy

PubMed Central

Coates, James; Souhami, Luis; El Naqa, Issam

2016-01-01

Radiation therapy is a first-line treatment option for localized prostate cancer and radiation-induced normal tissue damage are often the main limiting factor for modern radiotherapy regimens. Conversely, under-dosing of target volumes in an attempt to spare adjacent healthy tissues limits the likelihood of achieving local, long-term control. Thus, the ability to generate personalized data-driven risk profiles for radiotherapy outcomes would provide valuable prognostic information to help guide both clinicians and patients alike. Big data applied to radiation oncology promises to deliver better understanding of outcomes by harvesting and integrating heterogeneous data types, including patient-specific clinical parameters, treatment-related dose–volume metrics, and biological risk factors. When taken together, such variables make up the basis for a multi-dimensional space (the “RadoncSpace”) in which the presented modeling techniques search in order to identify significant predictors. Herein, we review outcome modeling and big data-mining techniques for both tumor control and radiotherapy-induced normal tissue effects. We apply many of the presented modeling approaches onto a cohort of hypofractionated prostate cancer patients taking into account different data types and a large heterogeneous mix of physical and biological parameters. Cross-validation techniques are also reviewed for the refinement of the proposed framework architecture and checking individual model performance. We conclude by considering advanced modeling techniques that borrow concepts from big data analytics, such as machine learning and artificial intelligence, before discussing the potential future impact of systems radiobiology approaches. PMID:27379211

Novel low-kVp beamlet system for choroidal melanoma

PubMed Central

Esquivel, Carlos; Fuller, Clifton D; Waggener, Robert G; Wong, Adrian; Meltz, Martin; Blough, Melissa; Eng, Tony Y; Thomas, Charles R

2006-01-01

Background Treatment of choroidal melanoma with radiation often involves placement of customized brachytherapy eye-plaques. However, the dosimetric properties inherent in source-based radiotherapy preclude facile dose optimization to critical ocular structures. Consequently, we have constructed a novel system for utilizing small beam low-energy radiation delivery, the Beamlet Low-kVp X-ray, or "BLOKX" system. This technique relies on an isocentric rotational approach to deliver dose to target volumes within the eye, while potentially sparing normal structures. Methods Monte Carlo N-Particle (MCNP) transport code version 5.0(14) was used to simulate photon interaction with normal and tumor tissues within modeled right eye phantoms. Five modeled dome-shaped tumors with a diameter and apical height of 8 mm and 6 mm, respectively, were simulated distinct positions with respect to the macula iteratively. A single fixed 9 × 9 mm2 beamlet, and a comparison COMS protocol plaque containing eight I-125 seeds (apparent activity of 8 mCi) placed on the scleral surface of the eye adjacent to the tumor, were utilized to determine dosimetric parameters at tumor and adjacent tissues. After MCNP simulation, comparison of dose distribution at each of the 5 tumor positions for each modality (BLOKX vs. eye-plaque) was performed. Results Tumor-base doses ranged from 87.1–102.8 Gy for the BLOKX procedure, and from 335.3–338.6 Gy for the eye-plaque procedure. A reduction of dose of at least 69% to tumor base was noted when using the BLOKX. The BLOKX technique showed a significant reduction of dose, 89.8%, to the macula compared to the episcleral plaque. A minimum 71.0 % decrease in dose to the optic nerve occurred when the BLOKX was used. Conclusion The BLOKX technique allows more favorable dose distribution in comparison to standard COMS brachytherapy, as simulated using a Monte Carlo iterative mathematical modeling. Future series to determine clinical utility of such an approach are warranted. PMID:16965624

Integrated Analysis of Genome-wide Copy Number Alterations and Gene Expression in MSS, CIMP-negative Colon Cancer

PubMed Central

Loo, Lenora WM; Tiirikainen, Maarit; Cheng, Iona; Lum-Jones, Annette; Seifried, Ann; Church, James M; Gryfe, Robert; Weisenberger, Daniel J; Lindor, Noralane M; Gallinger, Steven; Haile, Robert W; Duggan, David J; Thibodeau, Stephen N; Casey, Graham; Le Marchand, Loïc

2014-01-01

Microsatellite stable (MSS), CpG island methylator phenotype (CIMP)-negative colorectal tumors, the most prevalent molecular subtype of colorectal cancer, are associated with extensive copy number alteration (CNA) events and aneuploidy. We report on the identification of characteristic recurrent CNA (with frequency >25%) events and associated gene expression profiles for a total of 40 paired tumor and adjacent normal colon tissues using genome-wide microarrays. We observed recurrent CNAs, namely gains at 1q, 7p, 7q, 8p12-11, 8q, 12p13, 13q, 20p, 20q, Xp, and Xq and losses at 1p36, 1p31, 1p21, 4p15-12, 4q12-35, 5q21-22, 6q26, 8p, 14q, 15q11-12, 17p, 18p, 18q, 21q21-22, and 22q. Within these genomic regions we identified 356 genes with significant differential expression (P<0.0001 and ±1.5 fold change) in the tumor compared to adjacent normal tissue. Gene ontology and pathway analyses indicated that many of these genes were involved in functional mechanisms that regulate cell cycle, cell death, and metabolism. An amplicon present in >70% of the tumor samples at 20q11-20q13 contained several cancer-related genes (AHCY, POFUT1, RPN2, TH1L and PRPF6) that were up-regulated and demonstrated a significant linear correlation (P<0.05) for gene dosage and gene expression. Copy number loss at 8p, a CNA associated with adenocarcinoma and poor prognosis, was observed in >50% of the tumor samples and demonstrated a significant linear correlation for gene dosage and gene expression for two potential tumor suppressor genes, MTUS1 (8p22) and PPP2CB (8p12). The results from our integration analysis illustrate the complex relationship between genomic alterations and gene expression in colon cancer. PMID:23341073

Technical Note: A treatment plan comparison between dynamic collimation and a fixed aperture during spot scanning proton therapy for brain treatment

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

Smith, Blake, E-mail: bsmith34@wisc.edu; Gelover,

Purpose: To quantitatively assess the advantages of energy-layer specific dynamic collimation system (DCS) versus a per-field fixed aperture for spot scanning proton therapy (SSPT). Methods: Five brain cancer patients previously planned and treated with SSPT were replanned using an in-house treatment planning system capable of modeling collimated and uncollimated proton beamlets. The uncollimated plans, which served as a baseline for comparison, reproduced the target coverage and organ-at-risk sparing of the clinically delivered plans. The collimator opening for the fixed aperture-based plans was determined from the combined cross sections of the target in the beam’s eye view over all energy layersmore » which included an additional margin equivalent to the maximum beamlet displacement for the respective energy of that energy layer. The DCS-based plans were created by selecting appropriate collimator positions for each row of beam spots during a Raster-style scanning pattern which were optimized to maximize the dose contributions to the target and limited the dose delivered to adjacent normal tissue. Results: The reduction of mean dose to normal tissue adjacent to the target, as defined by a 10 mm ring surrounding the target, averaged 13.65% (range: 11.8%–16.9%) and 5.18% (2.9%–7.1%) for the DCS and fixed aperture plans, respectively. The conformity index, as defined by the ratio of the volume of the 50% isodose line to the target volume, yielded an average improvement of 21.35% (19.4%–22.6%) and 8.38% (4.7%–12.0%) for the DCS and fixed aperture plans, respectively. Conclusions: The ability of the DCS to provide collimation to each energy layer yielded better conformity in comparison to fixed aperture plans.« less

SU-E-T-187: Collimation Methods in Spot Scanning Proton Therapy: A Treatment Plan Comparison Between a Fixed Aperture and a Dynamic Collimation System

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

Smith, B; Gelover, E; Wang, D

2015-06-15

Purpose: Low-energy treatments during spot scanning proton therapy (SSPT) suffer from poor conformity due to increased spot size. Collimation devices can reduce the lateral penumbra of a proton therapy dose distribution and improve the overall plan quality. The purpose of this work was to study the advantages of individual energy-layer collimation, which is unique to a recently proposed Dynamic Collimation System (DCS), in comparison to a standard, fixed aperture that allows only a single shape for all energy layers. Methods: Three brain patients previously planned and treated with SSPT were re-planned using an in-house treatment planning system capable of modelingmore » collimated and un-collimated proton beamlets. The un-collimated plans, which served as a baseline for comparison, reproduced the target coverage of the clinically delivered plans. The collimator opening for the aperture based plans included a 0.6 cm expansion of the largest cross section of the target in the Beam’s Eye View, while the DCS based plans were created by optimizing the collimator position for beam spots near the periphery of the target in each energy layer. Results: The reduction of mean dose to normal tissue adjacent to the target, as defined by a 10 mm ring, averaged 9.13% and 3.48% for the DCS and aperture plans, respectively. The conformity index, as defined by the ratio of the volume of the 50% isodose line to the target volume, yielded an average improvement of 16.42% and 8.16% for the DCS and aperture plans, respectively. Conclusion: Collimation reduces the dose to normal tissue adjacent to the target and increases dose conformity to the target region for low-energy SSPT. The ability of the DCS to provide collimation to each energy layer yields better conformity in comparison to fixed aperture plans. This work was partially funded by IBA (Ion Beam Applications S.A.)« less

Long non-coding RNA expression profile in cervical cancer tissues

PubMed Central

Zhu, Hua; Chen, Xiangjian; Hu, Yan; Shi, Zhengzheng; Zhou, Qing; Zheng, Jingjie; Wang, Yifeng

2017-01-01

Cervical cancer (CC), one of the most common types of cancer of the female population, presents an enormous challenge in diagnosis and treatment. Long non-coding (lnc)RNAs, non-coding (nc)RNAs with length >200 nucleotides, have been identified to be associated with multiple types of cancer, including CC. This class of nc transcripts serves an important role in tumor suppression and oncogenic signaling pathways. In the present study, the microarray method was used to obtain the expression profile of lncRNAs and protein-coding mRNAs and to compare the expression of lncRNAs between CC tissues and corresponding adjacent non-cancerous tissues in order to screen potential lncRNAs for associations with CC. Overall, 3356 lncRNAs with significantly different expression pattern in CC tissues compared with adjacent non-cancerous tissues were identified, while 1,857 of them were upregulated. These differentially expressed lncRNAs were additionally classified into 5 subgroups. Reverse transcription quantitative polymerase chain reactions were performed to validate the expression pattern of 5 random selected lncRNAs, and 2lncRNAs were identified to have significantly different expression in CC samples compared with adjacent non-cancerous tissues. This finding suggests that those lncRNAs with different expression may serve important roles in the development of CC, and the expression data may provide information for additional study on the involvement of lncRNAs in CC. PMID:28789353

Dissociated overexpression of cathepsin D and estrogen receptor alpha in preinvasive mammary tumors.

PubMed

Roger, P; Daures, J P; Maudelonde, T; Pignodel, C; Gleizes, M; Chapelle, J; Marty-Double, C; Baldet, P; Mares, P; Laffargue, F; Rochefort, H

2000-05-01

The role of estrogen as a promoter agent of sporadic breast cancer has been considered by assaying, in benign breast disease (BBD) and in situ carcinomas (CIS), 2 markers, the estrogen receptor alpha (ERalpha) and cathepsin D (cath-D) involved in estrogen action on mammary tissue. ERalpha and cath-D were assayed by quantitative immunohistochemistry using an image analyzer in 170 lesions of varying histological risk (94 BBD and 76 CIS), and in "normal" glands close to these lesions. The ERalpha level increased significantly in proliferative BBD with atypia (P < .001), in non-high-grade CIS (P < .001), and in adjacent "normal" glands. ERalpha level was decreased in high-grade ductal CIS (DCIS) and also in adjacent "normal" glands. Cath-D level increased in ductal proliferative BBD (P < or = .01) and in high-grade DCIS (P < or = .003), but not in the other lesions. After menopause, ERalpha level was increased (P = .012) but not cath-D level. According to Mac Neman test, the high-grade DCIS were predominantly ERalpha negative and cath-D positive (P = .0017), and the other CIS were predominantly ERalpha positive and cath-D negative (P = .0002). The 2 markers are overexpressed early in premalignant lesions, but independently. This dissociation suggests a branched model of mammary carcinogenesis involving 1 estrogen-independent pathway with high cath-D and low ERalpha levels (including high-grade DCIS) and 1 estrogen-dependent pathway, with high ERalpha level (including proliferative BBD with atypia and low-grade DCIS). We propose that ERalpha-negative breast cancers may develop directly from high-grade DCIS and that ERalpha assay in preinvasive lesions should be considered in prevention trials with antiestrogens.

MicroRNAs associated with small bowel neuroendocrine tumours and their metastases.

PubMed

Miller, Helen C; Frampton, Adam E; Malczewska, Anna; Ottaviani, Silvia; Stronach, Euan A; Flora, Rashpal; Kaemmerer, Daniel; Schwach, Gert; Pfragner, Roswitha; Faiz, Omar; Kos-Kudła, Beata; Hanna, George B; Stebbing, Justin; Castellano, Leandro; Frilling, Andrea

2016-09-01

Novel molecular analytes are needed in small bowel neuroendocrine tumours (SBNETs) to better determine disease aggressiveness and predict treatment response. In this study, we aimed to profile the global miRNome of SBNETs, and identify microRNAs (miRNAs) involved in tumour progression for use as potential biomarkers. Two independent miRNA profiling experiments were performed (n=90), including primary SBNETs (n=28), adjacent normal small bowel (NSB; n=14), matched lymph node (LN) metastases (n=24), normal LNs (n=7), normal liver (n=2) and liver metastases (n=15). We then evaluated potentially targeted genes by performing integrated computational analyses. We discovered 39 miRNAs significantly deregulated in SBNETs compared with adjacent NSB. The most upregulated (miR-204-5p, miR-7-5p and miR-375) were confirmed by qRT-PCR. Two miRNAs (miR-1 and miR-143-3p) were significantly downregulated in LN and liver metastases compared with primary tumours. Furthermore, we identified upregulated gene targets for miR-1 and miR-143-3p in an existing SBNET dataset, which could contribute to disease progression, and show that these miRNAs directly regulate FOSB and NUAK2 oncogenes. Our study represents the largest global miRNA profiling of SBNETs using matched primary tumour and metastatic samples. We revealed novel miRNAs deregulated during SBNET disease progression, and important miRNA-mRNA interactions. These miRNAs have the potential to act as biomarkers for patient stratification and may also be able to guide treatment decisions. Further experiments to define molecular mechanisms and validate these miRNAs in larger tissue cohorts and in biofluids are now warranted. © 2016 Society for Endocrinology.

A pilot study on the use of cerebrospinal fluid cell-free DNA in intramedullary spinal ependymoma.

PubMed

Connolly, Ian David; Li, Yingmei; Pan, Wenying; Johnson, Eli; You, Linya; Vogel, Hannes; Ratliff, John; Hayden Gephart, Melanie

2017-10-01

Cerebrospinal fluid (CSF) represents a promising source of cell-free DNA (cfDNA) for tumors of the central nervous system. A CSF-based liquid biopsy may obviate the need for riskier tissue biopsies and serve as a means for monitoring tumor recurrence or response to therapy. Spinal ependymomas most commonly occur in adults, and aggressive resection must be delicately balanced with the risk of injury to adjacent normal tissue. In patients with subtotal resection, recurrence commonly occurs. A CSF-based liquid biopsy matched to the patient's spinal ependymoma mutation profile has potential to be more sensitive then surveillance MRI, but the utility has not been well characterized for tumors of the spinal cord. In this study, we collected matched blood, tumor, and CSF samples from three adult patients with WHO grade II intramedullary spinal ependymoma. We performed whole exome sequencing on matched tumor and normal DNA to design Droplet Digital™ PCR (ddPCR) probes for tumor and wild-type mutations. We then interrogated CSF samples for tumor-derived cfDNA by performing ddPCR on extracted cfDNA. Tumor cfDNA was not reliably detected in the CSF of our cohort. Anatomic sequestration and low grade of intramedullary spinal cord tumors likely limits the role of CSF liquid biopsy.

Increased lipoprotein lipase activity in non-small cell lung cancer tissue predicts shorter patient survival.

PubMed

Trost, Zoran; Sok, Miha; Marc, Janja; Cerne, Darko

2009-07-01

Cumulative evidence suggests the involvement of lipoprotein lipase (LPL) in tumor progression. We tested the hypothesis that increased LPL activity in resectable non-small cell lung cancer (NSCLC) tissue and the increased LPL gene expression in the surrounding non-cancer lung tissue found in our previous study are predictors of patient survival. Forty two consecutive patients with resected NSCLC were enrolled in the study. Paired samples of lung cancer tissue and adjacent non-cancer lung tissue were collected from resected specimens for baseline LPL activity and gene expression estimation. During a 4-year follow-up, 21 patients died due to tumor progression. One patient died due to a non-cancer reason and was not included in Cox regression analysis. High LPL activity in cancer tissue (relative to the adjacent non-cancer lung tissue) predicted shorter survival, independently of standard prognostic factors (p=0.003). High gene expression in the non-cancer lung tissue surrounding the tumor had no predictive value. Our study further underlines the involvement of cancer tissue LPL activity in tumor progression.

A biological approach to assembling tissue modules through endothelial capillary network formation.

PubMed

Riesberg, Jeremiah J; Shen, Wei

2015-09-01

To create functional tissues having complex structures, bottom-up approaches to assembling small tissue modules into larger constructs have been emerging. Most of these approaches are based on chemical reactions or physical interactions at the interface between tissue modules. Here we report a biological assembly approach to integrate small tissue modules through endothelial capillary network formation. When adjacent tissue modules contain appropriate extracellular matrix materials and cell types that support robust endothelial capillary network formation, capillary tubules form and grow across the interface, resulting in assembly of the modules into a single, larger construct. It was shown that capillary networks formed in modules of dense fibrin gels seeded with human umbilical vein endothelial cells (HUVECs) and mesenchymal stem cells (MSCs); adjacent modules were firmly assembled into an integrated construct having a strain to failure of 117 ± 26%, a tensile strength of 2208 ± 83 Pa and a Young's modulus of 2548 ± 574 Pa. Under the same culture conditions, capillary networks were absent in modules of dense fibrin gels seeded with either HUVECs or MSCs alone; adjacent modules disconnected even when handled gently. This biological assembly approach eliminates the need for chemical reactions or physical interactions and their associated limitations. In addition, the integrated constructs are prevascularized, and therefore this bottom-up assembly approach may also help address the issue of vascularization, another key challenge in tissue engineering. Copyright © 2015 John Wiley & Sons, Ltd.

Microscopic neural image registration based on the structure of mitochondria

NASA Astrophysics Data System (ADS)

Cao, Huiwen; Han, Hua; Rao, Qiang; Xiao, Chi; Chen, Xi

2017-02-01

Microscopic image registration is a key component of the neural structure reconstruction with serial sections of neural tissue. The goal of microscopic neural image registration is to recover the 3D continuity and geometrical properties of specimen. During image registration, various distortions need to be corrected, including image rotation, translation, tissue deformation et.al, which come from the procedure of sample cutting, staining and imaging. Furthermore, there is only certain similarity between adjacent sections, and the degree of similarity depends on local structure of the tissue and the thickness of the sections. These factors make the microscopic neural image registration a challenging problem. To tackle the difficulty of corresponding landmarks extraction, we introduce a novel image registration method for Scanning Electron Microscopy (SEM) images of serial neural tissue sections based on the structure of mitochondria. The ellipsoidal shape of mitochondria ensures that the same mitochondria has similar shape between adjacent sections, and its characteristic of broad distribution in the neural tissue guarantees that landmarks based on the mitochondria distributed widely in the image. The proposed image registration method contains three parts: landmarks extraction between adjacent sections, corresponding landmarks matching and image deformation based on the correspondences. We demonstrate the performance of our method with SEM images of drosophila brain.

Downregulation of Calcium-Binding Protein S100A9 Inhibits Hypopharyngeal Cancer Cell Proliferation and Invasion Ability Through Inactivation of NF-κB Signaling.

PubMed

Wu, Ping; Quan, Huatao; Kang, Jing; He, Jian; Luo, Shi; Xie, Chubo; Xu, Jing; Tang, Yaoyun; Zhao, Suping

2017-11-02

Hypopharyngeal cancer (HPC) frequently presents at an advanced stage and displays early submucosal spread, resulting in a poor prognosis. It is among the worst of all cancers in the head and neck subsites. Therefore, detection of HPC at an earlier stage would be beneficial to patients. In this study, we used differential in-gel electrophoresis (DIGE) and two-dimensional polyacrylamide gel electrophoresis (2-DE) proteomics analysis to identify the potential biomarkers for HPC. Among the differential proteins identified, calcium-binding protein S100A9 was overexpressed in HPC tissues compared with normal adjacent tissues, and S100A9 expression in metastatic tissues and advanced tumor tissues was higher than in nonmetastatic tissues and early tumor tissues. S100A9 expression was further confirmed in a large additional cohort. Our data showed that a higher S100A9 level was associated with a poor prognosis for HPC patients, and this may be an independent factor for predicting their prognosis. In addition, S100A9 protein expression was upregulated in human HPC cell lines compared with normal oral cavity epithelia. Knockdown of S100A9 induced significant inhibition of cell growth and their invasive ability. Mechanically, we found that downregulation of S100A9 significantly reduced the expression of NF-κB, phosphorylation of NF-κB and Bcl-2, as well as the expression of MMP7 and MMP2. Restoration of NF-κB expression sufficiently reversed the inhibitory effects on cell proliferation and invasion induced by S100A9 downregulation in vitro and in vivo. In conclusion, for the first time, we have identified S100A9 as an independent prognostic factor for HPC. Inhibiting S100A9 expression would be a potential novel diagnostic biomarker and therapeutic target for HPC treatment.

Local microcirculation disorders in uterus under laser tissue welding and their influence in the healing process

NASA Astrophysics Data System (ADS)

Kozlov, Valentine I.; Skobelkin, Oleg K.; Fatkullin, Ildar; Terman, Oleg A.; Chizhov, Gennadii; Gabidullina, Rushania

1994-12-01

To study the possibility of using Nd:YAG laser to weld the tissues of the uterus experiments in rats and dogs have been conducted. With the biomicroscopy and the laser Doppler flowmetry we have evaluated the microcirculation in the uterus wall under traditional suture and laser welding suture. As a model of the wound, the dissection of serosa and muscles of the organ wall have been used. In laser welding suture we have welded the zone of tissue about 1 mm3 with the laser (power density 270 W/cm2). Histological control has been fulfilled on various phases of the healing process. The investigation of the uterus wall demonstrates that there are zones of microcirculation disorders in tissues: (1) the zone of coagulation of microvessels and adjacent tissues (about 100 micrometers ); (2) the zone of stasis (150 - 200 micrometers ); (3) the zone of reactive-destructive changes of microvessels (300 micrometers ), (4) the zone of malfunctional microcirculatory changes (600 micrometers ). The coagulation of microvessels changes the character of inflammation and the healing process, decreases the exudation phase and the leucocyte infiltration of tissues, and accelerates the capillary growth. In contrast with traditional suture, in the case of laser welding suture the edema and hemorrhagic signs are less expressed. The complete restoration of microcirculation under laser welding suture has been observed by the fourteenth day of the healing process. Under the traditional suture method normalization of tissue nutritious blood flow has been achieved by 21 days.

Sodium-23 magnetic resonance imaging has potential for improving penumbra detection but not for estimating stroke onset time

PubMed Central

Wetterling, Friedrich; Gallagher, Lindsay; Mullin, Jim; Holmes, William M; McCabe, Chris; Macrae, I Mhairi; Fagan, Andrew J

2015-01-01

Tissue sodium concentration increases in irreversibly damaged (core) tissue following ischemic stroke and can potentially help to differentiate the core from the adjacent hypoperfused but viable penumbra. To test this, multinuclear hydrogen-1/sodium-23 magnetic resonance imaging (MRI) was used to measure the changing sodium signal and hydrogen-apparent diffusion coefficient (ADC) in the ischemic core and penumbra after rat middle cerebral artery occlusion (MCAO). Penumbra and core were defined from perfusion imaging and histologically defined irreversibly damaged tissue. The sodium signal in the core increased linearly with time, whereas the ADC rapidly decreased by >30% within 20 minutes of stroke onset, with very little change thereafter (0.5–6 hours after MCAO). Previous reports suggest that the time point at which tissue sodium signal starts to rise above normal (onset of elevated tissue sodium, OETS) represents stroke onset time (SOT). However, extrapolating core data back in time resulted in a delay of 72±24 minutes in OETS compared with actual SOT. At the OETS in the core, penumbra sodium signal was significantly decreased (88±6%, P=0.0008), whereas penumbra ADC was not significantly different (92±18%, P=0.2) from contralateral tissue. In conclusion, reduced sodium-MRI signal may serve as a viability marker for penumbra detection and can complement hydrogen ADC and perfusion MRI in the time-independent assessment of tissue fate in acute stroke patients. PMID:25335803

Quantitative proteomic analysis of paired colorectal cancer and non-tumorigenic tissues reveals signature proteins and perturbed pathways involved in CRC progression and metastasis.

PubMed

Sethi, Manveen K; Thaysen-Andersen, Morten; Kim, Hoguen; Park, Cheol Keun; Baker, Mark S; Packer, Nicolle H; Paik, Young-Ki; Hancock, William S; Fanayan, Susan

2015-08-03

Modern proteomics has proven instrumental in our understanding of the molecular deregulations associated with the development and progression of cancer. Herein, we profile membrane-enriched proteome of tumor and adjacent normal tissues from eight CRC patients using label-free nanoLC-MS/MS-based quantitative proteomics and advanced pathway analysis. Of the 948 identified proteins, 184 proteins were differentially expressed (P<0.05, fold change>1.5) between the tumor and non-tumor tissue (69 up-regulated and 115 down-regulated in tumor tissues). The CRC tumor and non-tumor tissues clustered tightly in separate groups using hierarchical cluster analysis of the differentially expressed proteins, indicating a strong CRC-association of this proteome subset. Specifically, cancer associated proteins such as FN1, TNC, DEFA1, ITGB2, MLEC, CDH17, EZR and pathways including actin cytoskeleton and RhoGDI signaling were deregulated. Stage-specific proteome signatures were identified including up-regulated ribosomal proteins and down-regulated annexin proteins in early stage CRC. Finally, EGFR(+) CRC tissues showed an EGFR-dependent down-regulation of cell adhesion molecules, relative to EGFR(-) tissues. Taken together, this study provides a detailed map of the altered proteome and associated protein pathways in CRC, which enhances our mechanistic understanding of CRC biology and opens avenues for a knowledge-driven search for candidate CRC protein markers. Copyright © 2015 Elsevier B.V. All rights reserved.

Upregulation of transferrin receptor-1 induces cholangiocarcinoma progression via induction of labile iron pool.

PubMed

Jamnongkan, Wassana; Thanan, Raynoo; Techasen, Anchalee; Namwat, Nisana; Loilome, Watcharin; Intarawichian, Piyapharom; Titapun, Attapol; Yongvanit, Puangrat

2017-07-01

Labile iron pool is a cellular source of ions available for Fenton reactions resulting in oxidative stress. Living organisms avoid an excess of free irons by a tight control of iron homeostasis. We investigated the altered expression of iron regulatory proteins and iron discrimination in the development of liver fluke-associated cholangiocarcinoma. Additionally, the levels of labile iron pool and the functions of transferrin receptor-1 on cholangiocarcinoma development were also identified. Iron deposition was determined using the Prussian blue staining method in human cholangiocarcinoma tissues. We investigated the alteration of iron regulatory proteins including transferrin, transferrin receptor-1, ferritin, ferroportin, hepcidin, and divalent metal transporter-1 in cholangiocarcinoma tissues using immunohistochemistry. The clinicopathological data of cholangiocarcinoma patients and the expressions of proteins were analyzed. Moreover, the level of intracellular labile iron pool in cholangiocarcinoma cell lines was identified by the RhoNox-1 staining method. We further demonstrated transferrin receptor-1 functions on cell proliferation and migration upon small interfering RNA for human transferrin receptor 1 transfection. Results show that Iron was strongly stained in tumor tissues, whereas negative staining was observed in normal bile ducts of healthy donors. Interestingly, high iron accumulation was significantly correlated with poor prognosis of cholangiocarcinoma patients. The expressions of iron regulatory proteins in human cholangiocarcinoma tissues and normal liver from cadaveric donors revealed that transferrin receptor-1 expression was increased in the cancer cells of cholangiocarcinoma tissues when compared with the adjacent normal bile ducts and was significantly correlated with cholangiocarcinoma metastasis. Labile iron pool level and transferrin receptor-1 expression were significantly increased in KKU-214 and KKU-213 when compared with cholangiocyte cells (MMNK1). Additionally, the suppression of transferrin receptor-1 expression significantly decreased intracellular labile iron pool, cholangiocarcinoma migration, and cell proliferation when compared with control media and control small interfering RNA. In Conclusion, high expression of transferrin receptor-1 resulting in iron uptake contributes to increase in the labile iron pool which plays roles in cholangiocarcinoma progression with aggressive clinical outcomes.

Modeling the response of normal and ischemic cardiac tissue to electrical stimulation

NASA Astrophysics Data System (ADS)

Kandel, Sunil Mani

Heart disease, the leading cause of death worldwide, is often caused by ventricular fibrillation. A common treatment for this lethal arrhythmia is defibrillation: a strong electrical shock that resets the heart to its normal rhythm. To design better defibrillators, we need a better understanding of both fibrillation and defibrillation. Fundamental mysteries remain regarding the mechanism of how the heart responds to a shock, particularly anodal shocks and the resultant hyperpolarization. Virtual anodes play critical roles in defibrillation, and one cannot build better defibrillators until these mechanisms are understood. We are using mathematical modeling to numerically simulate observed phenomena, and are exploring fundamental mechanisms responsible for the heart's electrical behavior. Such simulations clarify mechanisms and identify key parameters. We investigate how systolic tissue responds to an anodal shock and how refractory tissue reacts to hyperpolarization by studying the dip in the anodal strength-interval curve. This dip is due to electrotonic interaction between regions of depolarization and hyperpolarization following a shock. The dominance of the electrotonic mechanism over calcium interactions implies the importance of the spatial distribution of virtual electrodes. We also investigate the response of localized ischemic tissue to an anodal shock by modeling a regional elevation of extracellular potassium concentration. This heterogeneity leads to action potential instability, 2:1 conduction block (alternans), and reflection-like reentry at the boarder of the normal and ischemic regions. This kind of reflection (reentry) occurs due to the delay between proximal and distal segments to re-excite the proximal segment. Our numerical simulations are based on the bidomain model, the state-of-the-art mathematical description of how cardiac tissue responds to shocks. The dynamic LuoRudy model describes the active properties of the membrane. To model ischemia, the Luo-Rudy model is modified by adding ischemic-related ion currents and concentrations to mimic conditions during the initial phase of ischemia. The stimulus is applied through a unipolar electrode that induces a complicated spatial distribution of transmembrane potential, including adjacent regions of depolarization and hyperpolarization. This research is significant because it uncovers basic properties of excitation that are fundamental for understanding cardiac pacing and defibrillation.

Expression of Caspase-1 in breast cancer tissues and its effects on cell proliferation, apoptosis and invasion.

PubMed

Sun, Yanxia; Guo, Yingzhen

2018-05-01

The present study aimed to detect the expression of Caspase-1 in the tumor tissues and tumor-adjacent tissues of patients with breast cancer, and to investigate the effects of Caspase-1 on the proliferation, apoptosis and invasion of breast cancer cells. Reverse transcription-quantitative polymerase chain reaction was used to detect Caspase-1 mRNA expression in breast cancer tissues and tumor-adjacent tissues from patients. Additionally, the human breast cancer MDA-MB-231 cell line was treated with the Caspase-1 small molecule inhibitor Ac-YVAD-CMK, following which the changes to Caspase-1 protein expression were detected via western blotting. The MTT method detected the changes to cell proliferation, flow cytometry detected the rate of apoptosis, and a Transwell assay was employed to assess invasion. Caspase-1 mRNA expression was significantly decreased in the breast cancer tissues of patients, compared with in the tumor-adjacent tissues, a difference that was statistically significant (P<0.05). Treatment with the Ac-YVAD-CMK markedly decreased the protein expression of Caspase-1 in MDA-MB-231 cells, and the difference was statistically significant (P<0.05). Following this treatment of Ac-YVAD-CMK cells, the proliferation and invasion abilities markedly increased, while the apoptotic levels significantly decreased (P<0.05). In conclusion, the expression of Caspase-1 is low in breast cancer tissues, which may promote the proliferation and invasion of breast cancer cells and could be closely associated with the occurrence and development of breast cancer.

Development of Semiautomated Module for Preparation of 131I Labeled Lipiodol for Liver Cancer Therapy.

PubMed

Mukherjee, Archana; Subramanian, Suresh; Ambade, Rajwardhan; Avhad, Bhaurao; Dash, Ashutosh; Korde, Aruna

2017-02-01

Intra-arterial injection of 131 I Lipiodol is an effective treatment option for primary hepatocellular carcinoma as it delivers high radiation dose to liver tumor tissue with minimal accumulation in adjacent normal tissue. The present article demonstrates design, fabrication, and utilization of a semiautomated radiosynthesis module for preparation of 131 I labeled Lipiodol. The radiolabeling method was standardized for preparation of patient dose of 131 I labeled Lipiodol radiochemical yield (RCY); radiochemical purity (RCP) and pharmaceutical purity of the product were determined using optimized procedures. Sterile and apyrogenic 131 I labeled Lipiodol in >60% RCY could be prepared with >95% RCP. Preclinical evaluation in animals indicated retention of more than 90% of activity at 24 hours postportal vein injection. This is the first report demonstrating potential application of simple user friendly and safe semiautomated system for routine production of 131 I labeled Lipiodol, which is adaptable at centralized hospital radiopharmacies. The described prototype module can be modified as per demand for preparation of other therapeutic radiopharmaceuticals.

Cell division cycle 45 promotes papillary thyroid cancer progression via regulating cell cycle.

PubMed

Sun, Jing; Shi, Run; Zhao, Sha; Li, Xiaona; Lu, Shan; Bu, Hemei; Ma, Xianghua

2017-05-01

Cell division cycle 45 was reported to be overexpressed in some cancer-derived cell lines and was predicted to be a candidate oncogene in cervical cancer. However, the clinical and biological significance of cell division cycle 45 in papillary thyroid cancer has never been investigated. We determined the expression level and clinical significance of cell division cycle 45 using The Cancer Genome Atlas, quantitative real-time polymerase chain reaction, and immunohistochemistry. A great upregulation of cell division cycle 45 was observed in papillary thyroid cancer tissues compared with adjacent normal tissues. Furthermore, overexpression of cell division cycle 45 positively correlates with more advanced clinical characteristics. Silence of cell division cycle 45 suppressed proliferation of papillary thyroid cancer cells via G1-phase arrest and inducing apoptosis. The oncogenic activity of cell division cycle 45 was also confirmed in vivo. In conclusion, cell division cycle 45 may serve as a novel biomarker and a potential therapeutic target for papillary thyroid cancer.

Histopathological and Digital Morphometrical Evaluation of Uterine Leiomyoma in Brazilian Women

PubMed Central

da Silva, Ana Paula Fernandes; Mello, Luciano de Albuquerque; dos Santos, Erlene Roberta Ribeiro; Paz, Silvania Tavares; Cavalcanti, Carmelita Lima Bezerra; de Melo-Junior, Mario Ribeiro

2016-01-01

The current study aims to evaluate histopathological and digital morphometrical aspects associated with uterine leiomyomas in one hundred and fifty (150) patients diagnosed with leiomyoma. Uterine tissues were subjected to the histopathological and digital morphometric analyses of the interstitial collagen distribution. The analysis of medical records indicates that most of the women diagnosed with uterine leiomyomas (68.7%) are between 37 and 48 years old. As for the anatomic location of the tumors, approximately 61.4% of the patients had intramural and subserosal lesions. In 50% of the studied cases, the patients developed uterine leiomyomatosis (with more than eight tumors). As for the morphometric study, the average size of the interstitial collagen distribution held approximately 28.53% of the capture area, whereas it was of 7.43% in the normal tissue adjacent to the tumor. Another important aspect observed in the current study was the high rate of young women subjected to total hysterectomy, a fact that resulted in early and definitive sterility. PMID:27293441

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

PubMed

Liu, Hui; Wu, Yu

2018-05-01

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

SUSD2 is frequently downregulated and functions as a tumor suppressor in RCC and lung cancer.

PubMed

Cheng, Yingying; Wang, Xiaolin; Wang, Pingzhang; Li, Ting; Hu, Fengzhan; Liu, Qiang; Yang, Fan; Wang, Jun; Xu, Tao; Han, Wenling

2016-07-01

Sushi domain containing 2 (SUSD2) is type I membrane protein containing domains inherent to adhesion molecules. There have been few reported studies on SUSD2, and they have mainly focused on breast cancer, colon cancer, and HeLa cells. However, the expression and function of SUSD2 in other cancers remain unclear. In the present study, we conducted an integrated bioinformatics analysis based on the array data from the GEO database and found a significant downregulation of SUSD2 in renal cell carcinoma (RCC) and lung cancer. Western blotting and quantitative RT-PCR (qRT-PCR) confirmed that SUSD2 was frequently decreased in RCC and lung cancer tissues compared with the corresponding levels in normal adjacent tissues. The restoration of SUSD2 expression inhibited the proliferation and clonogenicity of RCC and lung cancer cells, whereas the knockdown of SUSD2 promoted A549 cell growth. Our findings suggested that SUSD2 functions as a tumor suppressor gene (TSG) in RCC and lung cancer.

Estrogen regulates Hippo signaling via GPER in breast cancer

PubMed Central

Zhou, Xin; Wang, Shuyang; Wang, Zhen; Feng, Xu; Liu, Peng; Lv, Xian-Bo; Li, Fulong; Yu, Fa-Xing; Sun, Yiping; Yuan, Haixin; Zhu, Hongguang; Xiong, Yue; Lei, Qun-Ying; Guan, Kun-Liang

2015-01-01

The G protein–coupled estrogen receptor (GPER) mediates both the genomic and nongenomic effects of estrogen and has been implicated in breast cancer development. Here, we compared GPER expression in cancerous tissue and adjacent normal tissue in patients with invasive ductal carcinoma (IDC) of the breast and determined that GPER is highly upregulated in cancerous cells. Additionally, our studies revealed that GPER stimulation activates yes-associated protein 1 (YAP) and transcriptional coactivator with a PDZ-binding domain (TAZ), 2 homologous transcription coactivators and key effectors of the Hippo tumor suppressor pathway, via the Gαq-11, PLCβ/PKC, and Rho/ROCK signaling pathways. TAZ was required for GPER-induced gene transcription, breast cancer cell proliferation and migration, and tumor growth. Moreover, TAZ expression positively correlated with GPER expression in human IDC specimens. Together, our results suggest that the Hippo/YAP/TAZ pathway is a key downstream signaling branch of GPER and plays a critical role in breast tumorigenesis. PMID:25893606

Mechanisms of urodele limb regeneration

PubMed Central

2017-01-01

Abstract This review explores the historical and current state of our knowledge about urodele limb regeneration. Topics discussed are (1) blastema formation by the proteolytic histolysis of limb tissues to release resident stem cells and mononucleate cells that undergo dedifferentiation, cell cycle entry and accumulation under the apical epidermal cap. (2) The origin, phenotypic memory, and positional memory of blastema cells. (3) The role played by macrophages in the early events of regeneration. (4) The role of neural and AEC factors and interaction between blastema cells in mitosis and distalization. (5) Models of pattern formation based on the results of axial reversal experiments, experiments on the regeneration of half and double half limbs, and experiments using retinoic acid to alter positional identity of blastema cells. (6) Possible mechanisms of distalization during normal and intercalary regeneration. (7) Is pattern formation is a self‐organizing property of the blastema or dictated by chemical signals from adjacent tissues? (8) What is the future for regenerating a human limb? PMID:29299322

FTO regulates the chemo-radiotherapy resistance of cervical squamous cell carcinoma (CSCC) by targeting β-catenin through mRNA demethylation.

PubMed

Zhou, Shun; Bai, Zhou-Lan; Xia, Di; Zhao, Zhi-Jun; Zhao, Ren; Wang, Yan-Yang; Zhe, Hong

2018-05-01

The role of N 6 -methyladenosine (m 6 A) demethylase fat mass and obesity-associated protein (FTO) in the regulation of chemo-radiotherapy resistance remains largely unknown. Here, we show that the mRNA level of FTO is elevated in cervical squamous cell carcinoma (CSCC) tissues when compared with respective adjacent normal tissues. FTO enhances the chemo-radiotherapy resistance both in vitro and in vivo through regulating expression of β-catenin by reducing m 6 A levels in its mRNA transcripts and in turn increases excision repair cross-complementation group 1 (ERCC1) activity. Clinically, the prognostic value of FTO for overall survival is found to be dependent on β-catenin expression in human CSCC samples. Taken together, these findings uncover a critical function for FTO and its substrate m 6 A in the regulation of chemo-radiotherapy resistance, which may bear potential clinical implications for CSCC treatment. © 2018 Wiley Periodicals, Inc.

Deformable anatomical templates for brachytherapy treatment planning in radiotherapy of cervical cancer

NASA Astrophysics Data System (ADS)

Christensen, Gary E.; Williamson, Jeffrey F.; Chao, K. S. C.; Miller, Michael I.; So, F. B.; Vannier, Michael W.

1997-10-01

This paper describes a new method to register serial, volumetric x-ray computed tomography (CT) data sets for tracking soft-tissue deformation caused by insertion of intracavity brachytherapy applicators to treat cervical cancer. 3D CT scans collected from the same patient with and without a brachytherapy applicator are registered to aid in computation of the radiation dose to tumor and normal tissue. The 3D CT image volume of pelvic anatomy with the applicator. Initial registration is accomplished by rigid alignment of the pelvic bones and non-rigid alignment of gray scale CT data and hand segmentations of the vagina, cervix, bladder, and rectum. A viscous fluid transformation model is used for non-rigid registration to allow for local, non-linear registration of the vagina, cervix, bladder, and rectum without disturbing the rigid registration of the bony pelvis and adjacent structures. Results are presented in which two 3D CT data sets of the same patient - imaged with and without a brachytherapy applicator - are registered.

[Association of Inorganics Accumulation with the Activation of NF-κB Signaling Pathway and the iNOS Expression of Lung Tissue in Xuanwei Lung Cancer Patients].

PubMed

Yang, Jiapeng; Li, Guangjian; Huang, Yunchao; Ye, Lianhua; Zhou, Yongchun; Zhao, Guangqiang; Lei, Yujie; Chen, Xiaobo; Wang, Kun; Chen, Ying; Dai, Chun; Zhang, Yanjun

2016-01-01

Indoor air pollution induces asthma, leads to chronic obstructive pulmonary disease, and may promote lung cancer. Our previous studies found that the accumulation of inorganic particulate matter that is due to indoor air pollution can lead to damage to alveolar cells and activation of signaling pathway, and ultimately provoke tumorigenesis. The aim of this study is to explore the accumulation of inorganics and activation of nuclear factor κB (NF-κB)-inducible nitric oxide synthase (iNOS) signaling pathway of lung tissue in Xuanwei lung cancer patients. From December 2013 to November 2014, 48 cases Xuanwei patients with lung cancer who underwent surgical treatment from the Third Affiliated Hospital of Kunming Medical University were enrolled in this study and compared with lung cancer patients from other regions. The ultrastructure of postoperative specimens was observed by transmission electron microscopy (TEM) to explore the occurrence of inorganic particles. Serum cytokines were analyzed. Then, the expression levels of NF-κB-p65 protein and iNOS protein in postoperative specimens was explored by immunohistochemistry and Western blot. Finally, 8-OHdG accumulation in lung cancer tissues and urine was measured. A large number of nanoscale inorganics were observed in alveolar type II cells and macrophages located in adjacent tissues of lung cancer with Xuanwei patients. Silicon (Si) content was found in inorganic elemental analysis. The serum interleukin (IL)-1β levels (31.50 ± 19.16) pg/mL of Xuanwei lung-cancer patients were remarkably higher than those from other regions (11.33 ± 6.94) pg/mL (P<0.01), with statistically significant difference. The pathological tissues of Xuanwei lung-cancer patients express NF-κB-p65, and iNOS expression were significantly higher than those of patients from non-Xuanwei regions. No significant difference was found between cancerous and normal adjacent tissues. Xuanwei lung-cancer tissues and urine 8-OHdG level (40.124 ± 8.597) ng/mgCr were significantly higher than those of patients from other regions (25.673 ± 7.986) ng/mg Cr (P<0.05), with statistically significant difference. The accumulation of inorganics and the activation of NF-κB-iNOS signaling pathway may contribute to Xuanwei lung cancer.
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Altered expression of cytokeratin 7 and CD117 in transitional mucosa adjacent to human colorectal cancer.

PubMed

Kigasawa, Hideaki; Fujiwara, Masachika; Ishii, Jun; Chiba, Tomohiro; Terado, Yuichi; Shimoyamada, Hiroaki; Mochizuki, Makoto; Kitamura, Osamu; Kamma, Hiroshi; Ohkura, Yasuo

2017-07-01

The multi-step progression of colorectal cancer through precancerous lesions (adenoma and dysplasia) is associated with cumulative molecular alterations, a number of which have also been demonstrated to be present in morphologically normal transitional mucosa adjacent to colorectal cancer. The cytoskeletal protein cytokeratin 7 (CK7) and the receptor tyrosine kinase, KIT proto-oncogene receptor tyrosine kinase (CD117), encoded by the proto-oncogene c-Kit, are lacking in normal colorectal crypt epithelium and are aberrantly expressed in a subset of colorectal cancer. The aim of the present study was to evaluate the expression of CK7 and CD117 in morphologically normal transitional mucosa adjacent to colorectal cancer. Immunohistochemical staining for CK7 and CD117 was performed in the mucosa adjacent to five groups of surgically resected colorectal tumors [low-grade adenoma, high-grade adenoma, mucosal adenocarcinoma, small-sized invasive adenocarcinoma (≤2 cm) and large-sized invasive adenocarcinoma (>2 cm)]. CK7 was expressed in the mucosa adjacent to a subset of colorectal tumors, and the positivity ratio increased according to tumor grade from low-grade adenoma up to small-sized invasive adenocarcinoma (61.2%). However, the positivity ratio of CK7 in the mucosa adjacent to the large-sized invasive adenocarcinoma (25.0%) was significantly lower compared with that of the next lower grade. CD117 was also expressed in the mucosa adjacent to a subset of colorectal tumors. In contrast to CK7, the positivity ratio of CD117 increased according to tumor grade from low-grade adenoma all the way through to the large-sized invasive adenocarcinoma (45.0%). Based on these results, the mechanism of CK7 and CD117 expression in the transitional mucosa adjacent to colorectal cancer may be different, and analysis of their individual expression may provide novel insights into the development and progression of colorectal cancer.

Altered expression of cytokeratin 7 and CD117 in transitional mucosa adjacent to human colorectal cancer

PubMed Central

Kigasawa, Hideaki; Fujiwara, Masachika; Ishii, Jun; Chiba, Tomohiro; Terado, Yuichi; Shimoyamada, Hiroaki; Mochizuki, Makoto; Kitamura, Osamu; Kamma, Hiroshi; Ohkura, Yasuo

2017-01-01

The multi-step progression of colorectal cancer through precancerous lesions (adenoma and dysplasia) is associated with cumulative molecular alterations, a number of which have also been demonstrated to be present in morphologically normal transitional mucosa adjacent to colorectal cancer. The cytoskeletal protein cytokeratin 7 (CK7) and the receptor tyrosine kinase, KIT proto-oncogene receptor tyrosine kinase (CD117), encoded by the proto-oncogene c-Kit, are lacking in normal colorectal crypt epithelium and are aberrantly expressed in a subset of colorectal cancer. The aim of the present study was to evaluate the expression of CK7 and CD117 in morphologically normal transitional mucosa adjacent to colorectal cancer. Immunohistochemical staining for CK7 and CD117 was performed in the mucosa adjacent to five groups of surgically resected colorectal tumors [low-grade adenoma, high-grade adenoma, mucosal adenocarcinoma, small-sized invasive adenocarcinoma (≤2 cm) and large-sized invasive adenocarcinoma (>2 cm)]. CK7 was expressed in the mucosa adjacent to a subset of colorectal tumors, and the positivity ratio increased according to tumor grade from low-grade adenoma up to small-sized invasive adenocarcinoma (61.2%). However, the positivity ratio of CK7 in the mucosa adjacent to the large-sized invasive adenocarcinoma (25.0%) was significantly lower compared with that of the next lower grade. CD117 was also expressed in the mucosa adjacent to a subset of colorectal tumors. In contrast to CK7, the positivity ratio of CD117 increased according to tumor grade from low-grade adenoma all the way through to the large-sized invasive adenocarcinoma (45.0%). Based on these results, the mechanism of CK7 and CD117 expression in the transitional mucosa adjacent to colorectal cancer may be different, and analysis of their individual expression may provide novel insights into the development and progression of colorectal cancer. PMID:28693143

Application of a flexible CO(2) laser fiber for neurosurgery: laser-tissue interactions.

PubMed

Ryan, Robert W; Wolf, Tamir; Spetzler, Robert F; Coons, Stephen W; Fink, Yoel; Preul, Mark C

2010-02-01

The CO(2) laser has an excellent profile for use in neurosurgery. Its high absorption in water results in low thermal spread, sparing adjacent tissue. Use of this laser has been limited to line-of-sight applications because no solid fiber optic cables could transmit its wavelength. Flexible photonic bandgap fiber technology enables delivery of CO(2) laser energy through a flexible fiber easily manipulated in a handheld device. The authors examined and compared the first use of this CO(2) laser fiber to conventional methods for incising neural tissue. Carbon dioxide laser energy was delivered in pulsed or continuous wave settings for different power settings, exposure times, and distances to cortical tissue of 6 anesthetized swine. Effects of CO(2) energy on the tissue were compared with bipolar cautery using a standard pial incision technique, and with scalpel incisions without cautery. Tissue was processed for histological analysis (using H & E, silver staining, and glial fibrillary acidic protein immunohistochemistry) and scanning electron microscopy, and lesion measurements were made. Light microscopy and scanning electron microscopy revealed laser incisions of consistent shape, with central craters surrounded by limited zones of desiccated and edematous tissue. Increased laser power resulted in deeper but not significantly wider incisions. Bipolar cautery lesions showed desiccated and edematous zones but did not incise the pia, and width increased more than depth with higher power. Incisions made without using cautery produced hemorrhage but minimal adjacent tissue damage. The photonic bandgap fiber CO(2) laser produced reliable cortical incisions, adjustable over a range of settings, with minimal adjacent thermal tissue damage. Ease of application under the microscope suggests this laser system has reached true practicality for neurosurgery.

Adipose-Derived Stromal Vascular Fraction Differentially Expands Breast Progenitors in Tissue Adjacent to Tumors Compared to Healthy Breast Tissue

PubMed Central

Chatterjee, Sumanta; Laliberte, Mike; Blelloch, Sarah; Ratanshi, Imran; Safneck, Janice; Buchel, Ed

2015-01-01

Background: Autologous fat grafts supplemented with adipose-derived stromal vascular fraction are used in reconstructive and cosmetic breast procedures. Stromal vascular fraction contains adipose-derived stem cells that are thought to encourage wound healing, tissue regeneration, and graft retention. Although use of stromal vascular fraction has provided exciting perspectives for aesthetic procedures, no studies have yet been conducted to determine whether its cells contribute to breast tissue regeneration. The authors examined the effect of these cells on the expansion of human breast epithelial progenitors. Methods: From patients undergoing reconstructive breast surgery following mastectomies, abdominal fat, matching tissue adjacent to breast tumors, and the contralateral non–tumor-containing breast tissue were obtained. Ex vivo co-cultures using breast epithelial cells and the stromal vascular fraction cells were used to study the expansion potential of breast progenitors. Breast reduction samples were collected as a source of healthy breast cells. Results: The authors observed that progenitors present in healthy breast tissue or contralateral non–tumor-containing breast tissue showed significant and robust expansion in the presence of stromal vascular fraction (5.2- and 4.8-fold, respectively). Whereas the healthy progenitors expanded up to 3-fold without the stromal vascular fraction cells, the expansion of tissue adjacent to breast tumor progenitors required the presence of stromal vascular fraction cells, leading to a 7-fold expansion, which was significantly higher than the expansion of healthy progenitors with stromal vascular fraction. Conclusions: The use of stromal vascular fraction might be more beneficial to reconstructive operations following mastectomies compared with cosmetic corrections of the healthy breast. Future studies are required to examine the potential risk factors associated with its use. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID:26090768

Deregulation of SYCP2 predicts early stage human papillomavirus-positive oropharyngeal carcinoma: A prospective whole transcriptome analysis.

PubMed

Masterson, Liam; Sorgeloos, Frederic; Winder, David; Lechner, Matt; Marker, Alison; Malhotra, Shalini; Sudhoff, Holger; Jani, Piyush; Goon, Peter; Sterling, Jane

2015-11-01

This study was designed to identify significant differences in gene expression profiles of human papillomavirus (HPV)-positive and HPV-negative oropharyngeal squamous cell carcinomas (OPSCC) and to better understand the functional and biological effects of HPV infection in the premalignant pathway. Twenty-four consecutive patients with locally advanced primary OPSCC were included in a prospective clinical trial. Fresh tissue samples (tumor vs. matched normal epithelium) were subjected to whole transcriptome analysis and the results validated on the same cohort with RT-quantitative real-time PCR. In a separate retrospective cohort of 27 OPSCC patients, laser capture microdissection of formalin-fixed, paraffin-embedded tissue allowed RNA extraction from adjacent regions of normal epithelium, carcinoma in situ (premalignant) and invasive SCC tissue. The majority of patients showed evidence of high-risk HPV16 positivity (80.4%). Predictable fold changes of RNA expression in HPV-associated disease included multiple transcripts within the p53 oncogenic pathway (e.g. CDKN2A/CCND1). Other candidate transcripts found to have altered levels of expression in this study have not previously been established (SFRP1, CRCT1, DLG2, SYCP2, and CRNN). Of these, SYCP2 showed the most consistent fold change from baseline in premalignant tissue; aberrant expression of this protein may contribute to genetic instability during HPV-associated cancer development. If further corroborated, this data may contribute to the development of a non-invasive screening tool. This study is registered with the UK Clinical Research Network (ref.: 11945). © 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

Fusobacterium in colonic flora and molecular features of colorectal carcinoma

PubMed Central

Tahara, Tomomitsu; Yamamoto, Eiichiro; Suzuki, Hiromu; Maruyama, Reo; Chung, Woonbok; Garriga, Judith; Jelinek, Jaroslav; Yamano, Hiro-o; Sugai, Tamotsu; An, Byonggu; Shureiqi, Imad; Toyota, Minoru; Kondo, Yutaka; Estécio, Marcos R. H.; Issa, Jean-Pierre J.

2015-01-01

Fusobacterium species are part of the gut microbiome in humans. Recent studies have identified over-representation of Fusobacterium in colorectal cancer (CRC) tissues but it is not yet clear whether this is pathogenic or simply an epiphenomenon. In this study, we evaluated the relationship between Fusobacterium status and molecular features in CRCs through quantitative real-time PCR in 149 CRC tissues, 89 adjacent normal appearing mucosae and 72 colonic mucosae from cancer-free individuals. Results were correlated with CpG island methylator phenotype (CIMP) status, microsatellite instability (MSI) and mutations in BRAF, KRAS, TP53, CHD7 and CHD8. Whole exome capture sequencing data were also available in 11 cases. Fusobacterium was detectable in 111/149 (74%) CRC tissues and heavily enriched in 9% (14/149) of the cases. As expected, Fusobacterium was also detected in normal appearing mucosae from both cancer and cancer-free individuals but the amount of bacteria was much lower compared to CRC tissues (a mean of 250-fold lower for Pan-fusobacterium). We found the Fusobacterium-high CRC group (FB-high) to be associated with CIMP positivity (p=0.001), TP53 wild type (p=0.015), hMLH1 methylation positivity (p=0.0028), MSI (p=0.018) and CHD7/8 mutation positivity (p=0.002). Among the 11 cases where whole exome sequencing data was available, two that were FB-high cases also had the highest number of somatic mutations (a mean of 736 per case in FB-high vs. 225 per case in all others). Taken together, our findings show that Fusobacterium enrichment is associated with specific molecular subsets of CRCs, offering support for a pathogenic role in CRC for this gut microbiome component PMID:24385213

MicroRNA-214-5p Inhibits the Invasion and Migration of Hepatocellular Carcinoma Cells by Targeting Wiskott-Aldrich Syndrome Like.

PubMed

Li, Hongdan; Wang, Haoqi; Ren, Zhen

2018-01-01

This study aims to explore the effects of microRNA-214-5p (miR-214-5p) on the invasion and migration of Hepatocellular Carcinoma cells (HCC). Hepatocellular Carcinoma tissues and adjacent normal tissues from 44 hepatocellular carcinoma patients were prepared for this study. The HepG2 and BEL-7402 cells were transfected with miR-214-5p mimic and inhibitor. qRT-PCR was performed to detect the expressions of miR-214-5p. Transwell assays were used to detect the invasion and migration assays in HepG2 and BEL-7402 cells. A dual-luciferase reporter assay was conducted to examine the effect of miR-214-5p on Wiskott-Aldrich Syndrome Like (WASL/ N-WASP). Western blot and qRT-PCR were used to measure the expressions of the E-cadherin, N-cadherin and Vimentin proteins. Transwell chamber assays were performed to detect cell invasion and migration. Compared with normal tissues, HCC tissues demonstrated significantly lower expression of miR-214-5p. Overexpression of miR-214-5p significantly inhibited the migration and invasion of HCC cells and inhibition of miR-214-5p promoted the migration and invasion. Additionally, miR-214-5p suppressed the epithelial-mesenchymal transition (EMT). Further study showed WASL was a putative target gene of miR-214-5p. Up-regulating the expression of WASL could reverse the inhibition effect of miR-214-5p on invasion and migration. Our data suggested that miR-214-5p inhibited the invasion and migration of HepG2 and BEL-7402 by targeting WASL in Hepatocellular carcinoma. © 2018 The Author(s). Published by S. Karger AG, Basel.

Loss of coxsackie and adenovirus receptor expression in human colorectal cancer: A potential impact on the efficacy of adenovirus-mediated gene therapy in Chinese Han population.

PubMed

Ma, Ying-Yu; Wang, Xiao-Jun; Han, Yong; Li, Gang; Wang, Hui-Ju; Wang, Shi-Bing; Chen, Xiao-Yi; Liu, Fan-Long; He, Xiang-Lei; Tong, Xiang-Min; Mou, Xiao-Zhou

2016-09-01

The coxsackie and adenovirus receptor (CAR) is considered a tumor suppressor and critical factor for the efficacy of therapeutic strategies that employ the adenovirus. However, data on CAR expression levels in colorectal cancer are conflicting and its clinical relevance remains to be elucidated. Immunohistochemistry was performed on tissue microarrays containing 251 pairs of colon cancer and adjacent normal tissue samples from Chinese Han patients to assess the expression levels of CAR. Compared with healthy mucosa, decreased CAR expression (40.6% vs. 95.6%; P<0.001) was observed in colorectal cancer samples. The CAR immunopositivity in tumor tissues was not significantly associated with gender, age, tumor size, differentiation, TNM stage, lymph node metastasis or distant metastasis in patients with colon cancer. However, expression of CAR is present in 83.3% of the tumor tissues from patient with colorectal liver metastasis, which was significantly higher than those without liver metastasis (39.6%; P=0.042). At the plasma membrane, CAR was observed in 29.5% normal mucosa samples, which was significantly higher than in colorectal cancer samples (4.0%; P<0.001). In addition, the survival analysis demonstrated that the expression level of CAR has no association with the prognosis of colorectal cancer. CAR expression was observed to be downregulated in colorectal cancer, and it exerts complex effects during colorectal carcinogenesis, potentially depending on the stage of the cancer development and progression. High CAR expression may promote liver metastasis. With regard to oncolytic therapy, CAR expression analysis should be performed prior to adenoviral oncolytic treatment to stratify Chinese Han patients for treatment.

A Network Biology Approach Identifies Molecular Cross-Talk between Normal Prostate Epithelial and Prostate Carcinoma Cells

PubMed Central

Trevino, Victor; Cassese, Alberto; Nagy, Zsuzsanna; Zhuang, Xiaodong; Herbert, John; Antzack, Philipp; Clarke, Kim; Davies, Nicholas; Rahman, Ayesha; Campbell, Moray J.; Bicknell, Roy; Vannucci, Marina; Falciani, Francesco

2016-01-01

Abstract The advent of functional genomics has enabled the genome-wide characterization of the molecular state of cells and tissues, virtually at every level of biological organization. The difficulty in organizing and mining this unprecedented amount of information has stimulated the development of computational methods designed to infer the underlying structure of regulatory networks from observational data. These important developments had a profound impact in biological sciences since they triggered the development of a novel data-driven investigative approach. In cancer research, this strategy has been particularly successful. It has contributed to the identification of novel biomarkers, to a better characterization of disease heterogeneity and to a more in depth understanding of cancer pathophysiology. However, so far these approaches have not explicitly addressed the challenge of identifying networks representing the interaction of different cell types in a complex tissue. Since these interactions represent an essential part of the biology of both diseased and healthy tissues, it is of paramount importance that this challenge is addressed. Here we report the definition of a network reverse engineering strategy designed to infer directional signals linking adjacent cell types within a complex tissue. The application of this inference strategy to prostate cancer genome-wide expression profiling data validated the approach and revealed that normal epithelial cells exert an anti-tumour activity on prostate carcinoma cells. Moreover, by using a Bayesian hierarchical model integrating genetics and gene expression data and combining this with survival analysis, we show that the expression of putative cell communication genes related to focal adhesion and secretion is affected by epistatic gene copy number variation and it is predictive of patient survival. Ultimately, this study represents a generalizable approach to the challenge of deciphering cell communication networks in a wide spectrum of biological systems. PMID:27124473

A Network Biology Approach Identifies Molecular Cross-Talk between Normal Prostate Epithelial and Prostate Carcinoma Cells.

PubMed

Trevino, Victor; Cassese, Alberto; Nagy, Zsuzsanna; Zhuang, Xiaodong; Herbert, John; Antczak, Philipp; Clarke, Kim; Davies, Nicholas; Rahman, Ayesha; Campbell, Moray J; Guindani, Michele; Bicknell, Roy; Vannucci, Marina; Falciani, Francesco

2016-04-01

The advent of functional genomics has enabled the genome-wide characterization of the molecular state of cells and tissues, virtually at every level of biological organization. The difficulty in organizing and mining this unprecedented amount of information has stimulated the development of computational methods designed to infer the underlying structure of regulatory networks from observational data. These important developments had a profound impact in biological sciences since they triggered the development of a novel data-driven investigative approach. In cancer research, this strategy has been particularly successful. It has contributed to the identification of novel biomarkers, to a better characterization of disease heterogeneity and to a more in depth understanding of cancer pathophysiology. However, so far these approaches have not explicitly addressed the challenge of identifying networks representing the interaction of different cell types in a complex tissue. Since these interactions represent an essential part of the biology of both diseased and healthy tissues, it is of paramount importance that this challenge is addressed. Here we report the definition of a network reverse engineering strategy designed to infer directional signals linking adjacent cell types within a complex tissue. The application of this inference strategy to prostate cancer genome-wide expression profiling data validated the approach and revealed that normal epithelial cells exert an anti-tumour activity on prostate carcinoma cells. Moreover, by using a Bayesian hierarchical model integrating genetics and gene expression data and combining this with survival analysis, we show that the expression of putative cell communication genes related to focal adhesion and secretion is affected by epistatic gene copy number variation and it is predictive of patient survival. Ultimately, this study represents a generalizable approach to the challenge of deciphering cell communication networks in a wide spectrum of biological systems.

Circular RNA hsa_circ_0016788 regulates hepatocellular carcinoma tumorigenesis through miR-486/CDK4 pathway.

PubMed

Guan, Zheng; Tan, Jing; Gao, Wei; Li, Xin; Yang, Yuandong; Li, Xiaogang; Li, Yingchao; Wang, Qiang

2018-06-19

Recent studies have revealed that circular RNAs (circRNAs) play important roles in the tumorigenesis of human cancer, including hepatocellular carcinoma (HCC). In present study, we screen the circular RNA expression profiles in HCC tissue and investigate the molecular roles on HCC tumorigenesis. Human circRNA microarray analysis showed there were total 1,245 differently expressed circular RNAs, including 756 up-regulated circRNAs and 489 down-regulated circRNAs, in three pairs of HCC tissue and adjacent normal tissue. Hsa_circ_0016788 was identified to be up-regulated in both HCC tissue and cell lines. Loss-of-functional experiments in vivo and vitro revealed that hsa_circ_0016788 silencing inhibited the proliferation, invasion and promoted the apoptosis in vitro, and inhibited the tumor growth in vivo. Bioinformatics tools and luciferase reporter assay validated that miR-486 targeted hsa_circ_0016788 and CDK4 accompanying with negatively correlated expression, suggesting the hsa_circ_0016788/miR-486/CDK4 pathway. Receiver operating characteristic (ROC) curve showed that hsa_circ_0016788 had high diagnostic value (AUC = 0.851). In summary, results reveal the role of hsa_circ_0016788/miR-486/CDK4 in HCC tumorigenesis, providing a novel therapeutic target for HCC. © 2018 Wiley Periodicals, Inc.

Depletion of Pokemon gene inhibits hepatocellular carcinoma cell growth through inhibition of H-ras.

PubMed

Zhang, Quan-Le; Tian, De-An; Xu, Xiang-Jiang

2011-01-01

Pokemon is a transcription repressor which plays a critical role in cell transformation and malignancy. However, little is known about its effect on the development and progression of hepatocellular carcinoma (HCC). The aim of this study was to investigate the expression of Pokemon in human HCC tissues and the biological behavior of Pokemon in HCC cells in which it is overexpressed. We also explored the expression of potential downstream cofactors of Pokemon. Reverse transcription polymerase chain reaction and Western blot analysis were used to investigate the expression of Pokemon in tissues of 30 HCC patients. We then examined cell proliferation or apoptosis and β-catenin or H-ras expression in Pokemon-depleted HepG(2) cells using DNA vector-based RNA interference technology. Pokemon was markedly expressed in 22/30 (73.3%) HCC tissues, with expression levels higher than in adjacent normal liver tissues (p < 0.05); expression is correlated with tumor size. In contrast, depletion of Pokemon inhibited proliferation of HepG(2) or induced apoptosis. Also, H-ras expression decreased to a large extent. Pokemon exerts its oncogenic activity in the development of HCC by promoting cancer cell growth and reducing apoptosis, and the effect may be mediated by H-ras. Copyright © 2011 S. Karger AG, Basel.

Quantitative mass spectrometry imaging of emtricitabine in cervical tissue model using infrared matrix-assisted laser desorption electrospray ionization

PubMed Central

Bokhart, Mark T.; Rosen, Elias; Thompson, Corbin; Sykes, Craig; Kashuba, Angela D. M.; Muddiman, David C.

2015-01-01

A quantitative mass spectrometry imaging (QMSI) technique using infrared matrix-assisted laser desorption electrospray ionization (IR-MALDESI) is demonstrated for the antiretroviral (ARV) drug emtricitabine in incubated human cervical tissue. Method development of the QMSI technique leads to a gain in sensitivity and removal of interferences for several ARV drugs. Analyte response was significantly improved by a detailed evaluation of several cationization agents. Increased sensitivity and removal of an isobaric interference was demonstrated with sodium chloride in the electrospray solvent. Voxel-to-voxel variability was improved for the MSI experiments by normalizing analyte abundance to a uniformly applied compound with similar characteristics to the drug of interest. Finally, emtricitabine was quantified in tissue with a calibration curve generated from the stable isotope-labeled analog of emtricitabine followed by cross-validation using liquid chromatography tandem mass spectrometry (LC-MS/MS). The quantitative IR-MALDESI analysis proved to be reproducible with an emtricitabine concentration of 17.2±1.8 μg/gtissue. This amount corresponds to the detection of 7 fmol/voxel in the IR-MALDESI QMSI experiment. Adjacent tissue slices were analyzed using LC-MS/MS which resulted in an emtricitabine concentration of 28.4±2.8 μg/gtissue. PMID:25318460

Apoptosis inhibitor 5 (API-5; AAC-11; FIF) is upregulated in human carcinomas in vivo.

PubMed

Koci, Lenka; Chlebova, Katarina; Hyzdalova, Martina; Hofmanova, Jirina; Jira, Miroslav; Kysela, Petr; Kozubik, Alois; Kala, Zdenek; Krejci, Pavel

2012-04-01

Apoptosis inhibitor 5 (API-5) is a 55 kDa nuclear protein with potent anti-apoptotic signaling in tumor cells in vitro. In this study, we analyzed the expression of the API-5 protein in vivo in a broad spectrum of human carcinomas, including those of the colon, lung, liver, kidney, pancreas, stomach and esophagus using tumor tissues obtained during tumor resection. The results showed significant upregulation of API-5 expression in biopsies of lung (23%, n=13) and colorectal tumors (33%, n=27) in comparison with biopsies from the adjacent normal tissue. Colon cancer biopsies were used to study the cell populations with an upregulated level of expression of API-5 more closely. Using a magnetic bead-based selection for the epithelial cell marker EpCAM, we purified epithelial cells from the tumor and control tissues and analyzed these cells for API-5 expression by western immunoblotting. We observed that EpCAM-positive tumor cells expressed API-5 in all three colorectal cancer cases tested, in contrast to the control EpCAM-positive and EpCAM-negative cells isolated from the control or tumor tissues. These data suggest that the expression of the API-5 protein is upregulated in tumor epithelial cells and may serve as a prognostic marker in colorectal cancer.

Mammary Gland Involution Provides a Unique Model to Study the TGF-β Cancer Paradox

PubMed Central

Guo, Qiuchen; Betts, Courtney; Pennock, Nathan; Mitchell, Elizabeth; Schedin, Pepper

2017-01-01

Transforming Growth Factor-β (TGF-β) signaling in cancer has been termed the “TGF-β paradox”, acting as both a tumor suppresser and promoter. The complexity of TGF-β signaling within the tumor is context dependent, and greatly impacted by cellular crosstalk between TGF-β responsive cells in the microenvironment including adjacent epithelial, endothelial, mesenchymal, and hematopoietic cells. Here we utilize normal, weaning-induced mammary gland involution as a tissue microenvironment model to study the complexity of TGF-β function. This article reviews facets of mammary gland involution that are TGF-β regulated, namely mammary epithelial cell death, immune activation, and extracellular matrix remodeling. We outline how distinct cellular responses and crosstalk between cell types during physiologically normal mammary gland involution contribute to simultaneous tumor suppressive and promotional microenvironments. We also highlight alternatives to direct TGF-β blocking anti-cancer therapies with an emphasis on eliciting concerted microenvironmental-mediated tumor suppression. PMID:28098775

Microarray profiles reveal that circular RNA hsa_circ_0007385 functions as an oncogene in non-small cell lung cancer tumorigenesis.

PubMed

Jiang, Ming-Ming; Mai, Zhi-Tao; Wan, Shan-Zhi; Chi, Yu-Min; Zhang, Xin; Sun, Bao-Hua; Di, Qing-Guo

2018-04-01

Circular RNAs (circRNAs) are a novel class of non-protein-coding RNA. Emerging evidence indicates that circRNAs participate in the regulation of many pathophysiological processes. This study aims to explore the expression profiles and pathological effects of circRNAs in non-small cell lung cancer (NSCLC). Human circRNAs microarray analysis was performed to screen the expression profile of circRNAs in NSCLC tissue. Expressions of circRNA and miRNA in NSCLC tissues and cells were quantified by qRTPCR. Functional experiments were performed to investigate the biological functions of circRNA, including CCK-8 assay, colony formation assay, transwell assay and xenograft in vivo assay. Human circRNAs microarray revealed a total 957 abnormally expressed circRNAs (> twofold, P < 0.05) in NSCLC tissue compared with adjacent normal tissue. In further studies, hsa_circ_0007385 was significantly up regulated in NSCLC tissue and cells. In vitro experiments with hsa_circ_0007385 knockdown resulted in significant suppression of the proliferation, migration and invasion of NSCLC cells. In vivo xenograft assay using hsa_circ_0007385 knockdown, significantly reduced tumor growth. Bioinformatics analysis and luciferase reporter assay verified the potential target miR-181, suggesting a possible regulatory pathway for hsa_circ_0007385. In summary, results suggest hsa_circ_0007385 plays a role in NSCLC tumorigenesis, providing a potential therapeutic target for NSCLC.

Biomechanics of Hybrid Anterior Cervical Fusion and Artificial Disc Replacement in 3-Level Constructs: An In Vitro Investigation

PubMed Central

Liao, Zhenhua; Fogel, Guy R.; Pu, Ting; Gu, Hongsheng; Liu, Weiqiang

2015-01-01

Background The ideal surgical approach for cervical disk disease remains controversial, especially for multilevel cervical disease. The purpose of this study was to investigate the biomechanics of the cervical spine after 3-level hybrid surgery compared with 3-level anterior cervical discectomy and fusion (ACDF). Material/Methods Eighteen human cadaveric spines (C2-T1) were evaluated under displacement-input protocol. After intact testing, a simulated hybrid construct or fusion construct was created between C3 to C6 and tested in the following 3 conditions: 3-level disc plate disc (3DPD), 3-level plate disc plate (3PDP), and 3-level plate (3P). Results Compared to intact, almost 65~80% of motion was successfully restricted at C3-C6 fusion levels (p<0.05). 3DPD construct resulted in slight increase at the 3 instrumented levels (p>0.05). 3PDP construct resulted in significant decrease of ROM at C3-C6 levels less than 3P (p<0.05). Both 3DPD and 3PDP caused significant reduction of ROM at the arthrodesis level and produced motion increase at the arthroplasty level. For adjacent levels, 3P resulted in markedly increased contribution of both upper and lower adjacent levels (p<0.05). Significant motion increases lower than 3P were only noted at partly adjacent levels in some conditions for 3DPD and 3PDP (p<0.05). Conclusions ACDF eliminated motion within the construct and greatly increased adjacent motion. Artificial cervical disc replacement normalized motion of its segment and adjacent segments. While hybrid conditions failed to restore normal motion within the construct, they significantly normalized motion in adjacent segments compared with the 3-level ACDF condition. The artificial disc in 3-level constructs has biomechanical advantages compared to fusion in normalizing motion. PMID:26529430

Biomechanics of Hybrid Anterior Cervical Fusion and Artificial Disc Replacement in 3-Level Constructs: An In Vitro Investigation.

PubMed

Liao, Zhenhua; Fogel, Guy R; Pu, Ting; Gu, Hongsheng; Liu, Weiqiang

2015-11-03

The ideal surgical approach for cervical disk disease remains controversial, especially for multilevel cervical disease. The purpose of this study was to investigate the biomechanics of the cervical spine after 3-level hybrid surgery compared with 3-level anterior cervical discectomy and fusion (ACDF). Eighteen human cadaveric spines (C2-T1) were evaluated under displacement-input protocol. After intact testing, a simulated hybrid construct or fusion construct was created between C3 to C6 and tested in the following 3 conditions: 3-level disc plate disc (3DPD), 3-level plate disc plate (3PDP), and 3-level plate (3P). Compared to intact, almost 65~80% of motion was successfully restricted at C3-C6 fusion levels (p<0.05). 3DPD construct resulted in slight increase at the 3 instrumented levels (p>0.05). 3PDP construct resulted in significant decrease of ROM at C3-C6 levels less than 3P (p<0.05). Both 3DPD and 3PDP caused significant reduction of ROM at the arthrodesis level and produced motion increase at the arthroplasty level. For adjacent levels, 3P resulted in markedly increased contribution of both upper and lower adjacent levels (p<0.05). Significant motion increases lower than 3P were only noted at partly adjacent levels in some conditions for 3DPD and 3PDP (p<0.05). ACDF eliminated motion within the construct and greatly increased adjacent motion. Artificial cervical disc replacement normalized motion of its segment and adjacent segments. While hybrid conditions failed to restore normal motion within the construct, they significantly normalized motion in adjacent segments compared with the 3-level ACDF condition. The artificial disc in 3-level constructs has biomechanical advantages compared to fusion in normalizing motion.

2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH) in a nude rat glioma model: implications for photodynamic therapy.

PubMed

Lobel, J; MacDonald, I J; Ciesielski, M J; Barone, T; Potter, W R; Pollina, J; Plunkett, R J; Fenstermaker, R A; Dougherty, T J

2001-01-01

In this study, we evaluated 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-alpha (HPPH or Photochlor) as a photosensitizer for the treatment of malignant gliomas by photodynamic therapy (PDT). We performed in vivo reflection spectroscopy in athymic rats to measure the attenuation of light in normal brain tissue. We also studied HPPH pharmacokinetics and PDT effects in nude rats with brain tumors derived from stereotactically implanted U87 human glioma cells. Rats implanted with tumors were sacrificed at designated time points to determine the pharmacokinetics of HPPH in serum, tumor, normal brain, and brain adjacent to tumor (BAT). HPPH concentrations in normal brain, BAT and tumor were determined using fluorescence spectroscopy. Twenty-four hours after intravenous injection of HPPH, we administered interstitial PDT treatment at a wavelength of 665 nm. Light was given in doses of 3.5, 7.5 or 15 J/cm at the tumor site and at a rate of 50 mW/cm. In vivo spectroscopy of normal brain tissue showed that the attenuation depth of 665 nm light is approximately 30% greater than that of 630 nm light used to activate Photofrin, which is currently being evaluated for PDT as an adjuvant to surgery for malignant gliomas. The t1/2 of disappearance of drug from serum and tumor was 25 and 30 hours, respectively. Twenty-four hours after injection of 0.5 mg/kg HPPH, tumor-to-brain drug ratios ranged from 5:1 to 15:1. Enhanced survival was observed in each of the HPPH/PDT-treated animal groups. These data suggest that HPPH may be a useful adjuvant for the treatment of malignant gliomas.

Variability in physical and biological exchange among coastal wetlands and their adjacent Great Lakes

EPA Science Inventory

Hydrology is a major governor of physically-driven exchange among coastal wetlands and the adjacent Great Lake, whereas fish movement is a major governor of biologically-driven exchange. We use data describing coastal wetland morphology, hydrology, water quality, and fish tissue...

Visualizing the Histotripsy Process: Bubble Cloud-Cancer Cell Interactions in a Tissue-Mimicking Environment.

PubMed

Vlaisavljevich, Eli; Maxwell, Adam; Mancia, Lauren; Johnsen, Eric; Cain, Charles; Xu, Zhen

2016-10-01

Histotripsy is a non-invasive ultrasonic ablation method that uses cavitation to mechanically fractionate tissue into acellular debris. With a sufficient number of pulses, histotripsy can completely fractionate tissue into a liquid-appearing homogenate with no cellular structures. The location, shape and size of lesion formation closely match those of the cavitation cloud. Previous work has led to the hypothesis that the rapid expansion and collapse of histotripsy bubbles fractionate tissue by inducing large stress and strain on the tissue structures immediately adjacent to the bubbles. In the work described here, the histotripsy bulk tissue fractionation process is visualized at the cellular level for the first time using a custom-built 2-MHz transducer incorporated into a microscope stage. A layer of breast cancer cells were cultured within an optically transparent fibrin-based gel phantom to mimic cells inside a 3-D extracellular matrix. To test the hypothesis, the cellular response to single and multiple histotripsy pulses was investigated using high-speed optical imaging. Bubbles were always generated in the extracellular space, and significant cell displacement/deformation was observed for cells directly adjacent to the bubble during both bubble expansion and collapse. The largest displacements were observed during collapse for cells immediately adjacent to the bubble, with cells moving more than 150-300 μm in less than 100 μs. Cells often underwent multiple large deformations (>150% strain) over multiple pulses, resulting in the bisection of cells multiple times before complete removal. To provide theoretical support to the experimental observations, a numerical simulation was conducted using a single-bubble model, which indicated that histotripsy exerts the largest strains and cell displacements in the regions immediately adjacent to the bubble. The experimental and simulation results support our hypothesis, which helps to explain the formation of the sharp lesions formed in histotripsy therapy localized to the regions directly exposed to the bubbles. Copyright © 2016 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Study of the expression and function of ACY1 in patients with colorectal cancer.

PubMed

Yu, Bing; Liu, Xuezhong; Cao, Xiuzhen; Zhang, Mingyue; Chang, Hong

2017-04-01

Aminoacylase 1 (ACY1) is important for regulating the proliferation of numerous types of cancer. However, the expression and mechanisms underlying the function of ACY1 in colorectal cancer remain unclear. In order to investigate the expression and function of ACY1 in colorectal cancer, tumor tissue and blood samples were collected for analysis from 132 patients diagnosed with colorectal cancer. Reverse transcription-quantitative polymerase chain reaction analysis and western blotting identified significantly increased expression of ACY1 mRNA in colorectal tumor tissue (P<0.05 vs. adjacent normal tissue) and notably increased ACY1 protein levels. This ACY1 mRNA expression was found to be positively correlated with tumor stage. In addition, plasma ACY1 concentration was increased in patients with colorectal cancer compared with healthy controls. Furthermore, in vitro knockdown of ACY1 in human colorectal cancer HT-29 cells was shown to inhibit proliferation and increase apoptosis. This effect was found to be associated with the activation of ERK1 and TGF-β1 signaling. In conclusion, the results of the present study suggest that ACY1 promotes tumor progression, and thus may be a potential target for the diagnosis and treatment of colorectal cancer.

Microstructure of enamel.

PubMed

Boyde, A

1997-01-01

Enamel is a composite material consisting of mineral and organic phases. The properties of the mineral phase are modulated dramatically by its division into microscopic crystals, cemented together by the organic matrix protein polymer. A good concept of the 3D orientations of the crystals derives from visualizing their growth perpendicular to the surface in which they develop, which is pitted by the secretory poles of the ameloblasts. The arrangement of the crystals is the cause of the discontinuities, known as the prism boundaries or junctions, in the otherwise continuous structure. These locations acquire a more concentrated organic matrix during maturation, and they are both crack stoppers and crack propagation tracks in the adult tissue. Any tendency of prisms to cleave may be reduced by their varicosities, which reflect daily variations in the rate of production; their cross-sectional shape; the non-parallelism of adjacent groups, which develops through translocation of groups of cells across the surface during development; and the support of any one microscopic tissue element by other tissue, including dentine, placed to resist an applied load. Incremental growth lines are preferential cleavage planes within the enamel. Failure patterns of enamel in normal and abnormal use can be explained by these parameters, with additional consideration of functional variation and fatigue.

29 CFR 1926.600 - Equipment.

Code of Federal Regulations, 2010 CFR

2010-07-01

... Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) SAFETY AND HEALTH REGULATIONS FOR CONSTRUCTION Motor Vehicles, Mechanized Equipment, and Marine..., adjacent to a highway in normal use, or adjacent to construction areas where work is in progress, shall...

Highly Tissue Substructure-Specific Effects of Human Papilloma Virus in Mucosa of HIV-Infected Patients Revealed by Laser-Dissection Microscopy-Assisted Gene Expression Profiling

PubMed Central

Baumgarth, Nicole; Szubin, Richard; Dolganov, Greg M.; Watnik, Mitchell R.; Greenspan, Deborah; Da Costa, Maria; Palefsky, Joel M.; Jordan, Richard; Roederer, Mario; Greenspan, John S.

2004-01-01

Human papilloma virus (HPV) causes focal infections of epithelial layers in skin and mucosa. HIV-infected patients on highly active antiretroviral therapy (HAART) appear to be at increased risk of developing HPV-induced oral warts. To identify the mechanisms that allow long-term infection of oral epithelial cells in these patients, we used a combination of laser-dissection microscopy (LDM) and highly sensitive and quantitative, non-biased, two-step multiplex real-time RT-PCR to study pathogen-induced alterations of specific tissue subcompartments. Expression of 166 genes was compared in three distinct epithelial and subepithelial compartments isolated from biopsies of normal mucosa from HIV-infected and non-infected patients and of HPV32-induced oral warts from HIV-infected patients. In contrast to the underlying HIV infection and/or HAART, which did not significantly elaborate tissue substructure-specific effects, changes in oral warts were strongly tissue substructure-specific. HPV 32 seems to establish infection by selectively enhancing epithelial cell growth and differentiation in the stratum spinosum and to evade the immune system by actively suppressing inflammatory responses in adjacent underlying tissues. With this highly sensitive and quantitative method tissue-specific expression of hundreds of genes can be studied simultaneously in a few cells. Because of its large dynamic measurement range it could also become a method of choice to confirm and better quantify results obtained by microarray analysis. PMID:15331396

Relationships between Circulating and Intraprostatic Sex Steroid Hormone Concentrations.

PubMed

Cook, Michael B; Stanczyk, Frank Z; Wood, Shannon N; Pfeiffer, Ruth M; Hafi, Muhannad; Veneroso, Carmela C; Lynch, Barlow; Falk, Roni T; Zhou, Cindy Ke; Niwa, Shelley; Emanuel, Eric; Gao, Yu-Tang; Hemstreet, George P; Zolfghari, Ladan; Carroll, Peter R; Manyak, Michael J; Sesterhann, Isabell A; Levine, Paul H; Hsing, Ann W

2017-11-01

Background: Sex hormones have been implicated in prostate carcinogenesis, yet epidemiologic studies have not provided substantiating evidence. We tested the hypothesis that circulating concentrations of sex steroid hormones reflect intraprostatic concentrations using serum and adjacent microscopically verified benign prostate tissue from prostate cancer cases. Methods: Incident localized prostate cancer cases scheduled for surgery were invited to participate. Consented participants completed surveys, and provided resected tissues and blood. Histologic assessment of the ends of fresh frozen tissue confirmed adjacent microscopically verified benign pathology. Sex steroid hormones in sera and tissues were extracted, chromatographically separated, and then quantitated by radioimmunoassays. Linear regression was used to account for variations in intraprostatic hormone concentrations by age, body mass index, race, and study site, and subsequently to assess relationships with serum hormone concentrations. Gleason score (from adjacent tumor tissue), race, and age were assessed as potential effect modifiers. Results: Circulating sex steroid hormone concentrations had low-to-moderate correlations with, and explained small proportions of variations in, intraprostatic sex steroid hormone concentrations. Androstane-3α,17β-diol glucuronide (3α-diol G) explained the highest variance of tissue concentrations of 3α-diol G (linear regression r 2 = 0.21), followed by serum testosterone and tissue dihydrotestosterone ( r 2 = 0.10), and then serum estrone and tissue estrone ( r 2 = 0.09). There was no effect modification by Gleason score, race, or age. Conclusions: Circulating concentrations of sex steroid hormones are poor surrogate measures of the intraprostatic hormonal milieu. Impact: The high exposure misclassification provided by circulating sex steroid hormone concentrations for intraprostatic levels may partly explain the lack of any consistent association of circulating hormones with prostate cancer risk. Cancer Epidemiol Biomarkers Prev; 26(11); 1660-6. ©2017 AACR . ©2017 American Association for Cancer Research.

New Technique of Exposed Glaucoma Drainage Tube Repair: Report of a Case.

PubMed

Berezina, Tamara L; Fechtner, Robert D; Cohen, Amir; Kim, Eliott E; Chu, David S

2015-01-01

We present the case of successful repair of an exposed glaucoma drainage tube by cornea graft fixation with tissue adhesive, and without subsequent coverage by adjacent conjunctiva or donor tissues. Patient with history of keratoglobus with thin cornea and sclera, and phthisical contralateral eye, underwent three unsuccessful corneal grafts followed by Boston type 1 keratoprosthesis in the right eye. Ahmed drainage device with sclera patch graft was implanted to control the intraocular pressure. Two years later the tube eroded through sclera graft and conjunctiva. Repair was performed by covering the tube with a corneal patch graft secured by tissue adhesive after the conjunctiva in this area was dissected away. The cornea graft was left uncovered due to fragility of adjacent conjunctiva. The healing of ocular and graft surfaces was complete prior to the 1 month follow-up. Conjunctival epithelium covered the corneal patch graft. At 12 months follow-up, the graft and the tube remained stable. Our report suggests that corneal patch graft fixation to the sclera by means of tissue adhesive, without closing the conjunctiva, can be considered as an effective alternative surgical approach for managing exposed glaucoma drainage tube, accompanied by adjacent conjunctiva tissue deficiency. How to cite this article: Berezina TL, Fechtner RD, Cohen A, Kim EE, Chu DS. New Technique of Exposed Glaucoma Drainage Tube Repair: Report of a Case. J Curr Glaucoma Pract 2015;9(2):62-64.

Fluid balance within the canine anterolateral compartment and its relationship to compartment syndromes.

PubMed

Hargens, A R; Akeson, W H; Mubarak, S J; Owen, C A; Evans, K L; Garetto, L P; Gonsalves, M R; Schmidt, D A

1978-06-01

Fluid homeostasis within muscle compartments is maintained by four pressures: capillary blood pressure, capillary blood oncotic pressure, tissue-fluid pressure, and tissue fluid oncotic pressure. As determined in the canine anterolateral compartment, capillary blood pressure is 25 +/- 3 millimeters of mercury; capillary blood oncotic pressure, 26 +/- 3 millimeters of mercury, tissue-pbessure, -2 +/- 2 millimeters of mercury; and tissue-fluid oncotic pressure, 11 +/- 1 millimeters of mercury. The wick technique allows direct measurement of tissue-fluid pressure in skeletal muscle and, with minor modifications, is adapted to collect microsamples of interstitial fluid for determinations of tissue-fluid oncotic pressure. The wick technique detects very slight fluctuations in intracompartmental pressure such as light finger compression, injection of small volumes of fluid, and even pulsation due to adjacent arterial pressure. Adjacent muscle compartments may contain different tissue-fluid pressure due to impermeable osseofascial barriers. Our results obtained in canine muscle compartments pressurized by infusion of autologous plasma suggest that risks of muscle damage are significant at intracompartmental pressures greater than thirty millimeters of mercury.

Polymorphism of A133S and promoter hypermethylation in Ras association domain family 1A gene (RASSF1A) is associated with risk of esophageal and gastric cardia cancers in Chinese population from high incidence area in northern China.

PubMed

Zhou, Sheng Li; Cui, Juan; Fan, Zong Min; Li, Xue Min; Li, Ji Lin; Liu, Bao Chi; Zhang, Dong Yun; Liu, Hong Yan; Zhao, Xue Ke; Song, Xin; Wang, Ran; Yan, Ze Chen; Yi, Hui Xing; Wang, Li Dong

2013-05-25

The role of tumor suppressor gene RASSF1A in the esophageal and gastric cardia carcinogenesis is still inconclusive. In this study, the polymorphism, promoter methylation and gene expression of RASSF1A were characterized in esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA). We firstly analyzed the prevalence of RASSF1A A133S in a total of 228 cancer patients with ESCC (n=112) and GCA (n=116) and 235 normal controls by polymerase chain reaction (PCR) and restriction enzyme-digestion assay. Then, the promoter methylation status of the RASSF1A in ESCC (n=143), GCA (n=92) and corresponding adjacent normal tissues were further investigated using methylation-specific PCR (MSP) approach. Finally, the RASSF1A protein expression were determined in ESCC (n=27), GCA (n=24) and the matched adjacent normal tissues by immunohistochemical method. The frequency of 133Ala/Se and Ser/Ser genotype was significantly higher in GCA patients than in normal controls (19.0% vs. 10.2%, P=0.02). Compared with Ala/Ala genotype, Ala/Se and Ser/Ser genotype significantly increased susceptibility to GCA (OR=2.06, 95% CI=1.09-3.97). However, this polymorphism had no association with ESCC (P=0.69). The promoter methylation of RASSF1A gene was significantly increased the risk to both ESCC (OR=5.90, 95% CI=2.78-12.52) and GCA (OR=7.50, 95% CI= 2.78-20.23). Promoter methylation of RASSF1A gene in ESCC was also associated with age and cancer cell differentiation (for age: OR=3.11, 95% CI=1.10-8.73; for differentiation: OR=0.29, 95% CI=0.12-0.69). RASSF1A positive expression was significantly decreased the risk of GCA (OR=0.16, 95% CI=0.03-0.83). In contrast, there was no statistical significance between RASSF1A positive expression and ESCC. The expression of RASSF1A protein trend to be positively related with older GCA patients (OR=16.20, 95% CI=1.57-167.74). The present findings suggest that alterations of RASSF1A may play an important role in gastric cardia carcinogenesis in terms of polymorphism, promoter hypermethylation and protein expression. Whereas, RASSF1A hypermethylation may probably also be involved in esophageal squamous cell carcinogenesis.

Differential expression of cytokeratin mRNA and protein in normal prostate, prostatic intraepithelial neoplasia, and invasive carcinoma.

PubMed Central

Yang, Y.; Hao, J.; Liu, X.; Dalkin, B.; Nagle, R. B.

1997-01-01

The expression of cytokeratin (CK) mRNA for CK5, -8, -14, -16, and -19 was investigated in normal prostate, prostatic intraepithelial neoplasia (PIN) lesions, and invasive carcinoma using in situ hybridization. Protein localization was carried out in adjacent sections using immunohistochemistry and correlated with mRNA expression. Snap-frozen human prostate samples including 22 examples of normal glands, 20 cases of PIN lesions, and 12 cases of invasive carcinoma were examined. CK5 and -14 mRNA and protein were prominently expressed only in the basal cells of normal glands and PIN lesions. CK14 mRNA was absent in the luminal cells of the most of the PIN lesions but was seen at a low level in some PIN lesions. CK14 protein was not detected in any PIN lesion, suggesting that, if the cell that makes up the PIN lesions is derived from a basal cell, CK14 translation is depressed although a low level of CK14 mRNA may persist. CK8 mRNA and protein were constitutively expressed in all epithelia of normal and abnormal prostate tissues. CK19 mRNA and protein were persistently expressed in both basal and luminal cells of the tubular portion of normal glands as well as PIN lesions, but were expressed heterogeneously in both basal and luminal cells of normal alveoli. CK16 mRNA was expressed in a similar pattern as CK19, but CK16 protein was not detected either in normal or in abnormal prostate tissues. In conclusion, the expression of CK19 in PIN lesions is similar to its tubular expression and would support an origin of PIN lesions from this structure rather than the alveolar portion of the glands. The similar cytokeratin expression between PIN lesions and invasive carcinoma further supports the concept that PIN is a precursor lesion of invasive carcinoma. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 PMID:9033282

Deep RNA sequencing analysis of readthrough gene fusions in human prostate adenocarcinoma and reference samples

PubMed Central

2011-01-01

Background Readthrough fusions across adjacent genes in the genome, or transcription-induced chimeras (TICs), have been estimated using expressed sequence tag (EST) libraries to involve 4-6% of all genes. Deep transcriptional sequencing (RNA-Seq) now makes it possible to study the occurrence and expression levels of TICs in individual samples across the genome. Methods We performed single-end RNA-Seq on three human prostate adenocarcinoma samples and their corresponding normal tissues, as well as brain and universal reference samples. We developed two bioinformatics methods to specifically identify TIC events: a targeted alignment method using artificial exon-exon junctions within 200,000 bp from adjacent genes, and genomic alignment allowing splicing within individual reads. We performed further experimental verification and characterization of selected TIC and fusion events using quantitative RT-PCR and comparative genomic hybridization microarrays. Results Targeted alignment against artificial exon-exon junctions yielded 339 distinct TIC events, including 32 gene pairs with multiple isoforms. The false discovery rate was estimated to be 1.5%. Spliced alignment to the genome was less sensitive, finding only 18% of those found by targeted alignment in 33-nt reads and 59% of those in 50-nt reads. However, spliced alignment revealed 30 cases of TICs with intervening exons, in addition to distant inversions, scrambled genes, and translocations. Our findings increase the catalog of observed TIC gene pairs by 66%. We verified 6 of 6 predicted TICs in all prostate samples, and 2 of 5 predicted novel distant gene fusions, both private events among 54 prostate tumor samples tested. Expression of TICs correlates with that of the upstream gene, which can explain the prostate-specific pattern of some TIC events and the restriction of the SLC45A3-ELK4 e4-e2 TIC to ERG-negative prostate samples, as confirmed in 20 matched prostate tumor and normal samples and 9 lung cancer cell lines. Conclusions Deep transcriptional sequencing and analysis with targeted and spliced alignment methods can effectively identify TIC events across the genome in individual tissues. Prostate and reference samples exhibit a wide range of TIC events, involving more genes than estimated previously using ESTs. Tissue specificity of TIC events is correlated with expression patterns of the upstream gene. Some TIC events, such as MSMB-NCOA4, may play functional roles in cancer. PMID:21261984

Triplex DNA-binding proteins are associated with clinical outcomes revealed by proteomic measurements in patients with colorectal cancer

PubMed Central

2012-01-01

Background Tri- and tetra-nucleotide repeats in mammalian genomes can induce formation of alternative non-B DNA structures such as triplexes and guanine (G)-quadruplexes. These structures can induce mutagenesis, chromosomal translocations and genomic instability. We wanted to determine if proteins that bind triplex DNA structures are quantitatively or qualitatively different between colorectal tumor and adjacent normal tissue and if this binding activity correlates with patient clinical characteristics. Methods Extracts from 63 human colorectal tumor and adjacent normal tissues were examined by gel shifts (EMSA) for triplex DNA-binding proteins, which were correlated with clinicopathological tumor characteristics using the Mann-Whitney U, Spearman’s rho, Kaplan-Meier and Mantel-Cox log-rank tests. Biotinylated triplex DNA and streptavidin agarose affinity binding were used to purify triplex-binding proteins in RKO cells. Western blotting and reverse-phase protein array were used to measure protein expression in tissue extracts. Results Increased triplex DNA-binding activity in tumor extracts correlated significantly with lymphatic disease, metastasis, and reduced overall survival. We identified three multifunctional splicing factors with biotinylated triplex DNA affinity: U2AF65 in cytoplasmic extracts, and PSF and p54nrb in nuclear extracts. Super-shift EMSA with anti-U2AF65 antibodies produced a shifted band of the major EMSA H3 complex, identifying U2AF65 as the protein present in the major EMSA band. U2AF65 expression correlated significantly with EMSA H3 values in all extracts and was higher in extracts from Stage III/IV vs. Stage I/II colon tumors (p = 0.024). EMSA H3 values and U2AF65 expression also correlated significantly with GSK3 beta, beta-catenin, and NF- B p65 expression, whereas p54nrb and PSF expression correlated with c-Myc, cyclin D1, and CDK4. EMSA values and expression of all three splicing factors correlated with ErbB1, mTOR, PTEN, and Stat5. Western blots confirmed that full-length and truncated beta-catenin expression correlated with U2AF65 expression in tumor extracts. Conclusions Increased triplex DNA-binding activity in vitro correlates with lymph node disease, metastasis, and reduced overall survival in colorectal cancer, and increased U2AF65 expression is associated with total and truncated beta-catenin expression in high-stage colorectal tumors. PMID:22682314

Food Impaction and Periodontal/Peri-Implant Tissue Conditions in Relation to the Embrasure Dimensions Between Implant-Supported Fixed Dental Prostheses and Adjacent Teeth: A Cross-Sectional Study.

PubMed

Jeong, Jin-Seok; Chang, Moontaek

2015-12-01

Food impaction and periodontal/peri-implant tissue conditions were evaluated in relation to the embrasure dimensions between implant-supported fixed dental prostheses (FDPs) and adjacent teeth. A total of 215 embrasures of 150 FDPs in 100 patients (55 males and 45 females, aged 27 to 83 years; mean age: 56 years) were included in the study. Clinical assessments of the periodontal/peri-implant mucosal conditions, radiographic assessments of embrasure dimensions, and overall patient satisfaction were used as explanatory variables for the food impaction and periodontal/peri-implant tissue conditions adjacent to implant-supported FDPs in the generalized estimating equation (GEE) analysis. Food impaction was reported in 96 (44.7%) of 215 embrasures between implant-supported FDPs and adjacent teeth. Food impaction was reported more frequently in the embrasures with proximal contact loss than in those with tight contact (P = 0.009). Overall patient satisfaction was influenced negatively by food impaction in the proximal embrasures (P = 0.01). Among embrasure dimensions, only the embrasure surface area (ESA) significantly influenced food impaction (P = 0.03). Significant influences of various embrasure dimensions on the periodontal/peri-implant mucosal conditions and bone level at the implant were found in the univariate and multivariate GEE analyses. Food impaction between implant-supported FDPs and adjacent teeth occurred more frequently when proximal contact was lost and ESA increased. Food impaction negatively affected overall patient satisfaction. Embrasure dimensions influenced the periodontal/peri-implant mucosal conditions and bone level at the implant.

Detection of doublecortin domain-containing 2 (DCDC2), a new candidate tumor suppressor gene of hepatocellular carcinoma, by triple combination array analysis

PubMed Central

2013-01-01

Background To detect genes correlated with hepatocellular carcinoma (HCC), we developed a triple combination array consisting of methylation array, gene expression array and single nucleotide polymorphism (SNP) array analysis. Methods A surgical specimen obtained from a 68-year-old female HCC patient was analyzed by triple combination array, which identified doublecortin domain-containing 2 (DCDC2) as a candidate tumor suppressor gene of HCC. Subsequently, samples from 48 HCC patients were evaluated for their DCDC2 methylation and expression status using methylation specific PCR (MSP) and semi-quantitative reverse transcriptase (RT) PCR, respectively. Then, we investigated the relationship between clinicopathological factors and methylation status of DCDC2. Results DCDC2 was revealed to be hypermethylated (methylation value 0.846, range 0–1.0) in cancer tissue, compared with adjacent normal tissue (0.212) by methylation array in the 68-year-old female patient. Expression array showed decreased expression of DCDC2 in cancerous tissue. SNP array showed that the copy number of chromosome 6p22.1, in which DCDC2 resides, was normal. MSP revealed hypermethylation of the promoter region of DCDC2 in 41 of the tumor samples. DCDC2 expression was significantly decreased in the cases with methylation (P = 0.048). Furthermore, the methylated cases revealed worse prognosis for overall survival than unmethylated cases (P = 0.048). Conclusions The present study indicates that triple combination array is an effective method to detect novel genes related to HCC. We propose that DCDC2 is a tumor suppressor gene of HCC. PMID:24034596

CD117 expression in operable oesophageal squamous cell carcinomas predicts worse clinical outcome

PubMed Central

Fan, Huijie; Yuan, Yuan; Wang, Junsheng; Zhou, Fuyou; Zhang, Mingzhi; Giercksky, Karl-Erik; Nesland, Jahn M; Suo, Zhenhe

2013-01-01

Aims To investigate the aberrant expression of CD117 in oesophageal squamous cell carcinoma (SCC) and its prognostic significance. Methods and results Immunohistochemical staining for CD117 was performed on tissue microarray and routine tissue sections from 157 oesophageal SCC patients and 10 normal oesophageal epithelia adjacent to tumour. The positive rate of CD117 expression was 29.9% in oesophageal SCC tissues, whereas no CD117 expression was detected in the 10 normal oesophageal epithelia. CD117 expression was significantly associated with T stage (P < 0.001), distant metastasis (P = 0.015), lymph node metastasis (P = 0.019), and clinical stage (P = 0.021). Progression-free survival in the patients with CD117-positive tumours was shorter than that in the patients with CD117-negative tumours (P = 0.010). In univariate analyses, CD117 expression was the most significant factor for overall survival of oesophageal SCC patients (P < 0.001), followed by lymph node metastasis (P = 0.001), T stage (P = 0.002), clinical stage (P = 0.006), distant metastasis (P = 0.020), and histological grade (P = 0.027). Multivariate analyses verified that CD117 expression was an independent prognostic marker for oesophageal SCC patients (P = 0.002). In addition, CD117 expression predicted poorer survival in patients without distant metastases. Conclusions CD117 expression in operable oesophageal SCC may be a valuable prognostic marker, and detection of its expression in clinical samples may be useful in defining a subclass of oesophageal SCCs with extremely poor clinical outcome, which may require a specially targeted treatment modality. PMID:23570416

Identification of the long non‑coding RNA LET as a novel tumor suppressor in gastric cancer.

PubMed

Tian, Jingjing; Hu, Xibao; Gao, Wei; Zhang, Jie; Chen, Ming; Zhang, Xinrong; Ma, Junhong; Yuan, Hongxia

2017-04-01

Long non-coding RNAs (lncRNAs) have emerged recently as important factors in regulating fundamental biological processes. Alterations in the expression and function of lncRNAs have been observed to promote tumor formation, progression and metastasis. Although downregulation of the expression levels of LET lncRNA in several tumors has been reported, its role in gastric cancer remains unknown. The aim of the present study was to investigate the expression and function of LET in gastric cancer development. The expression levels of LET in 37 pairs of gastric cancer and adjacent non‑tumor tissues were detected by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). In addition, LET expression in gastric cancer cell lines was analyzed by RT‑qPCR assay analysis. Furthermore, the impact of LET on cell proliferation, migration and apoptosis were detected using the cell counting kit‑8, wound scratch and ELISA assays, respectively. The results demonstrated that the expression level of LET was downregulated in gastric cancer tissues and cell lines (SGC‑7901 and MGC‑803) compared with normal tissues and a normal human gastric epithelial cell line (GES‑1). Restoration of LET expression using a synthesized recombinant overexpression vector transfected into SGC‑7901 and MGC‑803 cells, significantly inhibited cell proliferation and migration, and promoted cell apoptosis in vitro. The present study is the first to demonstrate that LET may function as a tumor suppressor in gastric cancer. The results indicate that LET may be a promising biomarker and/or a therapeutic target for gastric cancer.

Alterations of telomerase activity and terminal restriction fragment in gastric cancer and its premalignant lesions.

PubMed

Yang, S M; Fang, D C; Luo, Y H; Lu, R; Battle, P D; Liu, W W

2001-08-01

In order to explore the role of alterations of telomerase activity and terminal restriction fragment (TRF) length in the development and progression of gastric cancer. Telomerase activity was detected in 176 specimens of gastric mucosa obtained through an operation or endoscopical biopsy by using the telomeric repeat amplification protocol (TRAP) assay. Meanwhile, the mean length of TRF was measured with the use of a Southern blot in part of those samples. Telomerase activity was detected in 14 of 57 (24.6%) chronic atrophy gastritis patients, six of 18 (33.3%) intestinal metaplasia patients, three of eight (37.5%) dysplasia patients and 60 of 65 (92.3%) gastric cancer patients, respectively. Normal gastric mucosa revealed no telomerase activity. No association was found between telomerase activity and any clinicopathological parameters. The mean TRF length was decreased gradually with age in normal mucosa and in gastric cancer tissue. Regression analysis demonstrated that the reduction rate in these tissues was 41 +/- 12 base pairs/year. Among 35 gastric cancers, TRF length was shown to be shorter in 20 cases (57.1%), similar in 12 cases (34.3%) and elongated in three cases (7.6%), compared to the corresponding adjacent tissues. The mean TRF length tended to decrease as the mucosa underwent chronic atrophy gastritis, intestinal metaplasia, dysplasia and into gastric cancer. The mean TRF length in gastric cancer was not statistically correlated with clinicopathological parameters and telomerase activity. Our results suggest that telomerase is expressed during the early stage of gastric carcinogenesis, and that the clinical significance of TRF length appears to be limited in gastric cancer.

Suppression subtractive hybridization identified differentially expressed genes in lung adenocarcinoma: ERGIC3 as a novel lung cancer-related gene

PubMed Central

2013-01-01

Background To understand the carcinogenesis caused by accumulated genetic and epigenetic alterations and seek novel biomarkers for various cancers, studying differentially expressed genes between cancerous and normal tissues is crucial. In the study, two cDNA libraries of lung cancer were constructed and screened for identification of differentially expressed genes. Methods Two cDNA libraries of differentially expressed genes were constructed using lung adenocarcinoma tissue and adjacent nonmalignant lung tissue by suppression subtractive hybridization. The data of the cDNA libraries were then analyzed and compared using bioinformatics analysis. Levels of mRNA and protein were measured by quantitative real-time polymerase chain reaction (q-RT-PCR) and western blot respectively, as well as expression and localization of proteins were determined by immunostaining. Gene functions were investigated using proliferation and migration assays after gene silencing and gene over-expression. Results Two libraries of differentially expressed genes were obtained. The forward-subtracted library (FSL) and the reverse-subtracted library (RSL) contained 177 and 59 genes, respectively. Bioinformatic analysis demonstrated that these genes were involved in a wide range of cellular functions. The vast majority of these genes were newly identified to be abnormally expressed in lung cancer. In the first stage of the screening for 16 genes, we compared lung cancer tissues with their adjacent non-malignant tissues at the mRNA level, and found six genes (ERGIC3, DDR1, HSP90B1, SDC1, RPSA, and LPCAT1) from the FSL were significantly up-regulated while two genes (GPX3 and TIMP3) from the RSL were significantly down-regulated (P < 0.05). The ERGIC3 protein was also over-expressed in lung cancer tissues and cultured cells, and expression of ERGIC3 was correlated with the differentiated degree and histological type of lung cancer. The up-regulation of ERGIC3 could promote cellular migration and proliferation in vitro. Conclusions The two libraries of differentially expressed genes may provide the basis for new insights or clues for finding novel lung cancer-related genes; several genes were newly found in lung cancer with ERGIC3 seeming a novel lung cancer-related gene. ERGIC3 may play an active role in the development and progression of lung cancer. PMID:23374247

MMP13 is potentially a new tumor marker for breast cancer diagnosis.

PubMed

Chang, Hui-Jen; Yang, Ming-Je; Yang, Yu-Hsiang; Hou, Ming-Feng; Hsueh, Er-Jung; Lin, Shiu-Ru

2009-11-01

Within the past decade, the incidence of breast cancer in Taiwan has been rising year after year. Breast cancer is the first most prevalent cancer and the fourth leading cause of cancer-related deaths among women in Taiwan. The early stage of breast cancer not only have a wider range of therapeutic options, but also obtain a higher success rate of therapy than those with advanced breast cancer. A test for tumor markers is the most convenient method to screen for breast cancer. However, the tumor markers currently available for breast cancer detection include carcinoembryonic antigen (CEA), carbohydrate antigen 15.3 (CA15.3), and carbohydrate antigen 27.29 (CA27.29) exhibited certain limitations. Poor sensitivity and specificity greatly limits the diagnostic accuracy of these markers. This study aims to identify potential tumor markers for breast cancer. At first, we analyzed genes expression in infiltrating lobular carcinoma, metaplastic carcinoma, and infiltrating ductal carcinoma of paired specimens (tumor and normal tissue) from breast cancer patients using microarray technology. We selected 371 overexpressed genes in all of the three cell type. In advanced breast cancer tissue, we detected four genes MMP13, CAMP, COL10A1 and FLJ25416 from 25 overexpressed genes which encoded secretion protein more specifically for breast cancer than other genes. After validation with 15 pairs of breast cancer tissue and paired to normal adjacent tissues by membrane array and quantitative RT-PCR, we found MMP13 was 100% overexpressed and confirmed to be a secreted protein by Western blot analysis of the cell culture medium. The expression level of MMP13 was also measured by immunohistochemical staining. We suggest that MMP13 is a highly overexpressed secretion protein in breast cancer tissue. It has potential to be a new tumor marker for breast cancer diagnosis.

MicroRNA-145 is regulated by DNA methylation and p53 gene mutation in prostate cancer

PubMed Central

Suh, Seong O.; Chen, Yi; Zaman, Mohd Saif; Hirata, Hiroshi; Yamamura, Soichiro; Shahryari, Varahram; Liu, Jan; Tabatabai, Z.Laura; Kakar, Sanjay; Deng, Guoren; Tanaka, Yuichiro; Dahiya, Rajvir

2011-01-01

MiR-145 is downregulated in various cancers including prostate cancer. However, the underlying mechanisms of miR-145 downregulation are not fully understood. Here, we reported that miR-145 was silenced through DNA hypermethylation and p53 mutation status in laser capture microdissected (LCM) prostate cancer and matched adjacent normal tissues. In 22 of 27 (81%) prostate tissues, miR-145 was significantly downregulated in the cancer compared with the normal tissues. Further studies on miR-145 downregulation mechanism showed that miR-145 is methylated at the promoter region in both prostate cancer tissues and 50 different types of cancer cell lines. In seven cancer cell lines with miR-145 hypermethylation, 5-aza-2′-deoxycytidine treatment dramatically induced miR-145 expression. Interestingly, we also found a significant correlation between miR-145 expression and the status of p53 gene in both LCM prostate tissues and 47 cancer cell lines. In 29 cell lines with mutant p53, miR-145 levels were downregulated in 28 lines (97%), whereas in 18 cell lines with wild-type p53 (WT p53), miR-145 levels were downregulated in only 6 lines (33%, P < 0.001). Electrophoretic mobility shift assay showed that p53 binds to the p53 response element upstream of miR-145, but the binding was inhibited by hypermethylation. To further confirm that p53 binding to miR-145 could regulate miR-145 expression, we transfected WT p53 and MUT p53 into PC-3 cells and found that miR-145 is upregulated by WT p53 but not with MUTp53. The apoptotic cells are increased after WT p53 transfection. In summary, this is the first report documenting that downregulation of miR-145 is through DNA methylation and p53 mutation pathways in prostate cancer. PMID:21349819

Repair of Craniomaxillofacial Traumatic Soft Tissue Defects With Tissue Expansion in the Early Stage.

PubMed

Han, Yan; Zhao, Jianhui; Tao, Ran; Guo, Lingli; Yang, Hongyan; Zeng, Wei; Song, Baoqiang; Xia, Wensen

2017-09-01

Craniomaxillofacial traumatic soft tissue defects severely affect the function and appearance of the patients. The traditional skin grafting or free flap transplantation can only close the defects in the early stage of operation but cannot ensure similar color, texture, and relative aesthetic contour. In the present study, the authors have explored a novel strategy to repair craniomaxillofacial traumatic soft tissue defects by tissue expansion in the early stage and have obtained satisfactory results. Eighteen patients suffering large craniomaxillofacial traumatic soft tissue defects were treated by thorough debridement leaving the wounds unclosed or simply closed with thin split-thickness scalp grafts, adjacent expander implantation in the first stage, and expanded flap transposition in the second stage. There were 11 male patients and 7 female patients ranging in age from 3.5 to 40 years (mean, 19.4 ± 12.2 years), with average 15 months follow-up (range, 3-67 months). The average expansion time was 74.3 days (range, 53-96 days). The 18 patients with a total of 22 expanders were treated with satisfactory results. All the flaps survived and the skin color, texture, and contour well matched those of the peripheral tissue. Only 1 complication of infection happened in the 18 cases (5.56%) and the 22 expanders (4.55%), which was similar to the rate reported in the literature. No other complications related to the expanders occurred. Debridement and tissue expansion in the early stage has been proved to be a more effective strategy to repair craniomaxillofacial traumatic soft tissue defects. This strategy can not only achieve satisfactory color, unbulky and well-matched texture similar to normal, but also avoid unnecessary donor site injuries.

Polyisoprenylated methylated protein methyl esterase is both sensitive to curcumin and overexpressed in colorectal cancer: implications for chemoprevention and treatment.

PubMed

Amissah, Felix; Duverna, Randolph; Aguilar, Byron J; Poku, Rosemary A; Lamango, Nazarius S

2013-01-01

Inhibition of PMPMEase, a key enzyme in the polyisoprenylation pathway, induces cancer cell death. In this study, purified PMPMEase was inhibited by the chemopreventive agent, curcumin, with a K(i) of 0.3 μM (IC50 = 12.4 μM). Preincubation of PMPMEase with 1 mM curcumin followed by gel-filtration chromatography resulted in recovery of the enzyme activity, indicative of reversible inhibition. Kinetics analysis with N-para-nitrobenzoyl-S-trans,trans-farnesylcysteine methyl ester substrate yielded K M values of 23.6 ± 2.7 and 85.3 ± 15.3 μM in the absence or presence of 20 μM curcumin, respectively. Treatment of colorectal cancer (Caco2) cells with curcumin resulted in concentration-dependent cell death with an EC50 of 22.0 μg/mL. PMPMEase activity in the curcumin-treated cell lysate followed a similar concentration-dependent profile with IC50 of 22.6 μg/mL. In colorectal cancer tissue microarray studies, PMPMEase immunoreactivity was significantly higher in 88.6% of cases compared to normal colon tissues (P < 0.0001). The mean scores ± SEM were 91.7 ± 11.4 (normal), 75.0 ± 14.4 (normal adjacent), 294.8 ± 7.8 (adenocarcinoma), and 310.0 ± 22.6 (mucinous adenocarcinoma), respectively. PMPMEase overexpression in colorectal cancer and cancer cell death stemming from its inhibition is an indication of its possible role in cancer progression and a target for chemopreventive agents.

Polyisoprenylated Methylated Protein Methyl Esterase Is Both Sensitive to Curcumin and Overexpressed in Colorectal Cancer: Implications for Chemoprevention and Treatment

PubMed Central

Amissah, Felix; Duverna, Randolph; Aguilar, Byron J.; Poku, Rosemary A.; Lamango, Nazarius S.

2013-01-01

Inhibition of PMPMEase, a key enzyme in the polyisoprenylation pathway, induces cancer cell death. In this study, purified PMPMEase was inhibited by the chemopreventive agent, curcumin, with a K i of 0.3 μM (IC50 = 12.4 μM). Preincubation of PMPMEase with 1 mM curcumin followed by gel-filtration chromatography resulted in recovery of the enzyme activity, indicative of reversible inhibition. Kinetics analysis with N-para-nitrobenzoyl-S-trans,trans-farnesylcysteine methyl ester substrate yielded K M values of 23.6 ± 2.7 and 85.3 ± 15.3 μM in the absence or presence of 20 μM curcumin, respectively. Treatment of colorectal cancer (Caco2) cells with curcumin resulted in concentration-dependent cell death with an EC50 of 22.0 μg/mL. PMPMEase activity in the curcumin-treated cell lysate followed a similar concentration-dependent profile with IC50 of 22.6 μg/mL. In colorectal cancer tissue microarray studies, PMPMEase immunoreactivity was significantly higher in 88.6% of cases compared to normal colon tissues (P < 0.0001). The mean scores ± SEM were 91.7 ± 11.4 (normal), 75.0 ± 14.4 (normal adjacent), 294.8 ± 7.8 (adenocarcinoma), and 310.0 ± 22.6 (mucinous adenocarcinoma), respectively. PMPMEase overexpression in colorectal cancer and cancer cell death stemming from its inhibition is an indication of its possible role in cancer progression and a target for chemopreventive agents. PMID:23936796

Smad4 loss in mice causes spontaneous head and neck cancer with increased genomic instability and inflammation.

PubMed

Bornstein, Sophia; White, Ruth; Malkoski, Stephen; Oka, Masako; Han, Gangwen; Cleaver, Timothy; Reh, Douglas; Andersen, Peter; Gross, Neil; Olson, Susan; Deng, Chuxia; Lu, Shi-Long; Wang, Xiao-Jing

2009-11-01

Smad4 is a central mediator of TGF-beta signaling, and its expression is downregulated or lost at the malignant stage in several cancer types. In this study, we found that Smad4 was frequently downregulated not only in human head and neck squamous cell carcinoma (HNSCC) malignant lesions, but also in grossly normal adjacent buccal mucosa. To gain insight into the importance of this observation, we generated mice in which Smad4 was deleted in head and neck epithelia (referred to herein as HN-Smad4-/- mice) and found that they developed spontaneous HNSCC. Interestingly, both normal head and neck tissue and HNSCC from HN-Smad4-/- mice exhibited increased genomic instability, which correlated with downregulated expression and function of genes encoding proteins in the Fanconi anemia/Brca (Fanc/Brca) DNA repair pathway linked to HNSCC susceptibility in humans. Consistent with this, further analysis revealed a correlation between downregulation of Smad4 protein and downregulation of the Brca1 and Rad51 proteins in human HNSCC. In addition to the above changes in tumor epithelia, both normal head and neck tissue and HNSCC from HN-Smad4-/- mice exhibited severe inflammation, which was associated with increased expression of TGF-beta1 and activated Smad3. We present what we believe to be the first single gene-knockout model for HNSCC, in which both HNSCC formation and invasion occurred as a result of Smad4 deletion. Our results reveal an intriguing connection between Smad4 and the Fanc/Brca pathway and highlight the impact of epithelial Smad4 loss on inflammation.

DNA methylation analysis reveals distinct methylation signatures in pediatric germ cell tumors.

PubMed

Amatruda, James F; Ross, Julie A; Christensen, Brock; Fustino, Nicholas J; Chen, Kenneth S; Hooten, Anthony J; Nelson, Heather; Kuriger, Jacquelyn K; Rakheja, Dinesh; Frazier, A Lindsay; Poynter, Jenny N

2013-06-27

Aberrant DNA methylation is a prominent feature of many cancers, and may be especially relevant in germ cell tumors (GCTs) due to the extensive epigenetic reprogramming that occurs in the germ line during normal development. We used the Illumina GoldenGate Cancer Methylation Panel to compare DNA methylation in the three main histologic subtypes of pediatric GCTs (germinoma, teratoma and yolk sac tumor (YST); N = 51) and used recursively partitioned mixture models (RPMM) to test associations between methylation pattern and tumor and demographic characteristics. We identified genes and pathways that were differentially methylated using generalized linear models and Ingenuity Pathway Analysis. We also measured global DNA methylation at LINE1 elements and evaluated methylation at selected imprinted loci using pyrosequencing. Methylation patterns differed by tumor histology, with 18/19 YSTs forming a distinct methylation class. Four pathways showed significant enrichment for YSTs, including a human embryonic stem cell pluripotency pathway. We identified 190 CpG loci with significant methylation differences in mature and immature teratomas (q < 0.05), including a number of CpGs in stem cell and pluripotency-related pathways. Both YST and germinoma showed significantly lower methylation at LINE1 elements compared with normal adjacent tissue while there was no difference between teratoma (mature and immature) and normal tissue. DNA methylation at imprinted loci differed significantly by tumor histology and location. Understanding methylation patterns may identify the developmental stage at which the GCT arose and the at-risk period when environmental exposures could be most harmful. Further, identification of relevant genetic pathways could lead to the development of new targets for therapy.

[Expressions of heat shock protein (HSP) family HSP 60, 70 and 90alpha in colorectal cancer tissues and their correlations to pathohistological characteristics].

PubMed

Zhang, Wen-Li; Gao, Xue-Qin; Han, Jin-Xiang; Wang, Guo-Qiang; Yue, Long-Tao

2009-06-01

Colorectal cancer is the third common malignant tumor in the world. Heat shock protein (HSP) family has been reported to play an important role in carcinogenesis of various cancers. However, little is known about expressions of HSP60,HSP70 and HSP90alpha in colorectal cancer. This study was to investigate expressions of HSP 60, 70 and 90alpha, and analyzed their correlations to pathohistologic characteristics in colorectal cancer. Colorectal cancer tissues and adjacent normal tissues 2 cm away from the tumor focus were collected from 49 patients. Expressions of HSP60, HSP70 and HSP90alpha mRNA were detected by RT-PCR. The protein expressions of HSP60, HSP70 and HSP90alpha were determined by immunohistochemistry and western blot. The mRNA and protein levels of HSP60, HSP70 and HSP90alpha, as well as their positive rates were significantly increased in tumor tissues compared with those in para-cancerous tissues. The overexpression rates of HSP60, HSP70 and HSP90alpha were also significantly higher in the colorectal cancer tissues than those in the corresponding para-cancerous tissues. The positive and overexpression rates of HSP60, HSP70 and HSP90alpha in well, moderately and poorly differentiated colorectal cancer were not significantly different. HSP60, HSP70 and HSP90alpha may play important roles in the pathogenesis of colorectal cancer, although they are not correlated with the pathological grading.

Association between promoter hypermethylation of the DACT2 gene and tumor stages in breast cancer.

PubMed

Marusa Borgonio-Cuadra, Veronica; Miranda-Duarte, Antonio; Rojas-Toledo, Xochitl; Garcia-Hernandez, Normand; Alfredo Sierra-Ramirez, Jose; Cardenas-Garcia, Maura; Elena Hernandez-Caballero, Marta

2018-01-01

Aberrant methylation of CpG islands in the promoter is a hallmark of cancer, leading to transcriptional silencing of tumor suppressor genes. The aim of this work was to evaluate the promoter methylation status of the DACT2 gene in breast cancer (BC) tissue and to analyze its possible effect on tumor type or grade. CpG island from the DACT2 promoter in region -240 to -14 from transcriptional start site (TSS) were obtained. Through the use of sodium bisulfite DNA conversion analysis, followed by detection with MSP (methylation specific PCR), we analyzed 79 BC and 15 adjacent healthy samples. T he c ases a nalyzed w ere i n s tage I ( 2.5%), I I (38%), or III (59.5%). The most frequent tumor type was invasive ductal carcinoma (71.4%). Methylation analysis comparing tumor tissues with adjacent non-cancerous tissues showed statistical significance. Methylation was observed in 32.9% (26/79) of the samples; no methylation was found in adjacent healthy tissue. DACT2 methylation was associated with tumor stage I-II (p=0.03) and stage III (p=0.004). An association was found of DACT2 promoter methylation with advanced tumor stages. This gene has been suggested as a potential biomarker, however, more investigation is required to validate this function.

Autologous chondrocyte implantation in knee joint: MR imaging and histologic features at 1-year follow-up.

PubMed

Tins, Bernhard J; McCall, Iain W; Takahashi, Tomoki; Cassar-Pullicino, Victor; Roberts, Sally; Ashton, Brian; Richardson, James

2005-02-01

To evaluate magnetic resonance (MR) imaging features of autologous chondrocyte implantation (ACI) grafts and compare these with graft histologic features 1 year after ACI for treatment of femoral condylar defects. This study was approved by the regional ethics committee, and all patients gave informed consent. Forty-one patients (mean age, 35 years; 30 men, 11 women) underwent ACI for treatment of femoral condylar defects. One year later, knee joint MR imaging and graft biopsy were performed. Graft biopsy results were categorized into those showing hyaline, mixed fibrohyaline cartilage, fibrocartilage, and fibrous tissue. Standard T1-, T2-, T2*-, and intermediate-weighted sequences were performed, as well as three-dimensional (3D) fast low-angle shot (FLASH) and double-echo steady-state sequences for cartilage assessment. ACI grafts were assessed for signal intensity (with FLASH sequence), thickness, overgrowth, surface smoothness, integration to adjacent cartilage and underlying bone, bone marrow edema underneath graft, and contour of bone underneath graft. MR images were assessed by two observers, first independently and then in consensus. MR imaging findings were correlated with histologic findings. All 41 grafts were present at 1-year follow-up. The graft consisted of hyaline cartilage in four, mixed fibrohyaline cartilage in 10, fibrocartilage in 25, and fibrous tissue in two cases. Graft signal intensity was virtually always lower than adjacent normal cartilage signal intensity, and there was no relationship between graft signal intensity and histologic appearance (P = .34). Graft thickness (P = .83), overgrowth (P = .69), surface smoothness (P = .28), and integration with adjacent cartilage and underlying bone (P = .90); edema in bone marrow underneath graft (P = .63); and bone contour underneath graft (P = .94) at MR imaging had no correlation with graft histologic appearance. Graft overgrowth (n = 16; 39%) and edema-like signal in bone marrow underneath graft (n = 23; 56%) were common. The origin of graft overgrowth remains unclear. With the methods presented here, MR imaging findings cannot predict ACI graft histologic features, and graft histologic appearance determined at biopsy was not related to graft signal intensity, graft thickness, overgrowth, surface smoothness, integration with adjacent cartilage or underlying bone, signal intensity change in underlying bone marrow, or underlying bone contour. Overgrowth and bone marrow changes underneath the graft were common. (c) RSNA, 2004.

Targeted p120-catenin ablation disrupts dental enamel development.

PubMed

Bartlett, John D; Dobeck, Justine M; Tye, Coralee E; Perez-Moreno, Mirna; Stokes, Nicole; Reynolds, Albert B; Fuchs, Elaine; Skobe, Ziedonis

2010-09-16

Dental enamel development occurs in stages. The ameloblast cell layer is adjacent to, and is responsible for, enamel formation. When rodent pre-ameloblasts become tall columnar secretory-stage ameloblasts, they secrete enamel matrix proteins, and the ameloblasts start moving in rows that slide by one another. This movement is necessary to form the characteristic decussating enamel prism pattern. Thus, a dynamic system of intercellular interactions is required for proper enamel development. Cadherins are components of the adherens junction (AJ), and they span the cell membrane to mediate attachment to adjacent cells. p120 stabilizes cadherins by preventing their internalization and degradation. So, we asked if p120-mediated cadherin stability is important for dental enamel formation. Targeted p120 ablation in the mouse enamel organ had a striking effect. Secretory stage ameloblasts detached from surrounding tissues, lost polarity, flattened, and ameloblast E- and N-cadherin expression became undetectable by immunostaining. The enamel itself was poorly mineralized and appeared to be composed of a thin layer of merged spheres that abraded from the tooth. Significantly, p120 mosaic mouse teeth were capable of forming normal enamel demonstrating that the enamel defects were not a secondary effect of p120 ablation. Surprisingly, blood-filled sinusoids developed in random locations around the developing teeth. This has not been observed in other p120-ablated tissues and may be due to altered p120-mediated cell signaling. These data reveal a critical role for p120 in tooth and dental enamel development and are consistent with p120 directing the attachment and detachment of the secretory stage ameloblasts as they move in rows.

Microenvironments in tuberculous granulomas are delineated by distinct populations of macrophage subsets and expression of nitric oxide synthase and arginase isoforms

PubMed Central

Mattila, Joshua T.; Ojo, Olabisi O.; Kepka-Lenhart, Diane; Marino, Simeone; Kim, Jin Hee; Eum, Seok Yong; Via, Laura E.; Barry, Clifton E.; Klein, Edwin; Kirschner, Denise E.; Morris, Sidney M.; Lin, Philana Ling; Flynn, JoAnne L.

2013-01-01

Macrophages in granulomas are both anti-mycobacterial effector and host cell for Mycobacterium tuberculosis(M.tb), yet basic aspects of macrophage diversity and function within the complex structures of granulomas remain poorly understood. To address this, we examined myeloid cell phenotypes and expression of enzymes correlated with host defense in macaque and human granulomas. Macaque granulomas had upregulated inducible and endothelial nitric oxide synthase (iNOS and eNOS) and arginase (Arg1 and Arg2) expression and enzyme activity compared to non-granulomatous tissue. Immunohistochemical analysis indicated macrophages adjacent to uninvolved normal tissue were more likely to express CD163, while epithelioid macrophages in regions where bacteria reside strongly expressed CD11c, CD68 and HAM56. Calprotectin-positive neutrophils were abundant in regions adjacent to caseum. iNOS, eNOS, Arg1 and Arg2 proteins were identified in macrophages and localized similarly in granulomas across species, with greater eNOS expression and ratio of iNOS:Arg1 expression in epithelioid macrophages, as compared to cells in the lymphocyte cuff. iNOS, Arg1 and Arg2 expression in neutrophils was also identified. The combination of phenotypic and functional markers support that macrophages with anti-inflammatory phenotypes localized to outer regions of granulomas while the inner regions were more likely to contain macrophages with pro-inflammatory, presumably bactericidal, phenotypes. Together these data support the concept that granulomas have organized microenvironments that balance anti-microbial anti-inflammatory responses to limit pathology in the lungs. PMID:23749634

Incremental Value of Magnetic Resonance Imaging in Further Characterizing Hypodense Mediastinal and Paracardiac Lesions Identified on Computed Tomography

PubMed Central

Chaturvedi, Abhishek; Gange, Chris; Sahin, Hakan; Chaturvedi, Apeksha

2018-01-01

Mediastinal and paracardiac lesions are usually first diagnosed on a chest radiograph or echocardiogram. Often, a computed tomography is obtained to further delineate these lesions. CT may be suboptimal for evaluation of enhancement characteristics and direct extension into the adjacent mediastinal structures. With its intrinsic superior soft-tissue characterization, magnetic resonance imaging (MRI) can better delineate these lesions, their internal tissue characteristics, and identify adhesion/invasion into adjacent structures. This pictorial essay provides a brief synopsis of the key MRI sequences and their utility in further characterizing mediastinal and paracardiac lesions. PMID:29619281

Melorheostosis of the axial skeleton with associated fibrolipomatous lesions

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

Garver, P.; Resnick, D.; Haghighi, P.

1982-11-01

Two patients with melorheostotic-like lesions of the axial skeleton are described. In each case adjacent soft tissue masses containing both fatty and fibrous tissues were evident. The presence of such soft tissue tumors as well as other soft tissue abnormalities in melorheostosis emphasizes that the diesease should not be regarded as one confined to bone. The precise pathogenesis of the osseous and soft tissue abnormalities in melorheostosis remains obscure.

"Radiobiology of Proton Therapy": Results of an international expert workshop.

PubMed

Lühr, Armin; von Neubeck, Cläre; Pawelke, Jörg; Seidlitz, Annekatrin; Peitzsch, Claudia; Bentzen, Søren M; Bortfeld, Thomas; Debus, Jürgen; Deutsch, Eric; Langendijk, Johannes A; Loeffler, Jay S; Mohan, Radhe; Scholz, Michael; Sørensen, Brita S; Weber, Damien C; Baumann, Michael; Krause, Mechthild

2018-05-31

The physical properties of proton beams offer the potential to reduce toxicity in tumor-adjacent normal tissues. Toward this end, the number of proton radiotherapy facilities has steeply increased over the last 10-15 years to currently around 70 operational centers worldwide. However, taking full advantage of the opportunities offered by proton radiation for clinical radiotherapy requires a better understanding of the radiobiological effects of protons alone or combined with drugs or immunotherapy on normal tissues and tumors. This report summarizes the main results of the international expert workshop "Radiobiology of Proton Therapy" that was held in November 2016 in Dresden. It addresses the major topics (1) relative biological effectiveness (RBE) in proton beam therapy, (2) interaction of proton radiobiology with radiation physics in current treatment planning, (3) biological effects in proton therapy combined with systemic treatments, and (4) testing biological effects of protons in clinical trials. Finally, important research avenues for improvement of proton radiotherapy based on radiobiological knowledge are identified. The clinical distribution of radiobiological effectiveness of protons alone or in combination with systemic chemo- or immunotherapies as well as patient stratification based on biomarker expressions are key to reach the full potential of proton beam therapy. Dedicated preclinical experiments, innovative clinical trial designs, and large high-quality data repositories will be most important to achieve this goal. Copyright © 2018 Elsevier B.V. All rights reserved.

Genome-Wide DNA Methylation Indicates Silencing of Tumor Suppressor Genes in Uterine Leiomyoma

PubMed Central

Navarro, Antonia; Yin, Ping; Monsivais, Diana; Lin, Simon M.; Du, Pan; Wei, Jian-Jun; Bulun, Serdar E.

2012-01-01

Background Uterine leiomyomas, or fibroids, represent the most common benign tumor of the female reproductive tract. Fibroids become symptomatic in 30% of all women and up to 70% of African American women of reproductive age. Epigenetic dysregulation of individual genes has been demonstrated in leiomyoma cells; however, the in vivo genome-wide distribution of such epigenetic abnormalities remains unknown. Principal Findings We characterized and compared genome-wide DNA methylation and mRNA expression profiles in uterine leiomyoma and matched adjacent normal myometrial tissues from 18 African American women. We found 55 genes with differential promoter methylation and concominant differences in mRNA expression in uterine leiomyoma versus normal myometrium. Eighty percent of the identified genes showed an inverse relationship between DNA methylation status and mRNA expression in uterine leiomyoma tissues, and the majority of genes (62%) displayed hypermethylation associated with gene silencing. We selected three genes, the known tumor suppressors KLF11, DLEC1, and KRT19 and verified promoter hypermethylation, mRNA repression and protein expression using bisulfite sequencing, real-time PCR and western blot. Incubation of primary leiomyoma smooth muscle cells with a DNA methyltransferase inhibitor restored KLF11, DLEC1 and KRT19 mRNA levels. Conclusions These results suggest a possible functional role of promoter DNA methylation-mediated gene silencing in the pathogenesis of uterine leiomyoma in African American women. PMID:22428009

Mouse mammary tumor virus-like RNA transcripts and DNA are found in affected cells of human breast cancer.

PubMed

Ford, Caroline E; Faedo, Margaret; Rawlinson, William D

2004-11-01

Identifiable risk factors for the development of breast cancer include age, diet, family history, and lifetime estrogen exposure. An infectious agent (mouse mammary tumor virus; MMTV) is known to cause murine breast tumors and may be involved in the pathogenesis of human disease. Multiple studies have detected MMTV-like sequences in 30 to 60% of breast cancer samples and up to 1.8% of samples from normal breast. Using in situ PCR of MMTV-like sequences of formalin-fixed, paraffin-embedded breast tissue, viral sequences have been located in cancerous epithelial cells in breast acini of male and female breast tumors, but not in adjacent nonmalignant cells. MMTV-like sequences were also located in the epithelial cells of male gynecomastia samples. Using reverse transcriptase in situ PCR, RNA transcripts from the env gene were also detected within cancerous epithelial cells of 78% of DNA-positive tumors, 80% of gynecomastia samples, and 0% of normal tissues screened. This suggests the virus may be replicating in these cells. The epidemiologic and histopathological data are consistent with the association of an MMTV-like virus with breast cancers in men and women. The association with gynecomastia, a benign, possibly premalignant condition suggests hormonal influences, rather than cancer per se, may be the dominant factor in determining viral presence and replication.

Identification of differentially expressed genes in human lung squamous cell carcinoma using suppression subtractive hybridization.

PubMed

Sun, Wenyue; Zhang, Kaitai; Zhang, Xinyu; Lei, Wendong; Xiao, Ting; Ma, Jinfang; Guo, Suping; Shao, Shujuan; Zhang, Husheng; Liu, Yan; Yuan, Jinsong; Hu, Zhi; Ma, Ying; Feng, Xiaoli; Hu, Songnian; Zhou, Jun; Cheng, Shujun; Gao, Yanning

2004-08-20

Lung cancer is one of the major causes of cancer-related deaths. Over the past decade, much has been known about the molecular changes associated with lung carcinogenesis; however, our understanding to lung tumorigenesis is still incomplete. To identify genes that are differentially expressed in squamous cell carcinoma (SCC) of the lung, we compared the expression profiles between primarily cultured SCC tumor cells and bronchial epithelial cells derived from morphologically normal bronchial epithelium of the same patient. Using suppression subtractive hybridization (SSH), two cDNA libraries containing up- and down-regulated genes in the tumor cells were constructed, named as LCTP and LCBP. The two libraries comprise 258 known genes and 133 unknown genes in total. The known up-regulated genes in the library LCTP represented a variety of functional groups; including metabolism-, cell adhesion and migration-, signal transduction-, and anti-apoptosis-related genes. Using semi-quantitative reverse transcription-polymerase chain reaction, seven genes chosen randomly from the LCTP were analyzed in the tumor tissue paired with its corresponding adjacent normal lung tissue derived from 16 cases of the SCC. Among them, the IQGAP1, RAP1GDS1, PAICS, MLF1, and MARK1 genes showed a consistent expression pattern with that of the SSH analysis. Identification and further characterization of these genes may allow a better understanding of lung carcinogenesis.

Ski protein levels increase during in vitro progression of HPV16-immortalized human keratinocytes and in cervical cancer

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

Chen, Yi; Pirisi, Lucia; Creek, Kim E., E-mail: creekk@sccp.sc.edu

2013-09-15

We compared the levels of the Ski oncoprotein, an inhibitor of transforming growth factor-beta (TGF-β) signaling, in normal human keratinocytes (HKc), HPV16 immortalized HKc (HKc/HPV16), and differentiation resistant HKc/HPV16 (HKc/DR) in the absence and presence of TGF-β. Steady-state Ski protein levels increased in HKc/HPV16 and even further in HKc/DR, compared to HKc. TGF-β treatment of HKc, HKc/HPV16, and HKc/DR dramatically decreased Ski. TGF-β-induced Ski degradation was delayed in HKc/DR. Ski and phospho-Ski protein levels are cell cycle dependent with maximal Ski expression and localization to centrosomes and mitotic spindles during G2/M. ShRNA knock down of Ski in HKc/DR inhibited cellmore » proliferation. More intense nuclear and cytoplasmic Ski staining and altered Ski localization were found in cervical cancer samples compared to adjacent normal tissue in a cervical cancer tissue array. Overall, these studies demonstrate altered Ski protein levels, degradation and localization in HPV16-transformed human keratinocytes and in cervical cancer. - Highlights: • Ski oncoprotein levels increase during progression of HPV16-transformed cells. • Ski and phospho-Ski protein levels are cell cycle dependent. • Ski knock-down in HPV16-transformed keratinocytes inhibited cell proliferation. • Cervical cancer samples overexpress Ski.« less

Clearance mechanism of a mannosylated antibody-enzyme fusion protein used in experimental cancer therapy.

PubMed

Kogelberg, Heide; Tolner, Berend; Sharma, Surinder K; Lowdell, Mark W; Qureshi, Uzma; Robson, Mathew; Hillyer, Tim; Pedley, R Barbara; Vervecken, Wouter; Contreras, Roland; Begent, Richard H J; Chester, Kerry A

2007-01-01

MFECP1 is a mannosylated antibody-enzyme fusion protein used in antibody-directed enzyme prodrug therapy (ADEPT). The antibody selectively targets tumor cells and the targeted enzyme converts a prodrug into a toxic drug. MFECP1 is obtained from expression in the yeast Pichia pastoris and produced to clinical grade. The P. pastoris-derived mannosylation of the fusion protein aids rapid normal tissue clearance required for successful ADEPT. The work presented provides evidence that MFECP1 is cleared by the endocytic and phagocytic mannose receptor (MR), which is known to bind to mannose-terminating glycans. MR-transfected fibroblast cells internalize MFECP1 as revealed by flow cytometry and confocal microscopy. Immunofluorescence microscopy shows that in vivo clearance in mice occurs predominantly by MR on liver sinusoidal endothelial cells, although MR is also expressed on adjacent Kupffer cells. In the spleen, MFECP1 is taken up by MR-expressing macrophages residing in the red pulp and not by dendritic cells which are found in the marginal zone and white pulp. Clearance can be inhibited in vivo by the MR inhibitor mannan as shown by increased enzyme activities in blood. The work improves understanding of interactions of MFECP1 with normal tissue, shows that glycosylation can be exploited in the design of recombinant anticancer therapeutics and opens the ways for optimizing pharmacokinetics of mannosylated recombinant therapeutics.

Estrogen receptor β expression and colorectal cancer: a systematic review and meta-analysis.

PubMed

Niv, Yaron

2015-12-01

Estrogen receptor β (ERβ) is a potential tumor-suppressor gene in colorectal cancer (CRC). This hypothesis is supported by clinical and laboratory observations. In this meta-analysis, we looked at studies that investigated the relationship between ERβ protein expression and CRC, comparing the lesion with normal adjacent mucosa. English medical literature searches were performed for ERβ expression in patients with CRC, tumor tissue versus normal mucosa. Searches were performed up to 31 May 2015, using MEDLINE, PubMed, EMBASE, Scopus, and CENTRAL. Meta-analysis was carried out using Comprehensive Meta-analysis Software. Pooled odds ratios and 95% confidence intervals were calculated and ERβ expression was compared in individual studies using the fixed-effects model. The odds ratio of ERβ expression was 0.216 (95% confidence interval 0.152-0.307, P<0.0001), lower in cancer tissue than normal mucosa. Funnel plot did not indicate a significant publication bias. There was no significant heterogeneity in the studies included: Q=5.897, d.f.(Q)=9, I=0.000, P=0.750. In this meta-analysis, we confirm the observation of decreased ERβ expression in CRC. Our results support the hypothesis of ERβ being a tumor-suppressor gene in the large bowel, and the ERβ protein protects against carcinogenesis and development of CRC when activated by estrogen. Further studies are needed to examine the potential of selective/specific ligands to activate ERβ without the side effects found with estrogen and without activating ERα. In this meta-analysis, we looked at studies that investigated the relationship between CRC and ERβ expression in the tumor and normal mucosa of CRC patients. English medical literature searches were performed for studies comparing ERβ expression in the cancer and normal colonic mucosa in patients with CRC. Meta-analysis was carried out, pooled odds ratios were calculated, and ERβ expression was compared in individual studies.

The mitochondrial C16069T polymorphism, not mitochondrial D310 (D-loop) mononucleotide sequence variations, is associated with bladder cancer.

PubMed

Shakhssalim, Nasser; Houshmand, Massoud; Kamalidehghan, Behnam; Faraji, Abolfazl; Sarhangnejad, Reza; Dadgar, Sepideh; Mobaraki, Maryam; Rosli, Rozita; Sanati, Mohammad Hossein

2013-12-05

Bladder cancer is a relatively common and potentially life-threatening neoplasm that ranks ninth in terms of worldwide cancer incidence. The aim of this study was to determine deletions and sequence variations in the mitochondrial displacement loop (D-loop) region from the blood specimens and tumoral tissues of patients with bladder cancer, compared to adjacent non-tumoral tissues. The DNA from blood, tumoral tissues and adjacent non-tumoral tissues of twenty-six patients with bladder cancer and DNA from blood of 504 healthy controls from different ethnicities were investigated to determine sequence variation in the mitochondrial D-loop region using multiplex polymerase chain reaction (PCR), DNA sequencing and southern blotting analysis. From a total of 110 variations, 48 were reported as new mutations. No deletions were detected in tumoral tissues, adjacent non-tumoral tissues and blood samples from patients. Although the polymorphisms at loci 16189, 16261 and 16311 were not significantly correlated with bladder cancer, the C16069T variation was significantly present in patient samples compared to control samples (p < 0.05). Interestingly, there was no significant difference (p > 0.05) of C variations, including C7TC6, C8TC6, C9TC6 and C10TC6, in D310 mitochondrial DNA between patients and control samples. Our study suggests that 16069 mitochondrial DNA D-Loop mutations may play a significant role in the etiology of bladder cancer and facilitate the definition of carcinogenesis-related mutations in human cancer.

75 FR 42729 - Cellu Tissue Corporation; Notice of Application Accepted for Filing, Soliciting Motions To...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-07-22

... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission [Project No. 2851-016] Cellu Tissue... the right bank of the river; (5) a 570-foot-long bypassed reach; (6) a powerhouse containing three... adjacent to the north wall of the Powerhouse; and (8) other appurtenances. Cellu Tissue Corporation...

Raman Spectroscopy Study of Prostatic Adenocarcinoma Bulk Tissues

NASA Astrophysics Data System (ADS)

Devpura, S.; Dai, H.; Thakur, J. S.; Naik, R.; Cao, A.; Pandya, A.; Auner, G. W.; Sarkar, F.; Sakr, W.; Naik, V.

2009-03-01

Prostate cancer is one of the most common types of cancer among men. The mortality rate for this disease can be dramatically reduced if it can be diagnosed in its early stages. Raman spectroscopy is one of the optical techniques which can provide fingerprints of a disease in terms of its molecular composition which changes due to the onset of disease. The aim of this project is to investigate the differences in the Raman spectra to identify benign epithelium (BE), prostatic intraepithelial neoplasia (PIN) and adenocarcinoma of various Gleason grades in archived bulk tissues embedded in paraffin wax. For each tissue, two adjacent tissue sections were cut and dewaxed, where one of the sections was stained using haematoxylin and eosin for histological examination and the other unstained adjacent section was used for Raman spectroscopic studies. We have collected Raman spectra from 10 prostatic adenocarcinoma dewaxed tissue sections using Raman microscope (785 nm excitation laser). The data were analyzed using statistical methods of principal component analysis and discriminant function analysis to classify the tissue regions. The results indicate that Raman Spectroscopy can differentiate between BE, PIN and Cancer regions.

Precursor B cell lymphoblastic lymphoma presenting as periorbital swelling

PubMed Central

Galway, Niamh; Johnston, Robert; Cairns, Carole; Thompson, Andrew James

2016-01-01

An 11-year-old girl was admitted for further investigation as to the cause of her bilateral papilloedema and periorbital swelling. She had a 2-week history of headache and unilateral eyelid swelling, and a 2-day history of right-sided groin swelling. CT and MRI scans revealed soft tissue adjacent to the lateral orbital walls within the extraconal lateral aspects of both orbits, more on the right than the left. The scans also revealed extensive lymphadenopathy above and below the diaphragm. The patient underwent bone marrow studies and biopsy of the lymph node in her groin. The results revealed normal bone marrow with no evidence of malignancy. The lymph node histology confirmed malignant lymphoma in keeping with B cell lymphoblastic lymphoma. The patient was started on the UKALL 2011 chemotherapy trial. PMID:27166006

Suppression of Rabbit VX‐2 Subcutaneous Tumor Growth by Gadolinium Neutron Capture Therapy

PubMed Central

Tokita, Nobuhiko; Tokuuye, Koichi; Satoh, Michinao; Churei, Hisahiko; Pechoux, Cécile Le; Kobayashi, Tooru; Kanda, Keiji

1993-01-01

VX‐2 tumors growing in hind legs of New Zealand White rabbits (n=4) were exposed to thermal neutrons for 40 min (2.1 × 1012 neutrons cm−2) while one of two hind leg tumors of each rabbit was infused continuously with meglumine gadopentetate through a branch of the left femoral artery. The contralateral (uninfused) tumors served as controls. Although no differential distribution of gadolinium was achieved between the tumor and its adjacent normal tissue, the gadolinium concentration in the infused tumor was approximately 5–6 fold higher than that in the contralateral tumor. Growth of gadolinium‐infused tumors was significantly inhibited compared to that of control tumors (P<0.05) between the 16th and 23rd days after treatment. PMID:8407547

A Review of the Positive Influence of Crown Contours on Soft-Tissue Esthetics.

PubMed

Kinsel, Richard P; Pope, Bryan I; Capoferri, Daniele

2015-05-01

Successful crown restorations duplicate the natural tooth in hue, chroma, value, maverick colors, and surface texture. Equally important is the visual harmony of the facial and proximal soft-tissue contours, which requires the collaborative skills of the restorative dentist, periodontist, and dental technician. The treatment team must understand the biologic structures adjacent to natural dentition and dental implants. This report describes the potential for specifically designed restorative contours to dictate the optimal gingival profile for tooth-supported and implant-supported crowns. Showing several cases, the article explains how esthetic soft-tissue contours enhance the definitive crown restoration, highlights the importance of clinical evaluation of adjacent biologic structures, and discusses keys to predicting when the proximal papilla has the potential to return to a favorable height and shape.

Tissue adhesion to bioactive glass-coated silicone tubing in a rat model of peritoneal dialysis catheters and catheter tunnels.

PubMed

Ross, Edward A; Batich, Christopher D; Clapp, William L; Sallustio, Judith E; Lee, Nadeen C

2003-02-01

Silicone peritoneal dialysis catheters do not develop tissue ingrowth, lack a mechanical barrier to periluminal bacterial migration and need cuffs for anchorage. We hypothesized that a bioactive glass coating composed of silicon, calcium, sodium and phosphorous oxides would cause a beneficial tissue reaction causing catheter adhesion, and tested this in a rat model. A hexane solvent-based method of coating silicone tubes with Bioglass powder was used, which maintained flexibility, and then the ultrastructure was confirmed with scanning electron microscopy (EM). Segments 2.5 cm were implanted subcutaneously in 8 Sprague-Dawley rats, with uncoated tubes as a contralateral control, and histology was done at 2, 4 and 6 weeks, including special stains and EM. The uncoated segments grossly had no adherence to surrounding tissue, and were physically separate from a thin fibrous capsule of approximately 50 micro width. Trichrome stains demonstrated the capsule was rich in collagen. There was minimal adjacent tissue reaction. In contrast, the coated tubes were palpably fixed to the soft tissues, and sections demonstrated an adjacent prominent layer of macrophages and multinucleated giant cells. Small numbers of lymphocytes were noted. This cellular reaction increased over the 6-week implant duration, and was also associated with neovascularization of the tissue adjacent to the segments (33 vessels in coated vs. 20 in controls per x 200 field, P < 0.0001). Many refractile silicone particles and prominent multinucleated giant cells were present, with small numbers of lymphocytes and macrophages. Stains showed scattered discontinuous calcific deposits. These findings are consistent with reports that the Bioglass(R) silicon oxide leads to the formation of a layer of hydroxyapatite, which binds to collagen and induces a tissue cellular reaction. In summary, bioactive glass coatings can improve the tissue retention of silicone tubing by promoting adhesion by collagen and cell proliferation, and are promising for future studies of peritoneal dialysis catheters.

Evaluation of different tissue de-paraffinization procedures for infrared spectral imaging.

PubMed

Nallala, Jayakrupakar; Lloyd, Gavin Rhys; Stone, Nicholas

2015-04-07

In infrared spectral histopathology, paraffin embedded tissues are often de-paraffinized using chemical agents such as xylene and hexane. These chemicals are known to be toxic and the routine de-waxing procedure is time consuming. A comparative study was carried out to identify alternate de-paraffinization methods by using paraffin oil and electronic de-paraffinization (using a mathematical computer algorithm) and their effectiveness was compared to xylene and hexane. Sixteen adjacent tissue sections obtained from a single block of a normal colon tissue were de-paraffinized using xylene, hexane and paraffin oil (+ hexane wash) at five different time points each for comparison. One section was reserved unprocessed for electronic de-paraffinization based on a modified extended multiplicative signal correction (EMSC). IR imaging was carried out on these tissue sections. Coefficients based on the fit of a pure paraffin model to the IR images were then calculated to estimate the amount of paraffin remaining after processing. Results indicate that on average xylene removes more paraffin in comparison to hexane and paraffin oil although the differences were small. This makes paraffin oil, followed by a hexane wash, an interesting and less toxic alternative method of de-paraffinization. However, none of the chemical methods removed paraffin completely from the tissues at any given time point. Moreover, paraffin was removed more easily from the glandular regions than the connective tissue regions indicating a form of differential paraffin retention based on the histology. In such cases, the use of electronic de-paraffinization to neutralize such variances across different tissue regions might be considered. Moreover it is faster, reduces scatter artefacts by index matching and enables samples to be easily stored for further analysis if required.

Soft tissue hemangioma with osseous extension: a case report and review of the literature.

PubMed

Daoud, Alexander; Olivieri, Brandon; Feinberg, Daniel; Betancourt, Michel; Bockelman, Brian

2015-04-01

Soft tissue hemangiomas are commonly encountered lesions, accounting for 7-10 % of all benign soft tissue masses (Mitsionis et al. J Foot Ankle Surg 16(2):27-9, 2010). While the literature describes the great majority of hemangiomas as asymptomatic and discovered only as incidental findings, they do have the potential to induce reactive changes in neighboring structures (Pastushyn et al. Surg Neurol 50(6):535-47, 1998). When these variants occur in close proximity to bone, they may elicit a number of well-documented reactive changes in osseous tissue (Mitsionis et al. J Foot Ankle Surg 16(2):27-9, 2010; DeFilippo et al. Skelet Radiol 25(2):174-7, 1996; Ly et al. AJR Am J Roentgenol 180(6):1695-700, 2003; Sung et al. Skelet Radiol 27(4):205-10, 1998). However, instances of direct extension into bone by soft tissue hemangiomas--that is, infiltration of the mass's vascular components into nearby osseous tissue--are currently undocumented in the literature. In these cases, imaging plays an important role in differentiating hemangiomas from malignant lesions (Mitsionis et al. J Foot Ankle Surg 16(2):27-9, 2010; Sung et al. Skelet Radiol 27(4):205-10, 1998; Pourbagher, Br J Radiol 84(1008):1100-8, 2011). In this article, we present such a case that involved the sacral spine. Imaging revealed a soft tissue mass with direct extension of vascular components into osseous tissue of the adjacent sacral vertebrae. Biopsy and subsequent histopathologic examination led to definitive diagnosis of soft tissue hemangioma. While MRI is widely regarded as the gold standard imaging modality for evaluating hemangiomas, in this report we describe how CT can aid in narrowing the differential diagnosis when one encounters a vascular lesion with adjacent osseous changes. Furthermore, we review the literature as it pertains to the imaging of soft tissue hemangiomas that occur in proximity to osseous tissue, as well as correlate this case to current theories on the pathogenesis of hemangiomas. Radiologists should be aware that benign soft tissue hemangiomas demonstrate a spectrum of imaging findings, including aggressive-appearing changes to adjacent bone.

Tissue factor levels and the fibrinolytic system in thin and thick intraluminal thrombus and underlying walls of abdominal aortic aneurysms.

PubMed

Siennicka, Aldona; Zuchowski, Marta; Kaczmarczyk, Mariusz; Cnotliwy, Miłosław; Clark, Jeremy Simon; Jastrzębska, Maria

2018-03-20

The hemostatic system cooperates with proteolytic degradation in processes allowing abdominal aortic aneurysm (AAA) formation. In previous studies, it has been suggested that aneurysm rupture depends on intraluminal thrombus (ILT) thickness, which varies across each individual aneurysm. We hypothesized that hemostatic components differentially accumulate in AAA tissue in relation to ILT thickness. Thick (A1) and thin (B1) segments of ILTs and aneurysm wall sections A (adjacent to A1) and B (adjacent to B1) from one aneurysm sac were taken from 35 patients undergoing elective repair. Factor levels were measured using enzyme-linked immunosorbent assay of protein extract. Tissue factor (TF) activities were significantly higher in thinner segments of AAA (B1 vs A1, P = .003; B vs A, P < .001; B vs A1, P < .001; B vs B1, P = .001). Significantly higher tissue plasminogen activator was found in thick thrombus-covered wall segments (A) than in B, A1, and B1 (P = .015, P < .001, and P < .001, respectively). Plasminogen concentrations were highest in ILT. Concentrations of α 2 -antiplasmin in thin ILT adjacent walls (B) were higher compared with wall (A) adjacent to thick ILT (P = .021) and thick ILT (A1; P < .001). Significant correlations between levels of different factors were mostly found in thick ILT (A1). However, no correlations were found at B sites, except for a correlation between plasmin and TF activities (r = 0.55; P = .004). These results suggest that higher TF activities are present in thinner AAA regions. These parameters and local fibrinolysis may be part of the processes leading to destruction of the aneurysm wall. Copyright © 2018 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.

Optoacoustic monitoring of cutting efficiency and thermal damage during laser ablation.

PubMed

Bay, Erwin; Douplik, Alexandre; Razansky, Daniel

2014-05-01

Successful laser surgery is characterized by a precise cut and effective hemostasis with minimal collateral thermal damage to the adjacent tissues. Consequently, the surgeon needs to control several parameters, such as power, pulse repetition rate, and velocity of movements. In this study we propose utilizing optoacoustics for providing the necessary real-time feedback of cutting efficiency and collateral thermal damage. Laser ablation was performed on a bovine meat slab using a Q-switched Nd-YAG laser (532 nm, 4 kHz, 18 W). Due to the short pulse duration of 7.6 ns, the same laser has also been used for generation of optoacoustic signals. Both the shockwaves, generated due to tissue removal, as well as the normal optoacoustic responses from the surrounding tissue were detected using a single broadband piezoelectric transducer. It has been observed that the rapid reduction in the shockwave amplitude occurs as more material is being removed, indicating decrease in cutting efficiency, whereas gradual decrease in the optoacoustic signal likely corresponds to coagulation around the ablation crater. Further heating of the surrounding tissue leads to carbonization accompanied by a significant shift in the optoacoustic spectra. Our results hold promise for real-time monitoring of cutting efficiency and collateral thermal damage during laser surgery. In practice, this could eventually facilitate development of automatic cut-off mechanisms that will guarantee an optimal tradeoff between cutting and heating while avoiding severe thermal damage to the surrounding tissues.