DNA Repair Mechanisms in Colorectal Carcinogenesis

Colon cancer is among the most common cancers and the third cause of cancer deaths worldwide. If detected at an early stage, treatment might often lead to cure. The present review adduces the so far studied alterations in the expression of genes, as well as polymorphisms of genes engaged in DNA repair systems, with particular emphasis on indirect ones that are correlated with colorectal cancer. Such aberrations could be linked to an increased risk for the development of colorectal cancer and might serve as potential targets in the areas of prevention and therapy

DNA methylation-independent regulation of p16 in epithelial cells during mouse mammary gland development

p16 (INK4a) is a known negative regulator of the cell cycle acting up-stream of Rb to inhibit cellular growth. While the contribution of p16 to the tumorigenic process has been extensively studied, little is known about its role in the cellular differentiation process of normal cells. p16 expression in mammary gland epithelial cells and its possible mediation by DNA methylation was explored. The mammary glands from female mice (mus musculus) at distinct developmental stages (virgin, day 10 of lactation and day 3 of involution) were used. The expression pattern of p16 and the DNA methylases, DNMT1, 3a and 3b was investigated by semi-quantitative RT-PCR, in situ hybridization (ISH) and immunohistochemistry. The p16 methylation status was assesed by methylation-specific PCR (MSP). p16 was differentially expressed during distinct developmental stages and its transcriptional regulation was DNA methylation-independent, which was also corroborated by the expression pattern of the three known DNA methyltransferases (DNA MTase). The p16 expression level was elevated during involution compared to the corresponding expression level during lactation. p16 is differentially expressed during normal mammary gland development, which is not mediated by DNA methylation. © 2008 Landes Bioscience

An epitome of DNA repair related genes and mechanisms in thyroid carcinoma

Thyroid cancer presents a growing tendency during the last decades, particularly in regions affected by radiation exposure. The present review describes expression alterations and gene polymorphisms of DNA repair related molecules, leading to genomic instability and cell death, being associated with thyroid cancer. The referred variations in DNA repair related genes depict that indirect repair mechanisms are mainly correlated with thyroid gland carcinogenesis. Such abnormalities could participate in thyroid tumor development and progression and could be targeted for future prevention and therapy. © 2009 Elsevier Ireland Ltd. All rights reserved

Evaluation of FAK and src expression in human benign and malignant thyroid lesions

Focal Adhesion Kinase (FAK) and Src have been reported to regulate tumor growth, invasion, metastasis and angiogenesis. The present study aimed to evaluate by immunohistochemistry the clinical significance of FAK and Src expression in 108 patients with benign and malignant thyroid lesions. Total FAK expression provided a distinct discrimination between malignant and benign (p=0.00001), as well as between papillary carcinoma and hyperplastic nodules thyroid lesions (p=0.00005), being also associated with follicular cells' proliferative capacity (p=0.0003). In malignant thyroid lesions, total FAK expression was associated with tumor size (p=0.0455), and presence of capsular (p=0.0102) and lymphatic (p=0.0173) invasion. Total Src expression was borderline increased in cases of papillary carcinoma compared to hyperplastic nodules (p=0.0993), being also correlated with tumor size (p=0.0169). FAK and Src expression was ascribed to a significant extent to the phosphorylated forms of the enzymes, which provided a better discrimination between malignant and benign thyroid lesions. The current data revealed that FAK and to a lesser extent Src expression could be considered of clinical utility in thyroid neoplasia with potential use as therapeutic targets. © 2010 Arányi Lajos Foundation

Expression of DNA repair proteins MSH2, MLH1 and MGMT in human benign and malignant thyroid lesions: An immunohistochemical study

Background: DNA repair is a major defense mechanism, which contributes to the maintenance of genetic sequence, and minimizes cell death, mutation rates, replication errors, DNA damage persistence and genomic instability. Alterations in the expression levels of proteins participating in DNA repair mechanisms have been associated with several aspects of cancer biology. The present study aimed to evaluate the clinical significance of DNA repair proteins MSH2, MLH1 and MGMT in benign and malignant thyroid lesions. Material/Methods: MSH2, MLH1 and MGMT protein expression was assessed immunohistochemically on paraffinembedded thyroid tissues from 90 patients with benign and malignant lesions. Results: The expression levels of MLH1 was significantly upregulated in cases with malignant compared to those with benign thyroid lesions (p=0.038). The expression levels of MGMT was significantly downregulated in malignant compared to benign thyroid lesions (p=0.001). Similar associations for both MLH1 and MGMT between cases with papillary carcinoma and hyperplastic nodules were also noted (p=0.014 and p=0.026, respectively). In the subgroup of malignant thyroid lesions, MSH2 downregulation was significantly associated with larger tumor size (p=0.031), while MLH1 upregulation was significantly associated with the presence of lymphatic and vascular invasion (p=0.006 and p=0.002, respectively). Conclusions: Alterations in the mismatch repair proteins MSH2 and MLH1 and the direct repair protein MGMT may result from tumor development and/or progression. Further studies are recommended to draw definite conclusions on the clinical significance of DNA repair proteins in thyroid neoplasia. © Med Sci Monit

FAK-Src-paxillin system expression and disease outcome in human neuroblastoma

Background: Neuroblastoma (NB) often presents with metastatic disease and poor survival. The need for new prognostic markers remains invaluable. The FAK-Src-Paxillin protein system is associated with aggressive phenotype in adult malignancies but is largely unexplored in pediatric NB. Objective: To assess FAK-Src-Paxillin protein expression in human NB cell lines and clinical cytology material and to delineate its association with survival. Design/Methods: Western blot and immunohistochemistry were applied for FAK-Src-Paxillin expression in NB cell lines and 23 human cytology specimens, respectively. Protein expression in human clinical samples was correlated with clinicopathological parameters, MYCN amplification and survival. Results: FAK, Src and Paxillin proteins are expressed in human NB cells lines, and can be detected in clinical cytology specimens from NB patients, (59%, 32% and 33% respectively). Simultaneous FAK-Src-Paxillin expression was noted in 30% of NB patients. Children with concomitant positivity FAK, Src, and Paxillin tumors, as well as MYCN amplification, had increased mortality compared to those without. Conclusions: FAK-Src-Paxillin system is a marker of unfavorable prognosis for human NB patients but also a promising therapeutic target. © 2017 Taylor & Francis Group, LLC

Reliability, validity and minimal detectable change of the Mini-BESTest in Greek participants with chronic stroke.

OBJECTIVES: This study aimed to investigate the psychometric characteristics of reliability, validity and ability to detect change of a newly developed balance assessment tool, the Mini-BESTest, in Greek patients with stroke. DESIGN: A prospective, observational design study with test-retest measures was conducted. METHODS: A convenience sample of 21 Greek patients with chronic stroke (14 male, 7 female; age of 63 ± 16 years) was recruited. Two independent examiners administered the scale, for the inter-rater reliability, twice within 10 days for the test-retest reliability. Bland Altman Analysis for repeated measures assessed the absolute reliability and the Standard Error of Measurement (SEM) and the Minimum Detectable Change at 95% confidence interval (MDC95%) were established. The Greek Mini-BESTest (Mini-BESTestGR) was correlated with the Greek Berg Balance Scale (BBSGR) for assessing the concurrent validity and with the Timed Up and Go (TUG), the Functional Reach Test (FRT) and the Greek Falls Efficacy Scale-International (FES-IGR) for the convergent validity. RESULTS: The Mini-BESTestGR demonstrated excellent inter-rater reliability (ICC (95%CI) = 0.997 (0.995-0.999, SEM = 0.46) with the scores of two raters within the limits of agreement (meandif = -0.143 ± 0.727, p > 0.05) and test-retest reliability (ICC (95%CI) = 0.966 (0.926-0.988), SEM = 1.53). Additionally, the Mini-BESTestGRyielded very strong to moderate correlations with BBSGR(r = 0.924, p < 0.001), TUG (r = -0.823, p < 0.001), FES-IGR(r = -0.734, p < 0.001) and FRT (r = 0.689, p < 0.001). MDC95was 4.25 points. CONCLUSION: The exceptionally high reliability and the equally good validity of the Mini-BESTestGR, strongly support its utility in Greek people with chronic stroke. Its ability to identify clinically meaningful changes and falls risk need further investigation