The effect of chemotherapeutic agents on telomere length maintenance in breast cancer cell lines

Copyright @ 2014 the authors. This article is made available through the Brunel Open Access Publishing Fund. It is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.Mammalian telomeric DNA consists of tandem repeats of the sequence TTAGGG associated with a specialized set of proteins, known collectively as Shelterin. These telosomal proteins protect the ends of chromosomes against end-to-end fusion and degradation. Short telomeres in breast cancer cells confer telomere dysfunction and this can be related to Shelterin proteins and their level of expression in breast cancer cell lines. This study investigates whether expression of Shelterin and Shelterin-associated proteins are altered, and influence the protection and maintenance of telomeres, in breast cancer cells. 5-aza-2'-deoxycytidine (5-aza-CdR) and trichostatin A (TSA) were used in an attempt to reactivate the expression of silenced genes. Our studies have shown that Shelterin and Shelterin-associated genes were down-regulated in breast cancer cell lines; this may be due to epigenetic modification of DNA as the promoter region of POT1 was found to be partially methylated. Shelterin genes expression was up-regulated upon treatment of 21NT breast cancer cells with 5-aza-CdR and TSA. The telomere length of treated 21NT cells was measured by q-PCR showed an increase in telomere length at different time points. Our studies have shown that down-regulation of Shelterin genes is partially due to methylation in some epithelial breast cancer cell lines. Removal of epigenetic silencing results in up-regulation of Shelterin and Shelterin-associated genes which can then lead to telomere length elongation and stability

Telomere elongation in the breast cancer cell line 21NT after treatment with an epigenetic modifying drug

Background: Telomere length dysregulation plays a major role in cancer development and aging. Telomeres are maintained by a group of specialized genes known as shelterin and shelterin-associated proteins. In breast cancer lines it has been shown that shelterin proteins are dysregulated thereby affecting the telomere stability and contributing to the neoplastic conversion of the mammary epithelial cells. Interestingly, the regulation of some of the shelterin genes is thought to be controlled epigenetically. Methods and Results: In this study, we set out to measure the effect of increased shelterin gene expression on telomere length in breast cancer cell line 21NT treated with 5-aza-2-deoxycytidine (5-aza-CdR) using known telomere length assays. We measured telomere lengths using: Telomere Restriction Fragment length (TRF), absolute quantitative-PCR and cytogenetic Interphase Quantitative Fluorescent in situ Hybridization (iQ-FISH). We found that non-cytotoxic levels of 5-aza-CdR affect telomere lengths by causing a significant and stable increase in telomere lengths of the breast cancer cell line. The increase in telomere lengths was consistently observed when various telomere length methods were used. Conclusions: Further investigation is required to understand the underlying mechanism involved, and the significance of telomere length elongation in relation to clinical outcome when epigenetic modifying drugs are utilized.We thank Professor Robert Newbold for his support and for providing the opportunity to carry out this work within the Institute of Cancer Genetics and Pharmacogenomics, Brunel University London. HY was supported by a triennial project grant (Strategic Award) from the National Centre for Replacement, Refinement, and Reduction (NC3Rs) of animals in research (NC. K500045.1 and G0800697)

Efficacy of tenofovir disoproxil fumarate therapy in nucleoside-analogue naive Iranian patients treated for chronic hepatitis B

Background: Tenofovir disoproxil fumarate (TDF) is a new effective treatment option for patients with chronic hepatitis B (CHB). Objectives: To evaluate TDF efficacy in nucleos(t)ide analogues (NAs)-naive Iranian patients with CHB. Patients and Methods: The NA-naive patients received TDF for at least six months. The primary endpoint was the proportion of patients achieving a complete virological response (CVR) during the treatment. Multivariate Cox regression analysis determined predictive factors independently associated with the time to CVR. The secondary endpoints were biochemical and serological responses, frequency of virological breakthrough, genotypic resistance development, safety and tolerability. Results: In all, 93 patients (64.5 hepatitis B e antigen HBeAg-negative) were eligible. Of these, 70 patients completed 24 months of treatment. The cumulative CVR rates in HBeAg-negative and HBeAg-positive patients were 87% versus 53% at 24 months, respectively. The multivariate Cox regression model showed only HBeAg positivity at baseline and a high baseline HBV DNA level were independent factors predicting a CVR. No patient achieved hepatitis B surface antigen (HBsAg) and HBeAg loss or seroconversion and no virologic breakthrough occurred. A new amino acid substitution (rtD263E) was observed to develop in 60% of patients with viremia. Conclusions: The cumulative CVR rates showed that patients with HBeAg-negative have better virologic respond than those with HBeAg-positive during the same period. The rtD263E mutation might be associated with partial resistance to TDF. © 2015, Kowsar Corp

Fluoroscopic versus conventional computed tomography-guided biopsy

Background/Objective: To determine the success rate of computed tomographic (CT) fluoroscopic CT (CFT) and conventional CT (CCT) for needle navigation in biopsies from mediastinum. bone, and abdomen, liver and pelvis. Patients and Methods: Data from 122 consecutive percutaneous interventional biopsies performed with use of ECT guidance (mean age of 50.5: rage: 1-79 years) and 84 consecutive biopsis with CCT guidance (mean age: 50.7; range, 12-83 years) were gathered from the interventional radiologist and general practitioner. Results: The success rate of procedure was increased in the FCT group as compared with that of CCT group in some organs such as bone, abdomen, liver and pelvis. A statistically significant difference was noted when we compared FCT group with CCT in liver biopsies (P=0.019). The mean procedure time was lower in FCT group. The overall mean (±SD) FCT time was 200±90 (range: 20-400) sec; in CCT group, it was 420±260 (range: 605-800) second Conclusion: FCT facilities CT-guided biopsy procedure and reduces the procedure time by allowing visualization of the needle tip from skin entrance to the target point

Diagnostic accuracy of coronary calcium score less than 100 in excluding coronary artery disease

Background: Coronary artery calcium score (CACS) is a quantitative assessment of calcifications and an established predictor of cardiovascular events. Objectives: In this study, we evaluated the diagnostic accuracy, negative predictive value (NPV), positive predictive value (PPV), specificity and sensitivity of CACS less than 100 in predicting significant coronary artery stenosis in patients with risk of coronary artery disease (CAD) in a vessel-based analysis. Patients and Methods: A cross sectional study was carried out on a study population of 2527 consecutive stable patients with symptoms suggestive of CAD who were referred for coronary computed tomographic angiography (CCTA). We performed 1343 studies with 256 slice machine in Shahid Rajaee hospital and the other studies were carried out with 64 slice machine in Imam Khomeini hospital and the calcium score was quantified according to the Agatston method. Results: At the cutoff point of 100 for coronary calcium scoring, therewashigh specificity (87), high sensitivity (79), high efficiency (84), high PPV (79), and high NPV (87) in the diagnosis of significant stenosis in the whole heart. The frequency of zero calcium scoring was 59 in normal or nonsignificant stenosis and 7.6 in significant stenosis in the whole heart. Calcium scoring increased with greater severity of the arterial stenosis (P values < 0.001). Conclusion: We conclude that coronary calcium scoring provided useful information in the management of patients. In CACS less than 100, it has a NPV of 87 in excluding significant stenosis in patients with the risk of CAD but it does not have enough diagnostic accuracy for surely excluding coronary stenosis, so we should perform a combination of CACS and coronary CT angiography for patients. � 2016, Tehran University of Medical Sciences and Iranian Society of Radiology

Suprasternal innominate artery cannulation for reoperative aortic surgery: A technical note

Suprasternal cannulation of the innominate artery in aortic reoperations may be useful in specific situations. Over a period of 3.5 years, 9 patients (6 males, average age = 49.2 ± 16.1 years) underwent suprasternal cannulation prior to resternotomy. Cannulation was performed using a side graft. All operations were successfully completed. Two patients died after surgery because of coagulopathy and multiorgan failure. There were no complications related to access or technique, and no site complications were detected during follow-up. Suprasternal cannulation of the innominate artery may play a role in selected reoperations. © 2016 The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved

AN EVALUATION OF LANDSLIDE SUSCEPTIBILITY MAPPING USING REMOTE SENSING DATA AND MACHINE LEARNING ALGORITHMS IN IRAN

Landslide is painstaking as one of the most prevalent and devastating forms of mass movement that affects man and his environment. The specific objective of this research paper is to investigate the application and performances of some selected machine learning algorithms (MLA) in landslide susceptibility mapping, in Dodangeh watershed, Iran. A 112 sample point of the past landslide, occurrence or inventory data was generated from the existing and field observations. In addition, fourteen landslide-conditioning parameters were derived from DEM and other topographic databases for the modelling process. These conditioning parameters include total curvature, profile curvature, plan curvature, slope, aspect, altitude, topographic wetness index (TWI), topographic roughness index (TRI), stream transport index (STI), stream power index (SPI), lithology, land use, distance to stream, distance to the fault. Meanwhile, factor analysis was employed to optimize the landslide conditioning parameters and the inventory data, by assessing the multi-collinearity effects and outlier detections respectively. The inventory data is divided into 70% (78) training dataset and 30% (34) test dataset for model validation. The receiver operating characteristics (ROC) curve or area under curve (AUC) value was used for assessing the model's performance. The findings reveal that TRI has 0.89 collinearity effect based on variance-inflated factor (VIF) and based on Gini factor optimization total curvature is not significant in the model development, therefore the two parameters are excluded from the modelling. All the selected MLAs (RF, BRT, and DT) shown promising performances on landslide susceptibility mapping in Dodangeh watershed, Iran. The ROC curve for training and validation for RF are 86% success rate and 83% prediction rate implies the best model performance compared to BRT and DT, with ROC curve of 72% and 70% prediction rate, respectively. In conclusion, RF could be the best algorithm for producing landslide susceptibility map, and such results could be adopted for the decision-making process to support land use planner for improving landslide risk assessment in similar environmental settings