Investigation of DNA damage response and apoptotic gene methylation pattern in sporadic breast tumors using high throughput quantitative DNA methylation analysis technology

<p>Abstract</p> <p>Background-</p> <p>Sporadic breast cancer like many other cancers is proposed to be a manifestation of abnormal genetic and epigenetic changes. For the past decade our laboratory has identified genes involved in DNA damage response (DDR), apoptosis and immunesurvelliance pathways to influence sporadic breast cancer risk in north Indian population. Further to enhance our knowledge at the epigenetic level, we performed DNA methylation study involving 17 gene promoter regions belonging to DNA damage response (DDR) and death receptor apoptotic pathway in 162 paired normal and cancerous breast tissues from 81 sporadic breast cancer patients, using a high throughput quantitative DNA methylation analysis technology.</p> <p>Results-</p> <p>The study identified five genes with statistically significant difference between normal and tumor tissues. Hypermethylation of <it>DR5 </it>(P = 0.001)<it>, DCR1 </it>(P = 0.00001)<it>, DCR2 </it>(P = 0.0000000005) and <it>BRCA2 </it>(P = 0.007) and hypomethylation of <it>DR4 </it>(P = 0.011) in sporadic breast tumor tissues suggested a weak/aberrant activation of the DDR/apoptotic pathway in breast tumorigenesis. Negative correlation was observed between methylation status and transcript expression levels for <it>TRAIL</it>, <it>DR4</it>, <it>CASP8</it>, <it>ATM</it>, <it>CHEK2</it>, <it>BRCA1 </it>and <it>BRCA2 </it>CpG sites. Categorization of the gene methylation with respect to the clinicopathological parameters showed an increase in aberrant methylation pattern in advanced tumors. These uncharacteristic methylation patterns corresponded with decreased death receptor apoptosis (P = 0.047) and DNA damage repair potential (P = 0.004) in advanced tumors. The observation of BRCA2 -26 G/A 5'UTR polymorphism concomitant with the presence of methylation in the promoter region was novel and emerged as a strong candidate for susceptibility to sporadic breast tumors.</p> <p>Conclusion-</p> <p>Our study indicates that methylation of DDR-apoptotic gene promoters in sporadic breast cancer is not a random phenomenon. Progressive epigenetic alterations in advancing tumors result in aberrant DDR-apoptotic pathway thereby promoting tumor development. We propose, since pathological epigenetic changes of the DDR-apoptotic genes are reversible modifications, these could further be targeted for therapeutic interventions.</p

Financial considerations in the conduct of multi-centre randomised controlled trials: evidence from a qualitative study.

National Coordinating Centre for Research Methodology; Medical Research Council, UK Department of Health; Chief Scientist OfficeNot peer reviewedPublisher PD

The construction of an idealised urban masculinity among men with concurrent sexual partners in a South African township

Background : The perspectives of heterosexual males who have large sexual networks comprising concurrent sexual partners and who engage in high-risk sexual behaviours are scarcely documented. Yet these perspectives are crucial to understanding the high HIV prevalence in South Africa where domestic violence, sexual assault and rape are alarmingly high, suggesting problematic gender dynamics. Objective : To explore the construction of masculinities and men&#x0027;s perceptions of women and their sexual relationships, among men with large sexual networks and concurrent partners. Design : This qualitative study was conducted in conjunction with a larger quantitative survey among men at high risk of HIV, using respondent-driven sampling to recruit participants, where long referral chains allowed us to reach far into social networks. Twenty in-depth, open-ended interviews with South African men who had multiple and concurrent sexual partners were conducted. A latent content analysis was used to explore the characteristics and dynamics of social and sexual relationships. Results : We found dominant masculine ideals characterised by overt economic power and multiple sexual partners. Reasons for large concurrent sexual networks were the perception that women were too empowered, could not be trusted, and lack of control over women. Existing masculine norms encourage concurrent sexual networks, ignoring the high risk of HIV transmission. Biological explanations and determinism further reinforced strong and negative perceptions of women and female sexuality, which helped polarise men&#x0027;s interpretation of gender constructions. Conclusions : Our results highlight the need to address sexuality and gender dynamics among men in growing, informal urban areas where HIV prevalence is strikingly high. Traditional structures that could work as focal entry points should be explored for effective HIV prevention aimed at normative change among hard-to-reach men in high-risk urban and largely informal contexts

Intrinsic Doping in Electrodeposited ZnS Thin Films for Application in Large-Area Optoelectronic Devices

Zinc sulphide (ZnS) thin films with both n- and p-type electrical conductivity were grown on glass/fluorine-doped tin oxide-conducting substrates from acidic and aqueous solution containing ZnSO4 and (NH4)2S2O3 by simply changing the deposition potential in a two-electrode cell configuration. After deposition, the films were characterised using various analytical techniques. X-ray diffraction analysis reveals that the materials are amorphous even after heat treatment. Optical properties (transmittance, absorbance and optical bandgap) of the films were studied. The bandgaps of the films were found to be in the range (3.68–3.86) eV depending on the growth voltage. Photoelectrochemical cell measurements show both n- and p-type electrical conductivity for the films depending on the growth voltage. Scanning electron microscopy shows material clusters on the surface with no significant change after heat treatment at different temperatures. Atomic force microscopy shows that the surface roughness of these materials remain fairly constant reducing only from 18 nm to 17 nm after heat treatment. Thickness estimation of the films was also carried out using theoretical and experimental methods. Direct current conductivity measurements on both as-deposited and annealed films show that resistivity increased after heat treatment

Quality of life after gamma knife radiosurgery treatment in patients with a vestibular schwannoma: the patient’s perspective

This study evaluates the impact of gamma knife radiosurgery (GKRS) on the quality of life (QOL) of patients with a sporadic vestibular schwannoma (VS). This study pertains to 108 VS patients who had GKRS in the years 2003 through 2007. Two different QOL questionnaires were used: medical outcome study short form 36 (SF36) and Glasgow benefit inventory (GBI). Radiosurgery was performed using a Leksell 4C gamma knife. The results of the QOL questionnaires in relation to prospectively and retrospectively gathered data of the VS patients treated by GKRS. Eventually, 97 patients could be included in the study. Their mean tumor size was 17 mm (range 6–39 mm); the mean maximum dose on the tumor was 19.9 Gy (range 16–25.5 Gy) and the mean marginal dose on the tumor was 11.1 (range 9.3–12.5 Gy). SF36 scores showed results comparable to those for a normal Dutch population. GBI showed a marginal decline in QOL. No correlation was found between QOL and gender, age, tumor size, or radiation dose. Increased audiovestibular symptoms after GKRS were correlated with a decreased GBI score, and decreased symptoms were correlated with a higher QOL post-GKRS. In this study shows that GKRS for VS has little impact on the general QOL of the VS patient. However, there is a wide range in individual QOL results. Individual QOL was influenced by the audiovestibular symptoms. No predictive patient, tumor, or treatment factors for QOL outcome after GKRS could be determined. Comparison with microsurgery is difficult because of intra group variability

Side effects of analgesia may significantly reduce quality of life in symptomatic multiple myeloma: a cross-sectional prevalence study

Background Pain is a common symptom in patients with multiple myeloma (MM). Many patients are dependent on analgesics and in particular opioids, but there is limited information on the impact of these drugs and their side effects on health-related quality of life (HRQoL). Method In a cross-sectional study, semi-structured interviews were performed in 21 patients attending the hospital with symptomatic MM on pain medications. HRQoL was measured using items 29 and 30 of the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30. Results Patients were able to recall a median of two (range 0–4) analgesics. They spontaneously identified a median of two (range 1–5) side effects attributable to their analgesic medications. Patients’ assessment of HRQoL based on the EORTC QLQ-C30 questions 29/30 was mean 48.3 (95 % CI; 38.7–57.9) out of 100. Patients’ assessment of their HRQoL in the hypothetical situation, in which they would not experience any side effects from analgesics, was significantly higher: 62.6 (53.5–71.7) (t test, p=0.001). Conclusion This study provides, for the first time, evidence that side effects of analgesics are common in symptomatic MM and may result in a statistically and clinically significant reduction of self-reported HRQoL

Clearance of technetium-99m-DTPA and HRCT findings in the evaluation of patients with Idiopathic Pulmonary Fibrosis

BACKGROUND: Clearance of inhaled technetium-labeled diethylenetriamine pentaacetate ((99m)Tc-DTPA) is a marker of epithelial damage and an index of lung epithelial permeability. The aim of this study was to investigate the role of (99m)Tc-DTPA scan in patients with Idiopathic Pulmonary Fibrosis (IPF). Our hypothesis is that the rate of pulmonary (99m)Tc-DTPA clearance could be associated with extent of High Resolution Computed Tomography (HRCT) abnormalities, cell differential of bronchoalveolar lavage fluid (BALF) and pulmonary function tests (PFTs) in patients with IPF. METHODS: We studied prospectively 18 patients (14 male, 4 female) of median age 67yr (range 55–81) with histologically proven IPF. HRCT scoring included the mean values of extent of disease. Mean values of these percentages represented the Total Interstitial Disease Score (TID). DTPA clearance was analyzed according to a dynamic study using a Venticis II radioaerosol delivery system. RESULTS: The mean (SD) TID score was 36 ± 12%, 3 patients had mild, 11 moderate and 4 severe TID. Abnormal DTPA clearance half-time (t(1/2)<40 min) was found in 17/18 (94.5%) [mean (SD) 29.1 ± 8.6 min]. TID was weakly correlated with the DTPA clearance (r = -0.47, p = 0.048) and with % eosinophils (r = 0.475, p = 0.05). No correlation was found between TID score or DTPA and PFTs in IPF patients. CONCLUSION: Our data suggest that (99m)Tc-DTPA lung scan is not well associated with HRCT abnormalities, PFTs, and BALF cellularity in patients with IPF. Further studies in large scale of patients are needed to define the role of this technique in pulmonary fibrosis

Limits on WWZ and WW\gamma couplings from p\bar{p}\to e\nu jj X events at \sqrt{s} = 1.8 TeV

We present limits on anomalous WWZ and WW-gamma couplings from a search for WW and WZ production in p-bar p collisions at sqrt(s)=1.8 TeV. We use p-bar p -> e-nu jjX events recorded with the D0 detector at the Fermilab Tevatron Collider during the 1992-1995 run. The data sample corresponds to an integrated luminosity of 96.0+-5.1 pb^(-1). Assuming identical WWZ and WW-gamma coupling parameters, the 95% CL limits on the CP-conserving couplings are -0.33<lambda<0.36 (Delta-kappa=0) and -0.43<Delta-kappa<0.59 (lambda=0), for a form factor scale Lambda = 2.0 TeV. Limits based on other assumptions are also presented.Comment: 11 pages, 2 figures, 2 table

Search for New Physics in e mu X Data at D0 Using Sleuth: A Quasi-Model-Independent Search Strategy for New Physics

We present a quasi-model-independent search for the physics responsible for electroweak symmetry breaking. We define final states to be studied, and construct a rule that identifies a set of relevant variables for any particular final state. A new algorithm ("Sleuth") searches for regions of excess in those variables and quantifies the significance of any detected excess. After demonstrating the sensitivity of the method, we apply it to the semi-inclusive channel e mu X collected in 108 pb^-1 of ppbar collisions at sqrt(s) = 1.8 TeV at the D0 experiment during 1992-1996 at the Fermilab Tevatron. We find no evidence of new high p_T physics in this sample.Comment: 23 pages, 12 figures. Submitted to Physical Review