A-1A Supplemental Security Income Program, September 2009

A-1A - Supplemental Security Income Program

Contribution of in vitro neurotoxicology studies to the elucidation of neurodegenerative processes.

Only a small percentage of neurodegenerative diseases like Alzheimer's disease and Parkinson's disease is directly related to familial forms. The etiology of the most abundant, sporadic forms seems to involve both genetic and environmental factors. Environmental compounds are now extensively studied for their possible contribution to neurodegeneration. Chemicals were found which were able to reproduce symptoms of known neurodegenerative diseases, others may either predispose to the onset of neurodegeneration, or exacerbate distinct pathogenic processes of these diseases. In any case, in vitro studies performed with models presenting various degrees of complexity have shown that many environmental compounds have the potential to cause neurodegeneration, through a variety of pathways similar to those described in neurodegenerative diseases. Since the population is exposed to a huge number of potentially neurotoxic compounds, there is an important need for rapid and efficient procedures for hazard evaluation. Xenobiotics elicit a cascade of reactions that, most of the time, involve numerous interactions between the different brain cell types. A reliable in vitro model for the detection of environmental toxins potentially at risk for neurodegenerative diseases should therefore allow maximal cell-cell interactions and multiparametric endpoints determination. The combined use of in vitro models and new analytical approaches using "omics" technologies should help to map toxicity pathways, and advance our understanding of the possible role of xenobiotics in the etiology of neurodegenerative diseases.

Estimating the net contribution of interleukin-28B variation to spontaneous hepatitis C virus clearance.

The identification of associations between interleukin-28B (IL-28B) variants and the spontaneous clearance of hepatitis C virus (HCV) raises the issues of causality and the net contribution of host genetics to the trait. To estimate more precisely the net effect of IL-28B genetic variation on HCV clearance, we optimized genotyping and compared the host contributions in multiple- and single-source cohorts to control for viral and demographic effects. The analysis included individuals with chronic or spontaneously cleared HCV infections from a multiple-source cohort (n = 389) and a single-source cohort (n = 71). We performed detailed genotyping in the coding region of IL-28B and searched for copy number variations to identify the genetic variant or haplotype carrying the strongest association with viral clearance. This analysis was used to compare the effects of IL-28B variation in the two cohorts. Haplotypes characterized by carriage of the major alleles at IL-28B single-nucleotide polymorphisms (SNPs) were highly overrepresented in individuals with spontaneous clearance versus those with chronic HCV infections (66.1% versus 38.6%, P = 6 × 10(-9) ). The odds ratios for clearance were 2.1 [95% confidence interval (CI) = 1.6-3.0] and 3.9 (95% CI = 1.5-10.2) in the multiple- and single-source cohorts, respectively. Protective haplotypes were in perfect linkage (r(2) = 1.0) with a nonsynonymous coding variant (rs8103142). Copy number variants were not detected. We identified IL-28B haplotypes highly predictive of spontaneous HCV clearance. The high linkage disequilibrium between IL-28B SNPs indicates that association studies need to be complemented by functional experiments to identify single causal variants. The point estimate for the genetic effect was higher in the single-source cohort, which was used to effectively control for viral diversity, sex, and coinfections and, therefore, offered a precise estimate of the net host genetic contribution.

Bullying among adolescents in a sub-Saharan middle-income setting.

PURPOSE: This study explored factors associated with self-reported bullying among adolescents in a sub-Saharan country. METHODS: A cross-sectional sample of adolescents (n = 1,427) in the Seychelles was drawn from the Global School-based Student Health Survey. Bullied adolescents were compared with non-bullied adolescents with respect to several sociodemographic factors. Bivariate and multivariate analyses were performed. RESULTS: Within a 30 day period, 38.8% of adolescents reported being bullied. Bullied youths were more likely to be depressed (adjusted odds ratio [aOR] = 1.63; confidence intervals [CI] = 1.27-1.07) and socially deprived (aOR = 1.85; CI = 1.30-2.61). Being older (aOR = .83; CI = .77-.90) and having close friends (aOR = .53; CI = .31-.91) were protective factors. CONCLUSIONS: The prevalence of bullying in the Seychelles is high, and social correlates are similar to those in industrialized settings. More research is needed to examine bullying patterns outside the school environment.

A-1A Supplemental Security Income Program, October 2009

A-1A - Supplemental Security Income Program

Contribution of PaTrin-2 in Radiotherapy with Temozolomide for the Treatment of Glioblastoma Expressing MGMT

Purpose/Objective(s): Current standard treatment of glioblastoma is radiotherapy (RT) concomitant with temozolomide (TMZ), an alkylating agent. O6-methylguanine-DNA methyltransferase (MGMT) expression is a major mechanism of resistance to Proceedings of the alkylating agent chemotherapy, and MGMT gene promoter methylation (present in 30-45 % of tumors) has been shown to be predictive for tumor response to TMZ therapy. MGMT, an exhaustible repair protein can be depleted by specific inhibitors such as O6- benzylguanine or the non-toxic O6-(4-bromothenyl)guanine (PaTrin-2). Here we have studied the efficacy of the combination of TMZ, RT, and PaTrin-2 to improve the treatment outcome in glioblastoma expressing MGMT. Materials/Methods: 3 glioblastoma lines were chosen: LN18 and T98G expressing MGMT and U251 lacking MGMT expression. A shRNA approach was used to selectively and permanently knockdown level of MGMT in LN18 line. Cells were treated with 10 mM PaTrin-2. After 2 h, various concentrations of TMZ were added, cells were incubated for 24 h, and clonogenic assays were performed. After the same PaTrin-2 pretreatment and 100 mM TMZ exposure, cells were plated 4 h before irradiation with increasing RT doses of up to 6 Gy. Clonogenic survival was assessed after 14 days. Results: Western blot analysis confirmed that reduction of MGMT expression was achieved in LN18A1 expressing MGMT-targeting shRNA. The shRNA non-targeting control sequence did not influenceMGMTprotein level (LN18NT). PaTrin-2 showed no toxicity at 10 mMon the 5 cell lines. TMZ induced up to 70 and 97%of cell death on LN18A1 and U251, respectively, but was not toxic up to 50 mMfor T98G, LN18, and LN18NT. Up to 53%increased TMZ toxicity was observed on the 5 cell lines when treated with the 2 drugs. Irradiation of the 5 lines treated or not with PaTrin-2 showed no survival difference at any irradiation dose. When LN18A1 and U251 cells were irradiated post TMZ treatment, an up to 2.5 and 139.4 fold increase in toxicity, respectively, was observed compared to un-pretreated controls. By contrast, TMZ pretreatment did not increase irradiation toxicity on T98G, LN18, and LN18NT. When cells were incubated with PaTrin-2 and TMZ before the irradiation, up to 3.7, 3.9, 5.8, 6.6 and 348.5 fold increase in toxicity was observed compared to controls on LN18, LN18NT, LN18A1, T98G and U251, respectively. Conclusions: We present here results of TMZ and PaTrin-2 combination ± RT on glioblastoma lines. U251 and LN18A1 cells were much more sensitive to TMZ than LN18, LN18NT, and T98G. PaTrin-2 enhanced the toxicity of TMZ on the MGMT expressing glioblastoma lines. RT further increased TMZ and PaTrin-2 efficacy. These results are encouraging for the treatment of patients with glioblastoma expressing MGMT who have the worst prognosis and respond poorly to RT combined with TMZ.

A-1A Supplemental Security Income Program, November 2009

A-1A - Supplemental Security Income Program

A-1A Supplemental Security Income Program, December 2009

A-1A - Supplemental Security Income Program

A-1A Supplemental Security Income Program, January 2010

A-1A - Supplemental Security Income Program

A-1A Supplemental Security Income Program, February 2010

A-1A - Supplemental Security Income Program