Drug and Alcohol Rehabilitation: Associations of BDNF Genotype and Promoter Methylation With Acute and Long-Term Stroke Outcomes in an East Asian Cohort.

Associations of BDNF genotype and promoter methylation with acute and long-term stroke outcomes in an East asian cohort.

Filed under: Drug and Alcohol Rehabilitation

PLoS One. 2012; 7(12): e51280
Kim JM, Stewart R, Park MS, Kang HJ, Kim SW, Shin IS, Kim HR, Shin MG, Cho KH, Yoon JS

Brain derived neurotrophic factor (BDNF) has been shown to play an important role in poststroke recovery. BDNF secretion is influenced by genetic and epigenetic profiles. This study aimed to investigate whether BDNF val66met polymorphism and promoter methylation status were associated with outcomes at two weeks and one year after stroke.A total of 286 patients were evaluated at the time of admission and two weeks after stroke, and 222 (78%) were followed one year later in order to evaluate consequences of stroke at both acute and chronic stages. Stroke outcomes were dichotomised into good and poor by the modified Rankin Scale. Stroke severity (National Institutes of Health Stroke Scale), physical disability (Barthel Index), and cognitive function (Mini-Mental State Examination) were measured. Associations of BDNF genotype and methylation status on stroke outcomes and assessment scale scores were investigated using logistic regression, repeated measures ANOVA and partial correlation tests. BDNF val66met polymorphism was independently associated with poor outcome at 2 weeks and at 1 year, and with worsening physical disability and cognitive function over that period. Higher BDNF promoter methylation status was independently associated with worse outcomes at 1 year, and with the worsening of physical disability and cognitive function. No significant genotype-methylation interactions were found.A role for BDNF in poststroke recovery was supported, and clinical utility of BDNF genetic and epigenetic profile as prognostic biomarkers and a target for drug development was suggested.
HubMed – drug


A hormone receptor-based transactivator bridges different binary systems to precisely control spatial-temporal gene expression in Drosophila.

Filed under: Drug and Alcohol Rehabilitation

PLoS One. 2012; 7(12): e50855
Kuo SY, Tu CH, Hsu YT, Wang HD, Wen RK, Lin CT, Wu CL, Huang YT, Huang GS, Lan TH, Fu TF

The GAL4/UAS gene expression system is a precise means of targeted gene expression employed to study biological phenomena in Drosophila. A modified GAL4/UAS system can be conditionally regulated using a temporal and regional gene expression targeting (TARGET) system that responds to heat shock induction. However heat shock-related temperature shifts sometimes cause unexpected physiological responses that confound behavioral analyses. We describe here the construction of a drug-inducible version of this system that takes advantage of tissue-specific GAL4 driver lines to yield either RU486-activated LexA-progesterone receptor chimeras (LexPR) or ?-estradiol-activated LexA-estrogen receptor chimeras (XVE). Upon induction, these chimeras bind to a LexA operator (LexAop) and activate transgene expression. Using GFP expression as a marker for induction in fly brain cells, both approaches are capable of tightly and precisely modulating transgene expression in a temporal and dosage-dependent manner. Additionally, tissue-specific GAL4 drivers resulted in target gene expression that was restricted to those specific tissues. Constitutive expression of the active PKA catalytic subunit using these systems altered the sleep pattern of flies, demonstrating that both systems can regulate transgene expression that precisely mimics regulation that was previously engineered using the GeneSwitch/UAS system. Unlike the limited number of GeneSwitch drivers, this approach allows for the usage of the multitudinous, tissue-specific GAL4 lines for studying temporal gene regulation and tissue-specific gene expression. Together, these new inducible systems provide additional, highly valuable tools available to study gene function in Drosophila.
HubMed – drug


Algorithmic modeling quantifies the complementary contribution of metabolic inhibitions to gemcitabine efficacy.

Filed under: Drug and Alcohol Rehabilitation

PLoS One. 2012; 7(12): e50176
Kahramano?ullari O, Fantaccini G, Lecca P, Morpurgo D, Priami C

Gemcitabine (2,2-difluorodeoxycytidine, dFdC) is a prodrug widely used for treating various carcinomas. Gemcitabine exerts its clinical effect by depleting the deoxyribonucleotide pools, and incorporating its triphosphate metabolite (dFdC-TP) into DNA, thereby inhibiting DNA synthesis. This process blocks the cell cycle in the early S phase, eventually resulting in apoptosis. The incorporation of gemcitabine into DNA takes place in competition with the natural nucleoside dCTP. The mechanisms of indirect competition between these cascades for common resources are given with the race for DNA incorporation; in clinical studies dedicated to singling out mechanisms of resistance, ribonucleotide reductase (RR) and deoxycytidine kinase (dCK) and human equilibrative nucleoside transporter1 (hENT1) have been associated to efficacy of gemcitabine with respect to their roles in the synthesis cascades of dFdC-TP and dCTP. However, the direct competition, which manifests itself in terms of inhibitions between these cascades, remains to be quantified. We propose an algorithmic model of gemcitabine mechanism of action, verified with respect to independent experimental data. We performed in silico experiments in different virtual conditions, otherwise difficult in vivo, to evaluate the contribution of the inhibitory mechanisms to gemcitabine efficacy. In agreement with the experimental data, our model indicates that the inhibitions due to the association of dCTP with dCK and the association of gemcitabine diphosphate metabolite (dFdC-DP) with RR play a key role in adjusting the efficacy. While the former tunes the catalysis of the rate-limiting first phosphorylation of dFdC, the latter is responsible for depletion of dCTP pools, thereby contributing to gemcitabine efficacy with a dependency on nucleoside transport efficiency. Our simulations predict the existence of a continuum of non-efficacy to high-efficacy regimes, where the levels of dFdC-TP and dCTP are coupled in a complementary manner, which can explain the resistance to this drug in some patients.
HubMed – drug



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