Drug and Alcohol Rehabilitation: Development and Validation of a Composite Programmatic Assessment Tool for HIV Therapy.

Development and Validation of a Composite Programmatic Assessment Tool for HIV Therapy.

Filed under: Drug and Alcohol Rehabilitation

PLoS One. 2012; 7(11): e47859
Lima VD, Le A, Nosyk B, Barrios R, Yip B, Hogg RS, Harrigan PR, Montaner JS

We developed and validated a new and simple metric, the Programmatic Compliance Score (PCS), based on the IAS-USA antiretroviral therapy management guidelines for HIV-infected adults, as a predictor of all-cause mortality, at a program-wide level. We hypothesized that non-compliance would be associated with the highest probability of mortality.3543 antiretroviral-naive HIV-infected patients aged ?19 years who initiated antiretroviral therapy between January 1, 2000 and August 31, 2009 in British Columbia (BC), Canada, were followed until August 31, 2010. The PCS is composed by six non-performance indicators based on the IAS-USA guidelines: (1) having <3 CD4 count tests in the first year after starting antiretroviral therapy; (2) having <3 plasma viral load tests in the first year after starting antiretroviral therapy; (3) not having drug resistance testing done prior to starting antiretroviral therapy; (4) starting on a non-recommended antiretroviral therapy regimen; (5) starting therapy with CD4 <200 cells/mm(3); and (6) not achieving viral suppression within 6 months since antiretroviral therapy initiation. The sum of these six indicators was used to develop the PCS score - higher score indicates poorer performance. The main outcome was all-cause mortality. Each PCS component was independently associated with mortality. In the mortality analysis, the odds ratio (OR) for PCS ?4 versus 0 was 22.37 (95% CI 10.46-47.84).PCS was strongly associated with all-cause mortality. These results lend independent validation to the IAS-USA treatment guidelines for HIV-infected adults. Further efforts are warranted to enhance the PCS as a means to further improve clinical outcomes. These should be specifically evaluated and targeted at healthcare providers and patients. HubMed – drug

Pan-Bcl-2 Inhibitor AT-101 Enhances Tumor Cell Killing by EGFR Targeted T Cells.

Filed under: Drug and Alcohol Rehabilitation

PLoS One. 2012; 7(11): e47520
Thakur A, Lum LG, Schalk D, Azmi A, Banerjee S, Sarkar FH, Mohommad R

Pancreatic cancer is a deadly disease and has the worst prognosis among almost all cancers and is in dire need of new and improved therapeutic strategies. Conditioning of tumor cells with chemotherapeutic drug has been shown to enhance the anti-tumor effects of cancer vaccines and adoptive cell therapy. In this study, we investigated the immunomodulatory effects of pan-Bcl-2 inhibitor AT-101 on pancreatic cancer (PC) cell cytotoxicity by activated T cells (ATC). The effects of AT-101 on cytotoxicity, early apoptosis, and Granzyme B (GrzB) and IFN-? signaling pathways were evaluated during EGFR bispecific antibody armed ATC (aATC)-mediated killing of L3.6pl and MiaPaCa-2 PC cells pre-sensitized with AT-101. We found that pretreatment of tumor cells with AT-101 enhanced susceptibility of L3.6pl and MiaPaCa-2 tumor cells to ATC and aATC-mediated cytotoxicity, which was in part mediated via enhanced release of cytolytic granule GrzB from ATC and aATC. AT-101-sensitized L3.6pl cells showed up-regulation of IFN-?-mediated induction in the phosphorylation of Ser(727)-Stat1 (pS(727)-Stat1), and IFN-? induced dephosphorylation of phospho-Tyr(705)-Stat3 (pY(705)-Stat3). Priming (conditioning) of PC cells with AT-101 can significantly enhance the anti-tumor activity of EGFRBi armed ATC through increased IFN-? induced activation of pS(727)-Stat1 and inhibition of pY(705)-Stat3 phosphorylation, and resulting in increased ratio of pro-apoptotic to anti-apoptotic proteins. Our results verify enhanced cytotoxicity after a novel chemotherapy conditioning strategy against PC that warrants further in vivo and clinical investigations.
HubMed – drug

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