Extreme set-up and run-up on steep cliffs (Banneg Island, France)

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Use of HIV Case Surveillance System to Design and Evaluate Site-Randomized Interventions in an HIV Prevention Study: HPTN 065

Introduction: Modeling studies suggest intensified HIV testing, linkage-to-care and antiretroviral treatment to achieve viral suppression may reduce HIV transmission and lead to control of the epidemic. To study implementation of strategy, population-level data are needed to monitor outcomes of these interventions. US HIV surveillance systems are a potential source of these data. Methods: HPTN065 (TLC-Plus) Study is evaluating the feasibility of a test, linkage-to-care, and treat strategy for HIV prevention in two intervention communities - the Bronx, NY, and Washington, DC. Routinely collected laboratory data on diagnosed HIV cases in the national HIV surveillance system were used to select and randomize sites, and will be used to assess trial outcomes. Results: To inform study randomization, baseline data on site-aggregated study outcomes was provided from HIV surveillance data by New York City and Washington D.C. Departments of Health. The median site rate of linkage-to-care for newly diagnosed cases was 69% (IQR 50%-86%) in the Bronx and 54% (IQR 33%-71%) in Washington, D.C. In participating HIV care sites, the median site percent of patients with viral suppression (<400 copies/mL) was 57% (IQR 53%-61%) in the Bronx and 64% (IQR 55%-72%) in Washington, D.C. Conclusions: In a novel use of site-aggregated surveillance data, baseline data was used to design and evaluate site randomized studies for both HIV test and HIV care sites. Surveillance data have the potential to inform and monitor sitelevel health outcomes in HIV-infected patients

Influence of smoking on the prognostic value of cardiovascular computed tomography coronary angiography

Aims Computed tomography coronary angiography (CTA) is an important non-invasive imaging modality increasingly used for the diagnosis and prognosis of coronary artery disease (CAD). The purpose of the current study was to determine the influence of smoking status on the prognostic value of CTA in patients with suspected or known CAD. Methods and results In 1207 patients (57% male, age 57 ± 12 years) referred for CTA, the presence of significant CAD (≥50% stenosis) was determined. During follow-up (FU) the following events were recorded: all cause mortality, and non-fatal infarction. The prognostic value of CTA in smokers and non-smokers was compared using an interaction term in the Cox proportional hazard regression analysis. Significant CAD was observed in 327 patients (27%), and 273 patients (23%) were smokers. During a median FU time of 2.2 years, an event occurred in 50 patients. After correction for baseline characteristics including smoking in a multivariate model, significant CAD remained an independent predictor of events. Furthermore, a significant interaction (P < 0.05) was observed between significant CAD and smoking. The annualized event rate in smokers with significant CAD was 8.78% compared with 0.99% in smokers without significant CAD (P < 0.001). In non-smokers with significant CAD the annualized event rate was 2.07% compared with 1.01% in non-smokers without significant CAD (P= 0.058). Conclusion The prognostic value of CTA was significantly influenced by smoking status. The event rates in patients with significant CAD were approximately four-fold higher in smokers compared with non-smokers. These findings suggest that smoking cessation needs to be aggressively pursued, especially in smokers with significant CA

Synthesis of ticagrelor analogues belonging to 1,2,3-triazolo[4,5-d]pyrimidines and study of their antiplatelet and antibacterial activity.

peer reviewedBased on the recent observation that the antiplatelet agent ticagrelor and one of its metabolite exert bactericidal activity against gram-positive bacteria, a series of 1,2,3-triazolo[4,5-d]pyrimidines structurally related to ticagrelor were synthesized and examined as putative antiplatelet and antibacterial agents. The aim was to assess the possibility of dissociating the two biological properties and to find novel 1,2,3-triazolo[4,5-d]pyrimidines expressing antiplatelet activity and devoid of in vitro antibacterial activity. The new compounds synthesized were known metabolites of ticagrelor as well as structurally simplified analogues. Some of them were found to express antiplatelet activity and to lose the antibacterial activity, supporting the view that the two activities were not necessarily linked

Pharmacological targeting of the mitochondrial calcium-dependent potassium channel KCa3.1 triggers cell death and reduces tumor growth and metastasis in vivo

Ion channels are non-conventional, druggable oncological targets. The intermediate-conductance calcium-dependent potassium channel (K(Ca)3.1) is highly expressed in the plasma membrane and in the inner mitochondrial membrane (mitoK(Ca)3.1) of various cancer cell lines. The role mitoK(Ca)3.1 plays in cancer cells is still undefined. Here we report the synthesis and characterization of two mitochondria-targeted novel derivatives of a high-affinity K(Ca)3.1 antagonist, TRAM-34, which retain the ability to block channel activity. The effects of these drugs were tested in melanoma, pancreatic ductal adenocarcinoma and breast cancer lines, as well as in vivo in two orthotopic models. We show that the mitochondria-targeted TRAM-34 derivatives induce release of mitochondrial reactive oxygen species, rapid depolarization of the mitochondrial membrane, fragmentation of the mitochondrial network. They trigger cancer cell death with an EC50 in the mu M range, depending on channel expression. In contrast, inhibition of the plasma membrane K(Ca)3.1 by membrane-impermeant Maurotoxin is without effect, indicating a specific role of mitoK(Ca)3.1 in determining cell fate. At sub-lethal concentrations, pharmacological targeting of mitoK(Ca)3.1 significantly reduced cancer cell migration by enhancing production of mitochondrial reactive oxygen species and nuclear factor-kappa B (NF-kappa B) activation, and by downregulating expression of Bcl-2 Nineteen kD-Interacting Protein (BNIP-3) and of Rho GTPase CDC-42. This signaling cascade finally leads to cytoskeletal reorganization and impaired migration. Overexpression of BNIP-3 or pharmacological modulation of NF-kappa B and CDC-42 prevented the migration-reducing effect of mitoTRAM-34. In orthotopic models of melanoma and pancreatic ductal adenocarcinoma, the tumors at sacrifice were 60% smaller in treated versus untreated animals. Metastasis of melanoma cells to lymph nodes was also drastically reduced. No signs of toxicity were observed. In summary, our results identify mitochondrial K(Ca)3.1 as an unexpected player in cancer cell migration and show that its pharmacological targeting is efficient against both tumor growth and metastatic spread in vivo

Docking Analysis and Resistance Evaluation of Clinically Relevant Mutations Associated with the HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors Nevirapine, Efavirenz and Etravirine

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