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Guilluy C.,1Inserm | Guilluy C.,University of Nantes | Bregeon J.,1Inserm | Bregeon J.,University of Nantes | And 16 more authors.
Nature Medicine | Year: 2010

Hypertension is one of the most frequent pathologies in the industrialized world. Although recognized to be dependent on a combination of genetic and environmental factors, its molecular basis remains elusive. Increased activity of the monomeric G protein RhoA in arteries is a common feature of hypertension. However, how RhoA is activated and whether it has a causative role in hypertension remains unclear. Here we provide evidence that Arhgef1 is the RhoA guanine exchange factor specifically responsible for angiotensin II-induced activation of RhoA signaling in arterial smooth muscle cells. We found that angiotensin II activates Arhgef1 through a previously undescribed mechanism in which Jak2 phosphorylates Tyr738 of Arhgef1. Arhgef1 inactivation in smooth muscle induced resistance to angiotensin II-dependent hypertension in mice, but did not affect normal blood pressure regulation. Our results show that control of RhoA signaling through Arhgef1 is central to the development of angiotensin II-dependent hypertension and identify Arhgef1 as a potential target for the treatment of hypertension. © 2010 Nature America, Inc. All rights reserved.

PubMed | 1Inserm
Type: Journal Article | Journal: Journal of biomolecular screening | Year: 2010

Assay technologies that were originally developed for high-throughput screening (HTS) have recently proven useful in drug discovery for activities located upstream (target identification and validation) and downstream (ADMET) of HTS. Here the authors investigated and characterized the biological properties of a novel target, IRE1alpha, a bifunctional kinase/RNase stress sensor of the endoplasmic reticulum (ER). They have developed a novel assay platform using the HTS technology AlphaScreen to monitor the dimerization/oligomerization and phosphorylation properties of the cytosolic domain of IRE1alpha. They show in vitro that dimerization/oligomerization of the cytosolic domain of IRE1 correlated with the autophosphorylation ability of this domain and its endoribonuclease activity toward XBP1 mRNA. Using orthogonal in vitro and cell-based approaches, the authors show that the results obtained using AlphaScreen were biologically relevant. Preliminary characterization of assay robustness indicates that both AlphaScreen assays should be useful in HTS for the identification of IRE1 activity modulators.

Multiple myeloma is a plasma-cell tumor with heterogeneity in molecular abnormalities and treatment response.We have assessed whether human myeloma cell lines have kept patients heterogeneity using Affymetrix gene expression profiling of 40 human myeloma cell lines obtained with or without IL6 addition and could provide a signature for stratification of patient risk.Human myeloma cell lines, especially those derived in the presence of IL6, displayed a heterogeneity that overlaps that of the patients with multiple myeloma. Human myeloma cell lines segregated into 6 groups marked by overexpression of MAF, MMSET, CCND1, FRZB with or without overexpression of cancer testis antigens (CTA). Cell lines of CTA/MAF and MAF groups have a translocation involving C-MAF or MAFB, cell lines of groups CCND1-1 and CCND1-2like have a t(11;14) and cell lines of group MMSET have a t(4;14). The CTA/FRZB group comprises cell lines that had no or no recurrent 14q32 translocation. Expression of 248 genes accounted for human myeloma cell line molecular heterogeneity. Human myeloma cell line heterogeneity genes comprise genes with prognostic value for survival of patients making it possible to build a powerful prognostic score involving a total of 13 genes.Human myeloma cell lines derived in the presence of IL6 recapitulate the molecular diversity of multiple myeloma that made it possible to design, using human myeloma cell line heterogeneity genes, a high-risk signature for patients at diagnosis. We propose this classification to be used when addressing the physiopathology of multiple myeloma with human myeloma cell lines.

PubMed | 1INSERM and Bichat Claude Bernard Hospital
Type: Journal Article | Journal: Infection control and hospital epidemiology | Year: 2016

The best strategy for controlling extended-spectrum -lactamase-producing Enterobacteriaceae (ESBL-PE) transmission in intensive care units (ICUs) remains elusive.We developed a stochastic transmission model to quantify the effectiveness of interventions aimed at reducing the spread of ESBL-PE in an ICU.We modeled the evolution of an outbreak caused by the admission of a single carrier in a 10-bed ICU free of ESBL-PE. Using data obtained from recent muticenter studies, we studied 26 strategies combining different levels of the following 3 interventions: (1) increasing healthcare worker compliance with hand hygiene before and after contact with a patient; (2) cohorting; (3) reducing antibiotic prevalence at admission with or without reducing antibiotherapy duration.Improving hand hygiene compliance from 55% before patient contact and 60% after patient contact to 80% before and 80% after patient contact reduced the nosocomial incidence rate of ESBL-PE colonization by 91% at 90 days. Adding cohorting to hand hygiene improvement intervention decreased the proportion of ESBL-PE acquisitions by an additional 7%. Antibiotic restriction had the lowest impact on the epidemic. When combined with other interventions, it only marginally improved effectiveness, despite strong hypotheses regarding antibiotic impact on transmission.Our results suggest that hand hygiene is the most effective intervention to control ESBL-PE transmission in an ICU.

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