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Croissy-sur-Seine, France

Millan M.J.,Institute Of Recherche Servier
Dialogues in Clinical Neuroscience | Year: 2014

Early-onset, familial Alzheimer's disease (AD) is rare and may be attributed to disease-causing mutations. By contrast, late-onset, sporadic (non-Mendelian) AD is far more prevalent and reflects the interaction of multiple genetic and environmental risk factors, together with the disruption of epigenetic mechanisms controlling gene expression. Accordingly, abnormal patterns of histone acetylation and methylation, as well as anomalies in global and promoterspecific DNA methylation, have been documented in AD patients, together with a deregulation of noncoding RNA. In transgenic mouse models for AD, epigenetic dysfunction is likewise apparent in cerebral tissue, and it has been directly linked to cognitive and behavioral deficits in functional studies. Importantly, epigenetic deregulation interfaces with core pathophysiological processes underlying AD: excess production of Aβ42, aberrant post-translational modification of tau, deficient neurotoxic protein clearance, axonal-synaptic dysfunction, mitochondrial-dependent apoptosis, and cell cycle re-entry. Reciprocally, DNA methylation, histone marks and the levels of diverse species of microRNA are modulated by Aβ42, oxidative stress and neuroinflammation. In conclusion, epigenetic mechanisms are broadly deregulated in AD mainly upstream, but also downstream, of key pathophysiological processes. While some epigenetic shifts oppose the evolution of AD, most appear to drive its progression. Epigenetic changes are of irrefutable importance for AD, but they await further elucidation from the perspectives of pathogenesis, biomarkers and potential treatment. © 2014, AICH - Servier Research Group. Source

Braun F.,University of Nantes | De Carne Trecesson S.,University of Nantes | Bertin-Ciftci J.,University of Nantes | Bertin-Ciftci J.,Institute Of Recherche Servier | And 2 more authors.
Cell Cycle | Year: 2013

It is widely accepted that anti-apoptotic Bcl-2 family members promote cancer cell survival by binding to their pro-apoptotic counterparts, thereby preventing mitochondrial outer membrane permeabilization (MOMP) and cytotoxic caspase activation. Yet, these proteins do not only function as guardians of mitochondrial permeability, preserving it, and maintaining cell survival in the face of acute or chronic stress, they also regulate non-apoptotic functions of caspases and biological processes beyond MOMP from diverse subcellular localizations and in complex with numerous binding partners outside of the Bcl-2 family. In particular, some of the non-canonical effects and functions of Bcl-2 homologs lead to an interplay with E2F-1, NFκB, and Myc transcriptional pathways, which themselves influence cancer cell growth and survival. We thus propose that, by feedback loops that we currently have only hints of, Bcl-2 proteins may act as rulers of survival signaling, predetermining the apoptotic threshold that they also directly scaffold. This underscores the robustness of the control exerted by Bcl-2 homologs over cancer cell survival, and implies that small molecules compounds currently used in the clinic to inhibit their mitochondrial activity may be not always be fully efficient to override this control. © 2013 Landes Bioscience. Source

Levasseur P.,Novexel Inc. | Girard A.-M.,Novexel Inc. | Girard A.-M.,Institute Of Recherche Servier | Lavallade L.,Novexel Inc. | And 5 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2014

Avibactam is a novel non-β-lactam β-lactamase inhibitor that has been shown in vitro to inhibit class A, class C, and some class D β-lactamases. It is currently in phase 3 of clinical development in combination with ceftazidime. In this study, the efficacy of ceftazidime-avibactam was evaluated in a murine septicemia model against five ceftazidime-susceptible (MICs of 0.06 to 0.25 μg/ml) and 15 ceftazidime-resistant (MICs of 64 to>128 μg/ml) species of Enterobacteriaceae, bearing either TEM, SHV, CTX-M extended-spectrum, or AmpC β-lactamases. In the first part of the study, ceftazidime-avibactam was administered at ratios of 4:1 and 8:1 (wt/wt) to evaluate the optimal ratio for efficacy. Against ceftazidime-susceptible isolates of Klebsiella pneumoniae and Escherichia coli, ceftazidime and ceftazidime-avibactam demonstrated similar efficacies (50% effective doses [ED50] of<1.5 to 9 mg/kg of body weight), whereas against ceftazidime-resistant β-lactamase-producing strains (ceftazidime ED50 of >90 mg/kg), the addition of avibactam restored efficacy to ceftazidime (ED50 dropped to<5 to 65 mg/kg). In a subsequent study, eight isolates (two AmpC and six CTX-M producers) were studied in the septicemia model. Ceftazidime-avibactam was administered at a 4:1 (wt/wt) ratio, and the efficacy was compared to that of the 4:1 (wt/wt) ratio of either piperacillin-tazobactam or cefotaxime- avibactam. Against the eight isolates, ceftazidime-avibactam was the more effective combination, with ED50 values ranging from 2 to 27 mg/kg compared to>90 mg/kg and 14 to>90 mg/kg for piperacillin-tazobactam and cefotaxime-avibactam, respectively. This study demonstrates that the potent in vitro activity observed with the ceftazidime-avibactam combination against ceftazidime-resistant Enterobacteriaceae species bearing class A and class C β-lactamases translated into good efficacy in the mouse septicemia model. © 2014, American Society for Microbiology. All Rights Reserved. Source

Levasseur P.,Novexel Inc. | Girard A.-M.,Novexel Inc. | Girard A.-M.,Institute Of Recherche Servier | Miossec C.,Novexel Inc. | And 3 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2015

The novel β-lactamase inhibitor avibactam is a potent inhibitor of class A, class C, and some class D enzymes. The in vitro antibacterial activity of the ceftazidime-avibactam combination was determined for a collection of Enterobacteriaceae clinical isolates; this collection was enriched for resistant strains, including strains with characterized serine β-lactamases. The inhibitor was added either at fixed weight ratios to ceftazidime or at fixed concentrations, with the latter type of combination consistently resulting in greater potentiation of antibacterial activity. In the presence of 4 μg/ml of avibactam, the ceftazidime MIC50 and MIC90 (0.25 and 2 μg/ml, respectively) were both below the CLSI breakpoint for ceftazidime. Further comparisons with reference antimicrobial agents were performed using this fixed inhibitor concentration. Against most ceftazidime-susceptible and-nonsusceptible isolates, the addition of avibactam resulted in a significant increase in ceftazidime activity, with MICs generally reduced 256-fold for extended-spectrum β-lactamase (ESBL) producers, 8-to 32-fold for CTX-M producers, and >128-fold for KPC producers. Overall, MICs of a ceftazidime-avibactam combination were significantly lower than those of the comparators piperacillin-tazobactam, cefotaxime, ceftriaxone, and cefepime and similar or superior to those of imipenem. ©2015, American Society for Microbiology. All Rights Reserved. Source

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH-2007-2.4.1-3 | Award Amount: 4.84M | Year: 2008

Genomic instability is a characteristic of practically all human cancers. Recent results generated by members of this Consortium suggest that signs of genomic instability are evident from the very beginning of human cancer development, even in precancerous lesions. In these early lesions, the genomic instability affects primarily specific genomic loci, called common fragile sites. Because common fragile sites are very sensitive to perturbations in DNA replication, we proposed that cancer development from its very beginning is associated with DNA replication stress. A separate set of observations focused on telomeres and showed that short telomeres mimick DNA ends, activate the DNA damage checkpoint and promote genomic instability and cancer development. We propose here to study the role of DNA replication stress and short telomeres on driving genomic instability particularly in human precancerous lesions. Our studies will investigate the most common forms of cancer in the EU and will benefit from access to some of the largest databases of cancerous and precancerous lesions in Europe. Genomic instability will be explored using high resolution genomic arrays and the data will be correlated to clinical information on tumor progression. Further, analysis of proteins and genes involved in the cellular response to DNA replication stress and short telomeres will be explored using high throughput and targeted approaches and will be used to identify novel targets for cancer therapy.

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