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International audience

Dans l'ouvrage (dématérialisé) Lamy droit économique, le document se trouve dans la Partie 4 Droit de la distribution, Titre 1 Régime général du contrat de distribution, Chapitre 2 Conclusion du contrat de distribution.

The poor prognosis of inflammatory breast cancer (IBC) is due to its strong metastatic potential. During the last three decades, the introduction of neoadjuvant chemotherapy (CT), and its improvement with successive additions of anthracyclines and then taxanes, allowed to double the survival. However, the 5-year survival still remains lower than 50%, with the pathological complete response (pCR) to neoadjuvant CT being a major prognostic factor. Since 1995, several innovative approaches have been evaluated. Initially, the trials of high-dose CT with hematopoietic stem cell transplantation have generated promising results, but ultimately failed to change standards of treatment, in particular because of its toxicity. More recently, a few targeted therapies, combined to conventional CT, have been assessed, due to the frequent overexpression of HER2 and EGFR and the important vascularization of IBC. Trastuzumab, a monoclonal antibody targeting HER2, has shown a clear advantage in terms of pCR and survival in studies dedicated to, HER2-positive locally advanced breast cancers, including IBC. Lapatinib, a dual tyrosine kinase inhibitor anti-HER2 and EGFR, has shown significant activity in two phase II studies dedicated to HER2-positive IBC. The interest of HER2-double blockade by the combination of trastuzumab-pertuzumab combined to docetaxel has been demonstrated in term of pCR in the NEOSPHERE study which also included HER2-positive IBC. Among the anti-angiogenic drugs tested in studies dedicated to IBC, bevacizumab has given the most interesting results in term of efficacy/toxicity ratio. In the Beverly 2 study HER2-positive IBC patients were treated by the combination chemotherapy, trastuzumab and bevacizumab: the rate of pCR was 64%, and the 3-year disease-free and overall survivals were 68% and 90%, respectively; the increase of endothelial cells circulating was inversely correlated to the probability of pCR. All those treatments have been extrapolated from standard breast cancers. Thus, a deep molecular knowledge of IBC appears to be critical in order to develop specific treatments effectively targeting its particular aggressiveness.

International audience; Cannabis exposure during the perinatal period results in varied and significant consequences in affected offspring. The prevalence of detrimental outcomes of perinatal cannabis exposure is likely to increase in tandem with the broadening of legalization and acceptance of the drug. As such, it is crucial to highlight the immediate and protracted consequences of cannabis exposure on pre-and post-natal development. Here, we identify lasting changes in neurons' learning flexibility (synaptic plasticity) and epigenetic misregulation in animal models of perinatal cannabinoid exposure (using synthetic cannabinoids or active components of the cannabis plant) in addition to significant alterations in social behavior and executive functions. These findings are supported by epidemiological data indicating similar behavioral outcomes throughout life in human offspring exposed to cannabis during pregnancy. Further, we indicate important lingering questions regarding accurate modeling of perinatal cannabis exposure as well as the need for sex-and agedependent outcome measures in future studies.

International audience; Human mitoNEET (mNT) is the first identified Fe−S protein of the mammalian outer mitochondrial membrane. Recently, we demonstrated the involvement of mNT in a specific cytosolic pathway dedicated to the reactivation of oxidatively damaged cytosolic aconitase by cluster transfer. In vitro studies using apo-ferredoxin (FDX) reveal that mNT uses an Fe-based redox switch mechanism to regulate the transfer of its cluster. Using the "gold standard" cluster recipient protein, FDX, we show that this transfer is direct and that only one of the two mNT clusters is transferred when the second one is decomposed. Combining complementary biophysical and biochemical approaches, we show that pH affects both the sensitivity of the cluster to O 2 and dimer stability. Around physiological cytosolic pH, the ability of mNT to transfer its cluster is tightly regulated by the pH. Finally, mNT is extremely resistant to H 2 O 2 compared to ISCU and SufB, two other Fe−S cluster transfer proteins, which is consistent with its involvement in a repair pathway of stress-damaged Fe−S proteins. Taken together, our results suggest that the ability of mNT to transfer its cluster to recipient proteins is not only controlled by the redox state of its cluster but also tightly modulated by the pH of the cytosol. We propose that when pathophysiological conditions such as cancer and neurodegenerative diseases dysregulate cellular pH homeostasis, this pH-dependent regulation of mNT is lost, as is the regulation of cellular pathways under the control of mNT. I ron−sulfur (Fe−S) clusters are evolutionarily ancient and highly conserved prosthetic cofactors. Composed of only iron and sulfur, they are involved in many essential biological processes. 1,2 MitoNEET (mNT), also known as CISD1, is the first identified Fe−S protein of the mammalian outer mitochondrial membrane (OMM). 3,4 This is a small homodimeric protein (13 kDa for each monomer) anchored to the OMM by its 32-amino acid N-terminus with the major part of the protein, including the C-terminal Fe−S binding domain, located in the cytosol. 4 Each monomer accommodates one [2Fe-2S] cluster coordinated by three cysteines (C72, C74, and C83) and one histidine (H87) in a CDGSH domain 5−8 as other members of the NEET protein family, 9 which also includes Miner1 (or CISD2) and Miner2 (or CISD3) in mammals. 10 Although the biological activity of mNT is still debated, 11 studies have shown that it is involved in the regulation of iron/reactive oxygen species homeo-stasis, 12−14 in the regulation of lipid and glucose metabolism , 13,15 and in cell proliferation in breast cancer. 16 In vitro studies revealed that holo-mNT (the form of the protein with the cluster) is able to transfer its Fe−S cluster to very diverse apoprotein (an Fe−S protein, which has lost its cluster) recipients assembling either a [2Fe-2S] cluster as ferredoxin from various organisms, 17,18 human anamorsin 19 and CISD2, 20 or a [4Fe-4S] cluster as mammalian iron regulatory protein-1 (IRP-1)/cytosolic aconitase (c-aconi-tase). 14 On the basis of in cellulo experiments, we showed that mNT is able to repair the oxidatively damaged Fe−S cluster of human IRP-1/c-aconitase by transferring its cluster to the damaged protein. 14 Recently, we started to investigate in depth the in vitro cluster transfer reaction, focusing on the transfer from holo-mNT to [2Fe-2S] recipient protein. We unambiguously demonstrated that oxidized mNT ([2Fe-2S] 2+) triggers cluster transfer, whereas reduction of its cluster abrogates this transfer. Moreover, while O 2 significantly affects the lability of the oxidized mNT cluster, it does not interfere with the cluster

Background & Aims To determine the characteristics of hepatitis C (HCV)-infected patients in 2010 and compare this survey with those reported in 1995 and 2001. Patients and methods Observational multicentre study conducted in 2010 in French internal medicine, infectious diseases and hepatology departments. Results A total of 1621 HCV infected patients (mean age 50.1 ± 10.7 years; sex ratio M/F 1.8; genotype 1: 55.7%) were included. Of these, 910 (56.1%) were HIV–HCV co-infected, 463 (40.4%) were asymptomatic and 184 (16.1%) had cirrhosis at inclusion in this study. Positive viraemia was found in 1,025 patients (65.5%) at inclusion in this study. A complete pretreatment evaluation including investigation for HCV RNA, genotype determination and liver fibrosis was performed in 96.5, 80.5 and 68.7% of the 1,621 patients respectively. Previous and ongoing HCV treatments were noted in 49.6% and 20.1% of patients respectively. A sustained virological response (SVR) was observed in 271/801 (38.3%) patients, i.e. 44.1% and 30.7% in co-infected and mono-infected patients respectively. Cirrhosis was more frequent in the 2010 than in the 2001 and 1995 surveys (16.1% vs. 10.4% and 7.4% respectively; P < 0.0001). A complete pretreatment evaluation was performed in 57.9% and 50.9% of patients in 2010 and 2001 (P < 0.0001). Liver fibrosis evaluation was more frequent in 2010 than in the 2001 and 1995 surveys (68.7% vs. 62.7% and 28.7%, respectively, P < 0.0001). Conclusion The care of HCV-infected patients has changed significantly in ‘real life’ through an improvement of pretreatment evaluation before the antiviral introduction and the increased use of antivirals. New HCV therapy combinations including protease inhibitors are warranted to increase the SVR rate.

International audience

Commentaire 122; National audience

In this work we explore the fundamental structure-adaptiveness of accelerated randomized coordinate descent algorithms on regularized empirical risk minimization tasks, where the solution has intrinsic low-dimensional structure such as sparsity and low-rank, enforced by non-smooth regularization. We propose and analyze a two-stage accelerated coordinate descent algorithm ("two-stage APCG") utilizing the restricted strong-convexity framework. We provide the convergence analysis showing that the proposed method have a local accelerated linear convergence rate with respect to the low-dimensional structure of the solution. We also propose an adaptive variant of the two-stage APCG which does not need to foreknow the restricted strong convexity parameter beforehand, but estimates it on the fly. In our numerical experiments we test the proposed method on a number of machine learning datasets and demonstrate the effectiveness of our approach.

International audience; A large diameter Pulsating Heat Pipe (PHP) is a device operating as a thermosyphon on ground and as a PHP under microgravity conditions. Such a prototype with a transparent (sapphire) tube section in the adiabatic region has been tested during the 67th ESA parabolic flight campaign. Infrared visualizations of the fluid in the sapphire section along with measurements of all the relevant quantities, which characterize the device state (pressures, temperatures), are acquired during the tests and exploited for the validation of CASCO code of PHP simulation. After accurate implementation of the PHP geometry and material properties, transient simulations have been carried out. A comparison with the experiment is possible only for the cases where the PHP can be initially assumed at equilibrium. The transients for tube wall temperatures, liquid plug velocities, lengths and temperatures show a good agreement with the experiments during the start-up phase in microgravity conditions reducing the gap towards the development of a fully validated PHP design tool.