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Guerin C.,French Institute of Health and Medical Research
Minerva Anestesiologica | Year: 2011

This review summarizes knowledge and evidence on the use of positive end-expiratory pressure (PEEP) in patients with severely hypoxemic acute respiratory distress syndrome (ARDS). More specifically, it documents the current evidence on the effects of higher PEEP in preventing (or attenuating) lung damage during the ventilatory management of patients with severely hypoxemic ARDS. No established threshold has been set to define severely hypoxemic ARDS and higher PEEP. In this review, those variables are defined as PaO 2/FIO 2 ≤100 mmHg and ≥15 cmH 2O, respectively. In ARDS, the intensity of hypoxemia correlated with the amount of lung recruitability. In ARDS, the primary objective of PEEP is to increase the amount of non-aerated lung at the end of expiration. In early ARDS with a diffuse pattern and severe hypoxemia, higher PEEP contributes to lung recruitment by maintaining lung recruitment elicited by tidal breath and recruitment maneuvers as well as minimizes the repeated opening and closure with no significant overdistension. Three clinical trials comparing high PEEP + low tidal volume to low PEEP + large tidal volume found benefits favoring the former combination. Three large multicenter randomized controlled trials did not demonstrate a significant effect on patient outcome of higher or lower PEEP at a fixed low tidal volume. The meta-analysis on individual data of these three studies showed that the hospital mortality was not significantly different between the two groups of patients, was significantly lower in the higher PEEP group in the subset of ARDS patients (PaO 2/FIO 2 ≤200 mmHg), and tended to be higher in the higher PEEP group in the subset of patients with acute lung injury (200< PaO 2/FIO 2 ≤300 mmHg). Therefore, higher PEEP should be used in patients with the highest lung recruitability and in the most hypoxemic patients. Higher PEEP should be used with caution in patients less severe hypoxemic (acute lung injury).To deliver optimal PEEP to those ARDS patients with the highest lung recruitability, this technique should be monitored at the bedside. Alternative methods are under investigation as part of a decremental PEEP trial.


Long A.,University of California at Irvine | Liti G.,University of Nice Sophia Antipolis | Luptak A.,University of California at Irvine | Tenaillon O.,French Institute of Health and Medical Research
Nature Reviews Genetics | Year: 2015

Evolve and resequence (E&R) experiments use experimental evolution to adapt populations to a novel environment, then next-generation sequencing to analyse genetic changes. They enable molecular evolution to be monitored in real time on a genome-wide scale. Here, we review the field of E&R experiments across diverse systems, ranging from simple non-living RNA to bacteria, yeast and the complex multicellular organism Drosophila melanogaster. We explore how different evolutionary outcomes in these systems are largely consistent with common population genetics principles. Differences in outcomes across systems are largely explained by different starting population sizes, levels of pre-existing genetic variation, recombination rates and adaptive landscapes. We highlight emerging themes and inconsistencies that future experiments must address. © 2015 Macmillan Publishers Limited.


Langlet F.,French Institute of Health and Medical Research
Journal of neuroendocrinology | Year: 2014

The central regulation of energy balance relies on the ability of the brain to promptly and efficiently sense variations of metabolic state. To achieve this, circulating hormonal and metabolic signals have to cross the blood-brain interface, where unusual glial cells named tanycytes have been described to play a key role in this process. Tanycytes are specialised polarised ependymoglial cells that line the floor of the third ventricle and send a single process to contact hypothalamic neurones and blood vessels. Although their role in the regulation of energy balance via the modulation of neuronal activity or their chemosensitivity has been already described, recent studies ascribe a new function to tanycytes in the regulation of energy homeostasis as a result of their capacity to regulate the access of metabolic signals to the hypothalamus. This review discusses the peculiar place of tanycytes within the blood-hypothalamus interface, as well as a striking capacity to remodel their own interface to ensure an adaptive metabolic response to energy imbalances. © 2014 British Society for Neuroendocrinology.


Verhasselt V.,French Institute of Health and Medical Research | Verhasselt V.,University of Nice Sophia Antipolis
Current Opinion in Immunology | Year: 2010

Diseases due to defect in tolerance induction such as allergy, celiac disease, or Type 1 Diabetes develop mostly in childhood indicating the necessity of early intervention for primary prevention. Epidemiological studies report that breastfeeding could protect from these diseases. However, data are controversial and the mechanisms unclear. Experimental data suggest that breastfeeding-induced protection might rely on tolerance induction as long as some criteria are fulfilled. Thus, the tolerogenic potential of breast milk would depend on maternal exposure to common environmental and dietary antigens and the efficiency of antigen transfer across mammary epithelium. Induction of tolerance upon breast milk-mediated antigen transfer will also depend on the presence of immunomodulatory factors in breast milk and of its impact on neonatal gut and immune system maturation. The better understanding of maternal influence on tolerance induction through breastfeeding should allow the development of new strategies to prevent immune-mediated diseases. © 2010 Elsevier Ltd.


Pous C.,University Paris - Sud | Codogno P.,University Paris - Sud | Codogno P.,French Institute of Health and Medical Research
Nature Cell Biology | Year: 2011

Under nutrient-rich conditions, the nutrient-sensitive kinase mTOR (mammalian target of rapamycin) is recruited to the surface of lysosomes where it becomes activated and can promote cell growth and inhibit autophagy. In contrast, mTOR is inhibited in nutrient-poor conditions, leading to the induction of autophagy. The intracellular positioning of lysosomes in response to nutrient availability is now shown to orchestrate mTOR activation and regulate autophagy. © 2011 Macmillan Publishers Limited. All rights reserved.


Fernandez J.,University of Barcelona | Gustot T.,Erasme Hospital | Gustot T.,Free University of Colombia | Gustot T.,French Institute of Health and Medical Research
Journal of Hepatology | Year: 2012

Bacterial infections are very frequent in advanced cirrhosis and become the first cause of death of these patients. Despite numerous experimental data and significant advances in the understanding of the pathogenesis of sepsis in cirrhosis, the outcome remains poor. Classical diagnostic parameters such as C-reactive protein and SIRS criteria have less diagnostic capacity in the cirrhotic population, often delaying the diagnosis and the management of bacterial infection. Prompt and appropriate empirical antibiotic treatment of infection and early resuscitation of patients with severe sepsis or septic shock are essential in determining patient's outcome. A strategy of careful restriction of prophylactic antibiotics to the high-risk populations could reduce the spread of multidrug resistant bacteria. This review is focused on the currently recommended diagnostic, therapeutic and prophylactic strategies for bacterial infections in the cirrhotic population. © 2012 European Association for the Study of the Liver.


Rouaux C.,Harvard University | Rouaux C.,French Institute of Health and Medical Research | Arlotta P.,Harvard University
Nature Cell Biology | Year: 2013

Once programmed to acquire a specific identity and function, cells rarely change in vivo. Neurons of the mammalian central nervous system (CNS) in particular are a classic example of a stable, terminally differentiated cell type. With the exception of the adult neurogenic niches, where a limited set of neuronal subtypes continue to be generated throughout life, CNS neurons are born only during embryonic and early postnatal development. Once generated, neurons become permanently post-mitotic and do not change their identity for the lifespan of the organism. Here, we have investigated whether excitatory neurons of the neocortex can be instructed to directly reprogram their identity post-mitotically from one subtype into another, in vivo. We show that embryonic and early postnatal callosal projection neurons of layer II/III can be post-mitotically lineage reprogrammed into layer-V/VI corticofugal projection neurons following expression of the transcription factor encoded by Fezf2. Reprogrammed callosal neurons acquire molecular properties of corticofugal projection neurons and change their axonal connectivity from interhemispheric, intracortical projections to corticofugal projections directed below the cortex. The data indicate that during a window of post-mitotic development neurons can change their identity, acquiring critical features of alternative neuronal lineages. © 2013 Macmillan Publishers Limited. All rights reserved.


Ben-Ari Y.,French Institute of Health and Medical Research
Handbook of Clinical Neurology | Year: 2013

Cortical maturation is associated with a series of developmental programs encompassing neuronal and network-driven patterns. Thus, voltage-gated and synapse-driven ionic currents are very different in immature and adult neurons with slower kinetics in the former than in the latter. These features are neuron and developmental stage dependent. GABA, which is the main inhibitory neurotransmitter in adult brain, depolarizes and excites immature neurons and its actions are thought to exert a trophic role in developmental processes. Networks follow a parallel sequence with voltage-gated calcium currents followed by calcium plateaux and synapse-driven patterns in vitro. In vivo, early activity exhibits discontinuous temporal organization with alternating bursts. Early cortical patterns are driven by sensory input from the periphery providing a basis for activity-dependent modulation of the cortical networks formation. These features and notably the excitatory GABA underlie the high susceptibility of immature neurons to seizures. Alterations of these sequences play a central role in developmental malformations, notably migration disorders and associated neurological sequelae. © 2013 Elsevier B.V.


Swendsen J.,University of Bordeaux Segalen | Le Moal M.,French Institute of Health and Medical Research
Annals of the New York Academy of Sciences | Year: 2011

The process of addiction is often studied in the neurosciences as a function of the quantity or type of substance consumed, with the ultimate goal of counteracting these effects by other pharmacological means. However, epidemiology and clinical research have extensively demonstrated that most individuals who use drugs do not develop dependence. Numerous factors may explain an individual's propensity to addiction. This review discusses these paradigms and summarizes research on individual differences that encompass cultural and sociodemographic factors, psychiatric or psychological vulnerability, and biological or genetic propensity to addiction. Although these different factors often interact in the expression of vulnerable phenotypes, it is possible to alter or control specific sources of vulnerability. For these reasons, integrating individual vulnerability to addiction across different research disciplines is likely to provide the greatest advances for intervention and prevention efforts. © 2011 New York Academy of Sciences.


Patient-reported outcome measures are being developed for more relevant assessments of pain management. The patient acceptable symptom state (PASS) ("feeling well") and the minimal clinically important improvement (MCII) ("feeling better") have been determined in clinical trials, but not in daily pain management. We carried out a national multicenter cohort study of patients over the age of 50 years with painful knee osteoarthritis (KOA) or hip osteoarthritis (HOA) who had visited their general practitioner and required treatment for more than 7 days. Overall, 2414 patients (50.2% men, mean age 67.3 years, body mass index 27.9 kg/m2, 33.5% with HOA) were enrolled by 1116 general practitioners. After 7 days of treatment, PASS was estimated on a numerical rating scale as 4 at rest and 5 on movement, for both HOA and KOA, above the PASS threshold in clinical trials. In KOA, PASS was more frequently reached in men and younger people with less pain at rest and on movement, and in patients specifically seeking an improvement during sport activities. In HOA, PASS was most frequently reached in patients with low levels of pain at risk and in nonobese patients. MCII was -1 numerical rating scale point after 7 days of usual treatment. This improvement is smaller than that recorded in randomized controlled trials, and was the same for both sites, both at rest and on movement. In conclusion, patient-reported outcome values in daily practice differ from those in clinical trials, and their determinant factors may depend on the site of osteoarthritis. Assessments of the treatment of painful osteoarthritis should be adapted to the characteristics and daily life of the patient, to personalize patient management. © 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.


Pellanda H.,French Institute of Health and Medical Research
Clinical Chemistry and Laboratory Medicine | Year: 2013

Carcinogenesis is a multi-step and multifactorial process. It includes genetic, epigenetic, nutritional and environmental factors, which are closely interconnected. Human hepatocellular carcinoma (HCC) is among the most frequent and lethal cancers. Imbalance in the S-adenosylmethionine (SAM) concentration, the main methyl group donor, strongly influences the development of HCC. Key enzymes of carbon metabolism are greatly reduced in patients with cirrhosis and HCC. These alterations play a role in genetic instability and epigenetic modifications (DNA methylation, and histone modifications), however, the molecular underlying mechanisms are still poorly understood. We aimed to investigate betaine homocysteine methyltransferase (BHMT) expression in HepG2 cells and human hepatocarcinoma tissues. Tumor and surrounding healthy tissue were compared. HepG2 cells and tumor samples showed a strong decrease in BHMT transcripts resulting from the transcription of a splicing variant that contained a frameshift mutation generating a premature termination codon and gene loss of function. This splicing variant, not detected in normal adult and fetal liver, cannot be explained by any mechanism involving the known splicing consensus sequences. BHMT activity was abolished in HepG2 cells and protein expression was detected neither in HepG2 cells nor in five of the six tumor samples investigated. Further investigation is needed to elucidate whether this abnormal BHMT transcription is part of cause or consequence of liver carcinogenesis.


Anty R.,French Institute of Health and Medical Research
Clinics and research in hepatology and gastroenterology | Year: 2011

Mechanisms of liver fibrosis are complex and varied. Among them, metabolic factors are particularly important in the development of fibrosis associated with nonalcoholic steatohepatitis (NASH). These factors are some of the "multiple parallel hits" responsible for liver damage during NASH. Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. Major profibrogenic protagonists, such as hepatic stellate cells and Kupffer cells, are activated by insulin resistance, apoptosis and local inflammation. Relations between steatosis, insulin resistance and fibrosis are complex. Initially, simple steatosis may be a way to store deleterious free fatty acid in neutral triglycerides. If the lipid storage threshold is exceeded, steatosis may become associated with lipotoxicity. Similarly, interindividual variations of adipose tissue expandability might explain various phenotypes, ranging from "metabolically obese patients with normal weight" to "metabolically normal morbidly obese patients". The metabolic abnormalities in subcutaneous and visceral adipose tissue are insulin resistance and low-grade inflammation, which are associated with increased release of free fatty acid flux and changes in adipocytokines production such as leptin, adiponectin and interleukin 6. The nuclear transcription factor peroxisome proliferator-activated receptor gamma (PPARγ) and the endocannabinoid system might have important roles in liver fibrogenesis and are potential therapeutic targets. Finally, with the development of new molecular tools, gut microbiota has been recently identified for its pleiotropic functions, including metabolism regulation. Better knowledge of these mechanisms should lead to new strategies for the treatment of metabolic factors that play a key role in liver injuries. Copyright © 2011 Elsevier Masson SAS. All rights reserved.


Schouten J.N.,Rotterdam University | Garcia-Pagan J.C.,CIBER ISCIII | Valla D.C.,French Institute of Health and Medical Research | Janssen H.L.,Rotterdam University
Hepatology | Year: 2011

Idiopathic noncirrhotic portal hypertension (INCPH) is characterized by an increased portal venous pressure gradient in the absence of a known cause of liver disease and portal vein thrombosis. In contrast to the high prevalence of this disorder in India, INCPH is a rare disease in the Western world. The etiology of INCPH can be divided in five categories: chronic infections, exposure to medication or toxins, thrombophilia, immunological disorders, and genetic disorders. Multifactorial etiology can also be encountered. Chronic abdominal infection is incriminated as the most important etiological factor in Eastern patients and thrombophilia in Western patients. The majority of patients with INCPH initially present with signs or complications of portal hypertension (mainly variceal bleeding and splenomegaly). These patients usually have preserved liver function. Liver function impairment occurs mainly in the context of intercurrent conditions. Patients with INCPH are often clinically and radiologically misdiagnosed as liver cirrhosis, so that a liver biopsy is indispensable to discriminate cirrhosis from INCPH. Histopathological characteristics of INCPH are heterogeneous, demonstrating overlap between several pathological entities (e.g., hepatoportal sclerosis, nodular regenerative hyperplasia, and incomplete septal cirrhosis). Even though hemodynamical changes in INCPH patients are not comparable to those in cirrhotics, prophylaxis and treatment of variceal bleeding are recommended to be similar. Anticoagulation therapy must be considered only in patients who develop portal vein thrombosis. INCPH has been considered a disorder with a relatively benign disease course. However, liver failure, hepatic encephalopathy, and hepatopulmonary syndrome can occur and are considered indications for liver transplantation. © 2011 American Association for the Study of Liver Diseases.


London G.M.,French Institute of Health and Medical Research
Journal of Nephrology | Year: 2012

Increasing numbers of cross-sectional studies on general populations and chronic kidney disease (CKD) or end-stage renal disease (ESRD) patients have reported relationships between cardiovascular calcifications and bone disorders, including osteoporosis, osteopenia and high or low bone activity. The mechanisms underlying this bone-cardiovascular axis and biological links between bone and arterial abnormalities are suggestive of bone-vascular cross-talk. The nature of these links is not well understood and could result from: 1) common factors acting on bone remodeling and arterial calcification; 2) compromised bone blood supply responsible for arteriosclerosis of bone vessels and reduced perfusion; and/or 3) direct action of bone cells (osteoblasts/osteocytes) on vascular biology and structure. Inflammation and accumulation of reactive oxygen species are the principal common pathways linking bone and arterial pathologies. © 2012 Società Italiana di Nefrologia.


Willier S.,University of Wurzburg | Butt E.,University of Wurzburg | Grunewald T.G.P.,French Institute of Health and Medical Research
Biology of the Cell | Year: 2013

Lysophosphatidic acid (LPA) is a ubiquitously present signalling molecule involved in diverse cellular processes such as cell migration, proliferation and differentiation. LPA acts as an autocrine and/or paracrine signalling molecule via different G-protein-coupled LPA receptors (LPARs) that trigger a broad range of intracellular signalling cascades, especially the RHOA pathway. Mounting evidence suggests a crucial role of the LPA/LPAR-axis in cancer cell metastasis and promising studies are underway to investigate the therapeutic potential of LPAR-antagonists. This review summarises current knowledge on how LPA promotes cytoskeletal remodelling to enhance the migratory and invasive properties of cells, which may ultimately contribute to cancer metastasis. Furthermore, we provide comprehensive transcriptome analyses of published microarrays of more than 350 normal tissues and more than 1700 malignant tissues to define the expression signatures of LPARs and the LPA-generating enzymes autotaxin (ATX) and lipase member 1 (LIPI). These analyses demonstrate that ATX is highly expressed in a variety of carcinomas and sarcomas, whereas LIPI is almost exclusively overexpressed in highly aggressive Ewing's sarcomas, which underscores the potential contribution of LPA in metastatic disease. In addition, these analyses show that different cancer entities display distinct expression signatures of LPARs that distinguish them from one another. Finally, we discuss current approaches to specifically target the LPA/LPAR circuits in experimental cancer therapy. © 2013 Société Française des Microscopies and Société de Biologie Cellulaire de France.


Srinivasan S.V.,Columbia University | Dominguez-Sola D.,Columbia University | Wang L.C.,Columbia University | Hyrien O.,French Institute of Health and Medical Research | Gautier J.,Columbia University
Cell Reports | Year: 2013

c-Myc oncogenic activity is thought to be mediated in part by its ability to generate DNA replication stress and subsequent genomic instability when deregulated. Previous studies have demonstrated a nontranscriptional role for c-Myc in regulating DNA replication. Here, we analyze the mechanisms by which c-Myc deregulation generates DNA replication stress. We find that overexpression of c-Myc alters the spatiotemporal program of replication initiation by increasing the density of early-replicating origins. We further show that c-Myc deregulation results inelevated replication-fork stalling or collapse and subsequent DNA damage. Notably, these phenotypes are independent of RNA transcription. Finally, we demonstrate that overexpression of Cdc45 recapitulates all c-Myc-induced replication and damage phenotypes and that Cdc45 and GINS function downstream of Myc. © 2013 The Authors.


Gerber Y.N.,French Institute of Health and Medical Research
PloS one | Year: 2012

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by selective motoneurons degeneration. There is today no clear-cut pathogenesis sequence nor any treatment. However growing evidences are in favor of the involvement, besides neurons, of several partners such as glia and muscles. To better characterize the time course of pathological events in an animal model that recapitulates human ALS symptoms, we investigated functional and cellular characteristics of hSOD1(G93A) mice. We have evaluated locomotor function of hSOD1(G93A) mice through dynamic walking patterns and spontaneous motor activity analysis. We detected early functional deficits that redefine symptoms onset at 60 days of age, i.e. 20 days earlier than previously described. Moreover, sequential combination of these approaches allows monitoring of motor activity up to disease end stage. To tentatively correlate early functional deficit with cellular alterations we have used flow cytometry and immunohistochemistry approaches to characterize neuromuscular junctions, astrocytes and microglia. We show that (1) decrease in neuromuscular junction's number correlates with motor impairment, (2) astrocytes number is not altered at pre- and early-symptomatic ages but intraspinal repartition is modified at symptoms onset, and (3) microglia modifications precede disease onset. At pre-symptomatic age, we show a decrease in microglia number whereas at onset of the disease two distinct microglia sub-populations emerge. In conclusion, precise motor analysis updates the onset of the disease in hSOD1(G93A) mice and allows locomotor monitoring until the end stage of the disease. Early functional deficits coincide with alterations of neuromuscular junctions. Importantly, we identify different sets of changes in microglia before disease onset as well as at early-symptomatic stage. This finding not only brings a new sequence of cellular events in the natural history of the disease, but it may also provide clues in the search for biomarkers of the disease, and potential therapeutic targets.


Niso-Santano M.,French Institute of Health and Medical Research
Autophagy | Year: 2012

General (macro)autophagy and the activation of NFκB constitute prominent responses to a large array of intracellular and extracellular stress conditions. The depletion of any of the three subunits of the inhibitor of NFκB (IκB) kinase (IKKα, IKKβ, IKKγ/NEMO), each of which is essential for the canonical NFκB activation pathway, limits autophagy induction by physiological or pharmacological triggers, while constitutive active IKK subunits suffice to stimulate autophagy. The activation of IKK usually relies on TGFβ-activated kinase 1 (TAK1), which is also necessary for the optimal induction of autophagy in multiple settings. TAK1 interacts with two structurally similar co-activators, TAK1-binding proteins 2 and 3 (TAB2 and TAB3). Importantly, in resting conditions both TAB2 and TAB3 bind the essential autophagic factor Beclin 1, but not TAK1. In response to pro-autophagic stimuli, TAB2 and TAB3 dissociate from Beclin 1 and engage in stimulatory interactions with TAK1. The inhibitory interaction between TABs and Beclin 1 is mediated by their coiled-coil domains (CCDs). Accordingly, the overexpression of either TAB2 or TAB3 CCD stimulates Beclin 1- and TAK1-dependent autophagy. These results point to the existence of a direct molecular crosstalk between the canonical NFκB activation pathway and the autophagic core machinery that guarantees the coordinated induction of these processes in response to stress.


Etchevers H.,French Institute of Health and Medical Research
Nature Protocols | Year: 2011

A highly enriched population of neural crest cells (NCCs) from amniote embryos, such as from chicks, mice and humans, is desirable for experiments in fate determination. NCCs are also useful for testing the functional effects of molecular changes underlying numerous human diseases of neural crest derivatives and for investigating their potential for therapeutic compensation. This protocol details embryonic microdissection followed by neural tube explantation. Conditions favoring NCC expansion and the maintenance of their stem cell-like properties are described. Although neural crest-like cells can be derived from a number of sites in the mature organism, full potential is best ensured by their purification from their source tissue at the outset of migration. Going from embryo to established cell line takes 4 d; the first is the most labor-intensive day, but minimal intervention is required thereafter. © 2011 Nature America, Inc. All rights reserved.


Thery C.,French Institute of Health and Medical Research
F1000 Biology Reports | Year: 2011

Exosomes are small membrane vesicles of endocytic origin secreted by most cell types, and are thought to play important roles in intercellular communications. Although exosomes were originally described in 1983, interest in these vesicles has really increased dramatically in the last 3 years, after the finding that they contain mRNA and microRNA. This discovery sparked renewed interest for the general field of membrane vesicles involved in intercellular communications, and research on these structures has grown exponentially over the last few years, probing their composition and function, as well as their potential value as biomarkers. © 2011 Faculty of 1000 Ltd.


Kubicki A.,French Institute of Health and Medical Research
Neuroscience Letters | Year: 2014

In order to assess functional skills of older adults, both timed up and go (TUG) test and gait speed (GS) test are well validated concerning their predictive capacities. However, the question remains unclear which one of these tests represents better the whole physical performance of older adults. The aim of this study is to determine the more representative test, between TUG and GS, of the whole motor control quality. To study links between locomotion capacities and arm function, we measured, in a population of frail aged patients, the locomotion tests and the mean arm maximal velocity developed during a speed-accuracy trade-off. This arm movement consisted in reaching the hand toward a target in a virtual game scene. We plotted the different couples of variables obtained on graphs, and calculate Pearson correlation coefficients between each couple. The Pearson correlation between GS and hand maximal velocity was significant (r= 0.495; p= 0.046). Interestingly, we found a non significant Pearson correlation between timed up and go score (TUG) and hand maximal velocity (r= -0.139; p= 0.243). Our results suggest that GS score is more representative of the whole motor ability of frail patients than the TUG. We propose that the relative complexity of the TUG motor sequence could be involved in this difference. For a few patients with motor automatisms deficiencies, this motor sequence complexity could leads to a dual task perturbation. In this way, we conclude that GS should be preferred over the TUG with older adults. © 2014 Elsevier Ireland Ltd.


Galmiche A.,French Institute of Health and Medical Research | Rassow J.,Ruhr University Bochum
Gut Microbes | Year: 2010

One of the major virulence factors of Helicobacter pylori is the vacuolating toxin VacA. It has been known for a long time that the toxin enters host cells by endocytosis. On the other hand there is ample evidence that VacA is able to trigger apoptosis and this effect has been attributed in part to interactions with mitochondria. However, for 10 years it was difficult to reconcile the obvious accumulation of VacA in endosomes with mitochondrial targeting. The accessibility of the mitochondria to the toxin was enigmatic. In our new study, we investigated the activities of p34, the toxic subunit of VacA, in more detail. We found that the p34 N-terminus carries a unique targeting sequence for import into mitochondria and for insertion into the mitochondrial inner membrane. By forming an anion channel in this membrane, the toxin has the ability to interfere directly with mitochondrial functions. Taking into account additional results from independent studies, we discuss the implications of our findings with respect to intracellular traffic, the remarkable possibility of a direct transfer of VacA from endosomes to mitochondria and VacA-dependent cell death. © 2010 Landes Bioscience.


Ferry B.,French Institute of Health and Medical Research
Frontiers in Behavioral Neuroscience | Year: 2014

A large variety of behaviors that are essential for animal survival depend on the perception and processing of surrounding smells present in the natural environment. In particular, food-search behavior, which is conditioned by hunger, is directly driven by the perception of odors associated with food, and feeding status modulates olfactory sensitivity. The orexinergic hypothalamic peptide orexin A (OXA), one of the central and peripheral hormones that triggers food intake, has been shown to increase olfactory sensitivity in various experimental conditions including the conditioned odor aversion learning paradigm (COA). COA is an associative task that corresponds to the association between an olfactory conditioned stimulus (CS) and a delayed gastric malaise. Previous studies have shown that this association is formed only if the delay separating the CS presentation from the malaise is short, suggesting that the memory trace of the odor is relatively unstable. To test the selectivity of the OXA system in olfactory sensitivity, a recent study compared the effects of fasting and of central infusion of OXA during the acquisition of COA. Results showed that the increased olfactory sensitivity induced by fasting and by OXA infusion was accompanied by enhanced COA learning performances. In reference to the duration of action of OXA, the present work details the results obtained during the successive COA extinction tests and suggests a hypothesis concerning the role of the OXA component of fasting on the memory processes underlying CS-malaise association during COA. Moreover, referring to previous data in the literature we suggest a functional circuit model where fasting modulates olfactory memory processes through direct and/or indirect activation of particular OXA brain targets including the olfactory bulb, the locus coeruleus (LC) and the amygdala. © 2014 Ferry.


Billard C.,French Institute of Health and Medical Research | Billard C.,University Pierre and Marie Curie
Molecular Cancer Research | Year: 2012

Despite real advances made in chemoimmunotherapy, chronic lymphocytic leukemia (CLL) is still an incurable disease. New therapeutic strategies based on the restoration of the cell death program seemed relevant. Some members of the Bcl-2 family are critical players in the defective apoptotic program in CLL cells and/or targets of apoptosis inducers in vitro. The concept of BH3 mimetics has led to the characterization of small molecules mimicking proapoptotic BH3-only members of the Bcl-2 family by their ability to bind and antagonize the prosurvival members. Some putative or actual BH3 mimetics are already being tested in clinical trials with somewhat promising results. However, none of them has a high enough interaction affinity with Mcl-1, a crucial antiapoptotic factor in CLL. It has been suggested that resistance to BH3 mimetics can be overcome by using inhibitors of Mcl-1 expression. An alternative and more direct strategy is to design mimetics of the Noxa BH3 domain, which is a specific antagonistic Mcl-1 ligand. The development of such Noxa-like BH3 mimetics, capable of directly interacting with Mcl-1 and efficiently neutralizing its antiapoptotic activity, is extremely important to evaluate their impact on the clinical outcome of patients with CLL. ©2012 AACR.


Lebouvier T.,French Institute of Health and Medical Research
PloS one | Year: 2010

The presence of Lewy bodies and Lewy neurites (LN) has been demonstrated in the enteric nervous system (ENS) of Parkinson's disease (PD) patients. The aims of the present research were to use routine colonoscopy biopsies (1) to analyze, in depth, enteric pathology throughout the colonic submucosal plexus (SMP), and (2) to correlate the pathological burden with neurological and gastrointestinal (GI) symptoms. A total of 10 control and 29 PD patients divided into 3 groups according to disease duration were included. PD and GI symptoms were assessed using the Unified Parkinson's Disease Rating Scale part III and the Rome III questionnaire, respectively. Four biopsies were taken from the ascending and descending colon during the course of a total colonoscopy. Immunohistochemical analysis was performed using antibodies against phosphorylated alpha-synuclein, neurofilaments NF 220 kDa (NF) and tyrosine hydroxylase (TH). The density of LN, labeled by anti-phosphorylated alpha-synuclein antibodies, was evaluated using a quantitative rating score. Lewy pathology was apparent in the colonic biopsies from 21 patients and in none of the controls. A decreased number of NF-immunoreactive neurons per ganglion was observed in the SMP of PD patients compared to controls. The amount of LN in the ENS was inversely correlated with neuronal count and positively correlated with levodopa-unresponsive features and constipation. Analysis of the ENS by routine colonoscopy biopsies is a useful tool for pre-mortem neuropathological diagnosis of PD, and also provides insight into the progression of motor and non-motor symptoms.


De Jong D.,Netherlands Cancer Institute | Fest T.,French Institute of Health and Medical Research
Best Practice and Research: Clinical Haematology | Year: 2011

It has become increasingly clear that proliferation and survival in FL is not only driven by genetic changes, but also and possibly even predominantly by the close interaction with the immune microenvironment and stromal cells. Based on in vitro studies and experimental models and supported by immunohistochemical studies in biopsy specimens of FL patients, classes of CD4+ T-cell populations including follicular helper T cells and regulatory T cells are now identified as major players to regulate the delicate balance of effector populations into a supportive microenvironment. These insights may thoroughly change the therapeutic approaches in FL and translate into programs that combine direct cytotoxic and indirect immunomodulatory aspects. © 2011 Elsevier Ltd. All rights reserved.


Hamel C.P.,French Institute of Health and Medical Research
Comptes Rendus - Biologies | Year: 2014

Inherited retinal dystrophies are Mendelian neurodegenerative conditions classified as pigmentary retinopathies, macular dystrophies and others. Over a 21-year period, from 1990 to 2011, we have screened in Montpellier 107 genes in 609 families and have identified a causal mutation in 68.5% of them. Following a gene candidate approach, we established that RPE65, the isomerohydrolase of the visual cycle, is responsible for severe childhood blindness (Leber congenital amaurosis or early onset retinal dystrophy). In an ongoing study, we screened the genes in a series of 283 families with dominant retinitis pigmentosa and we have estimated that 80% of the families have a mutation in a known gene. A similar study is currently undergoing for autosomal recessive retinitis pigmentosa. Finally, we have identified IMPG1 as a responsible gene for rare cases of macular vitelliform dystrophy with a dominant or recessive inheritance. © 2014 Académie des sciences.


Trocoli A.,French Institute of Health and Medical Research
Cell Death and Differentiation | Year: 2014

The p62/SQSTM1 adapter protein has an important role in the regulation of several key signaling pathways and helps transport ubiquitinated proteins to the autophagosomes and proteasome for degradation. Here, we investigate the regulation and roles of p62/SQSTM1 during acute myeloid leukemia (AML) cell maturation into granulocytes. Levels of p62/SQSTM1 mRNA and protein were both significantly increased during all-trans retinoic acid (ATRA)-induced differentiation of AML cells through a mechanism that depends on NF-κB activation. We show that this response constitutes a survival mechanism that prolongs the life span of mature AML cells and mitigates the effects of accumulation of aggregated proteins that occurs during granulocytic differentiation. Interestingly, ATRA-induced p62/SQSTM1 upregulation was impaired in maturation-resistant AML cells but was reactivated when differentiation was restored in these cells. Primary blast cells of AML patients and CD34+ progenitors exhibited significantly lower p62/SQSTM1 mRNA levels than did mature granulocytes from healthy donors. Our results demonstrate that p62/SQSTM1 expression is upregulated in mature compared with immature myeloid cells and reveal a pro-survival function of the NF-κB/SQSTM1 signaling axis during granulocytic differentiation of AML cells. These findings may help our understanding of neutrophil/granulocyte development and will guide the development of novel therapeutic strategies for refractory and relapsed AML patients with previous exposure to ATRA.Cell Death and Differentiation advance online publication, 18 July 2014; doi:10.1038/cdd.2014.102.


Hatem S.N.,Institute of cardiometabolism and nutrition | Hatem S.N.,French Institute of Health and Medical Research | Sanders P.,University of Adelaide
Cardiovascular Research | Year: 2014

Atrial fibrillation (AF) is the most frequent cardiac arrhythmia in clinical practice. AF is often associated with profound functional and structural alterations of the atrial myocardium that compose its substrate. Recently, a relationship between the thickness of epicardial adipose tissue (EAT) and the incidence and severity of AF has been reported. Adipose tissue is a biologically active organ regulating the metabolism of neighbouring organs. It is also a major source of cytokines. In the heart, EAT is contiguous with the myocardium without fascia boundaries resulting in paracrine effects through the release of adipokines. Indeed, Activin A, which is produced in abundance by EAT during heart failure or diabetes, shows a marked fibrotic effect on the atrial myocardium. The infiltration of adipocytes into the atrial myocardium could also disorganize the depolarization wave front favouring micro re-entry circuits and local conduction block. Finally, EAT contains progenitor cells in abundance and therefore could be a source of myofibroblasts producing extracellular matrix. The study on the role played by adipose tissue in the pathogenesis of AF is just starting and is highly likely to uncover new biomarkers and therapeutic targets for AF. © The Author 2014.


Zoulim F.,French Institute of Health and Medical Research
Nature Reviews Gastroenterology and Hepatology | Year: 2011

The failure of antiviral therapy for chronic hepatitis B can involve both virological breakthrough and genotypic resistance. A study of the failure of nucleoside analogue therapy suggests that drug-resistant mutants are not solely responsible for treatment failure. Suboptimal treatment adherence might also have an important role.


Lelievre E.C.,French Institute of Health and Medical Research
Journal of molecular neuroscience : MN | Year: 2012

Foxn4, a member of the N-family forkhead transcription factors, controls fate decision in mouse retina and spinal cord as well as in zebrafish heart. Analysis of Foxn4 amino acid sequence revealed the presence of a region homologous to the activation domain of its close relative Foxn1 in between C-terminal amino acids 402 and 455 of Foxn4 protein. The requirement of Foxn4 putative activation domain remains to be elucidated. Using a gain-of function approach in rat and chick retinal explants, we report that deletion of Foxn4 putative activation domain results in a complete loss of its activity during retinogenesis. Target promoter transcription assay indicates that this domain is critical for Foxn4 transcriptional regulatory properties in vitro. Accordingly, in chick retinal explants, this domain is required for proper regulation of target retinogenic factors expression by Foxn4. Thus, our study demonstrates that the domain between amino acids 402 and 455 is necessary for Foxn4 transcriptional activity both in vitro and in the retina.


Nandrot E.F.,French Institute of Health and Medical Research
Advances in Experimental Medicine and Biology | Year: 2010

It took 62 years from the description of the retinal dystrophy in rats from the Royal College of Surgeons (RCS) strain to the discovery of the molecular defect underlying the phenotype. Phagocytosis of photoreceptor outer segments (POS) by retinal pigment epithelial (RPE) cells follows a daily rhythm with a peak of activity 1.5-2 h after light onset for rod photoreceptors. We identified a deletion in the Mer tyrosine kinase (MerTK) receptor in RCS rat that abolishes internalization of POS by RPE cells. Accumulation of debris in the subretinal space then leads to drastic photoreceptor degeneration and rapid loss of vision. Interestingly, in wild-type mice and rats, MerTK is phosphorylated at the time of the phagocytic peak.We also demonstrated that the couple αvβ5 integrin receptor and MFG-E8 ligand synchronizes daily retinal phagocytosis. Indeed, when either one is absent in knockout mice, phagocytosis follows steady-state levels, and peak activation of integrin-associated protein and of MerTK does not occur. We now have a more precise picture of the sequence of molecular events governing retinal phagocytosis. However, requirement of MerTK ligands in vivo and linked signaling pathways still remain elusive so far. © Springer Science+Business Media, LLC 2010.


Trepo C.,Croix Rousse Hospital | Trepo C.,French Institute of Health and Medical Research | Chan H.L.Y.,Chinese University of Hong Kong | Lok A.,University of Michigan
The Lancet | Year: 2014

Hepatitis B virus infection is a major public health problem worldwide; roughly 30% of the world's population show serological evidence of current or past infection. Hepatitis B virus is a partly double-stranded DNA virus with several serological markers: HBsAg and anti-HBs, HBeAg and anti-HBe, and anti-HBc IgM and IgG. It is transmitted through contact with infected blood and semen. A safe and effective vaccine has been available since 1981, and, although variable, the implementation of universal vaccination in infants has resulted in a sharp decline in prevalence. Hepatitis B virus is not cytopathic; both liver damage and viral control - and therefore clinical outcome - depend on the complex interplay between virus replication and host immune response. Overall, as much as 40% of men and 15% of women with perinatally acquired hepatitis B virus infection will die of liver cirrhosis or hepatocellular carcinoma. In addition to decreasing hepatic inflammation, long-term antiviral treatment can reverse cirrhosis and reduce hepatocellular carcinoma. Development of new therapies that can improve HBsAg clearance and virological cure is warranted. © 2014 Elsevier Ltd.


Perelson A.S.,Los Alamos National Laboratory | Guedj J.,French Institute of Health and Medical Research
Nature Reviews Gastroenterology and Hepatology | Year: 2015

Mathematically modelling changes in HCV RNA levels measured in patients who receive antiviral therapy has yielded many insights into the pathogenesis and effects of treatment on the virus. By determining how rapidly HCV is cleared when viral replication is interrupted by a therapy, one can deduce how rapidly the virus is produced in patients before treatment. This knowledge, coupled with estimates of the HCV mutation rate, enables one to estimate the frequency with which drug resistant variants arise. Modelling HCV also permits the deduction of the effectiveness of an antiviral agent at blocking HCV replication from the magnitude of the initial viral decline. One can also estimate the lifespan of an HCV-infected cell from the slope of the subsequent viral decline and determine the duration of therapy needed to cure infection. The original understanding of HCV RNA decline under interferon-based therapies obtained by modelling needed to be revised in order to interpret the HCV RNA decline kinetics seen when using direct-acting antiviral agents (DAAs). There also exist unresolved issues involving understanding therapies with combinations of DAAs, such as the presence of detectable HCV RNA at the end of therapy in patients who nonetheless have a sustained virologic response. © 2015 Macmillan Publishers Limited.


de Breyne S.,French Institute of Health and Medical Research
Virus research | Year: 2013

The human immunodeficiency virus (HIV) unspliced full length genomic RNA possesses features of an eukaryotic cellular mRNA as it is capped at its 5' end and polyadenylated at its 3' extremity. This genomic RNA is used both for the production of the viral structural and enzymatic proteins (Gag and Pol, respectively) and as genome for encapsidation in the newly formed viral particle. Although both of these processes are critical for viral replication, they should be controlled in a timely manner for a coherent progression into the viral cycle. Some of this regulation is exerted at the level of translational control and takes place on the viral 5' untranslated region and the beginning of the gag coding region. In this review, we have focused on the different initiation mechanisms (cap- and internal ribosome entry site (IRES)-dependent) that are used by the HIV-1 and HIV-2 genomic RNAs and the cellular and viral factors that can modulate their expression. Interestingly, although HIV-1 and HIV-2 share many similarities in the overall clinical syndrome they produce, in some aspects of their replication cycle, and in the structure of their respective genome, they exhibit some differences in the way that ribosomes are recruited on the gag mRNA to initiate translation and produce the viral proteins; this will be discussed in the light of the literature. Copyright © 2012 Elsevier B.V. All rights reserved.


Passeron T.,Nice University Hospital Center | Ortonne J.-P.,French Institute of Health and Medical Research
Journal of Investigative Dermatology | Year: 2012

Vitiligo is characterized by a substantial loss of functional melanocytes in the epidermis and sometimes in hair follicles. Genetic and pathophysiological studies have provided strong evidence that vitiligo is a polygenetic, multifactorial disorder. The key roles of oxidative stress within melanocytes and anti-melanocyte immune responses have been addressed in many studies, but the relationship between these mechanisms remains unclear. In this issue, Toosi et al. report the upregulation of IL-6 and IL-8 after the activation of the unfolded protein response (UPR) following exposure of melanocytes to phenols. Their results shed light on the missing link between oxidative stress and immune responses in vitiligo. © 2012 The Society for Investigative Dermatology.


Le Douarin N.M.,College de France | Dupin E.,French Institute of Health and Medical Research
Current Opinion in Genetics and Development | Year: 2012

Vertebrates belong to the group of chordates characterized by a dorsal neural tube and an anteroposterior axis, the notochord. They are the only chordates to possess an embryonic and pluripotent structure associated with their neural primordium, the neural crest (NC). The NC is at the origin of multiple cell types and plays a major role in the construction of the head, which has been an important asset in the evolutionary success of vertebrates. We discuss here the contribution of the rostral domain of the NC to craniofacial skeletogenesis. Moreover, recent data show that cephalic NC cells regulate the activity of secondary brain organizers, hence being critical for preotic brain development, a role that had not been suspected before. © 2012 Elsevier Ltd.


Szulc P.,French Institute of Health and Medical Research
Clinical Biochemistry | Year: 2012

Bone metabolism is assessed using biochemical bone turnover markers (BTM). BTM reflect the metabolic effect of drugs on bone turnover, help to establish the lowest dose inducing the largest change in the BTM, predict treatment-related reduction in fracture risk, and are helpful in bridging studies. Changes in BTM during anti-osteoporotic therapy depend on the cellular mechanism of action of the drug, degree of change in bone turnover rate and route of administration. BTM help to establish the optimal dose of anti-osteoporotic drugs because treatment-related changes in BTM are more rapid compared with change in BMD. A greater decrease in BTM levels during the first year of tantiresorptive treatment is associated with greater antifracture efficacy over 3. years. According to preliminary data, measurement of BTM can improve persistence with anti-resorptive treatment. The use of BTM to monitor anti-osteoporotic therapy in "real life" is limited at this stage. © 2012 The Canadian Society of Clinical Chemists.


Burcelin R.,French Institute of Health and Medical Research
Physiology | Year: 2012

The recent epidemic of obesity and diabetes and the diversity at the individual level could be explained by the intestinal microbiota-to-host relationship. More than four million gene products from the microbiome could interact with the immune system to induce a tissue metabolic infection, which is the molecular origin of the low-grade inflammation that characterizes the onset of obesity and diabetes. ©2012 Int. Union Physiol. Sci./Am. Physiol. Soc.


Gandarillas A.,Fund Marques Of Valdecilla Institute Formacion E Investigacion Marques Of Valdecilla Ifimav | Gandarillas A.,French Institute of Health and Medical Research
Cell Cycle | Year: 2012

Fifteen years ago, we reported that proto-oncogene MYC promoted differentiation of human epidermal stem cells, a finding that was surprising to the MYC and the skin research communities. MYC was one of the first human oncogenes identified, and it had been strongly associated with proliferation. However, it was later shown that MYC could induce apoptosis under low survival conditions. Currently, the notion that MYC promotes epidermal differentiation is widely accepted, but the cell cycle mechanisms that elicit this function remain unresolved. We have recently reported that keratinocytes respond to cell cycle deregulation and DNA damage by triggering terminal differentiation. This mechanism might constitute a homeostatic protection face to cell cycle insults. Here, I discuss recent and not-so-recent evidence suggesting the existence of a largely unexplored oncogene-induced differentiation response (OID) analogous to oncogene-induced apoptosis (OIA) or senescence (OIS). In addition, I propose a model for the role of the cell cycle in skin homeostasis maintenance and for the dual role of MYC in differentiation. © 2012 Landes Bioscience.


Natoli G.,Italian National Cancer Institute | Andrau J.-C.,Aix - Marseille University | Andrau J.-C.,French Institute of Health and Medical Research | Andrau J.-C.,French National Center for Scientific Research
Annual Review of Genetics | Year: 2012

Mammalian genomes are extensively transcribed outside the borders of protein-coding genes. Genome-wide studies recently demonstrated that cis-regulatory genomic elements implicated in transcriptional control, such as enhancers and locus-control regions, represent major sites of extragenic noncoding transcription. Enhancer-templated transcripts provide a quantitatively small contribution to the total amount of cellular nonribosomal RNA; nevertheless, the possibility that enhancer transcription and the resulting enhancer RNAs may, in some cases, have functional roles, rather than represent mere transcriptional noise at accessible genomic regions, is supported by an increasing amount of experimental data. In this article we review the current knowledge on enhancer transcription and its functional implications. © 2012 by Annual Reviews.


Buddelmeijer N.,French Institute of Health and Medical Research
FEMS Microbiology Reviews | Year: 2015

Posttranslational modification of proteins by lipidation is a common process in biological systems. Lipids provide protein stability, interaction with other membrane components, and in some cases, due to reversibility of the process, a mechanism for regulating protein localization and function. Bacterial lipoproteins possess fatty acids at their amino-termini that are derived from phospholipids, and this lipid moiety anchors the proteins into the membrane. These lipids, as is the case for lipopolysaccharides and lipoteichoic acids, play an important role in signaling of the innate immune system through the interaction with Toll-like receptors. Over the past three years, tremendous progress has been made in understanding the mechanism by which lipoproteins become lipidated. Advanced methodology in mass spectrometry, proteomics and genome-wide analyses allowed precise characterization of lipoprotein modifications and the identification of the enzymes catalyzing the reactions in diverse bacterial species. This review will highlight new findings on bacterial lipoprotein modification with focus on the reaction mechanisms and the role of lipoproteins in cell envelope homeostasis. © FEMS 2015. All rights reserved.


Kitabgi P.,French Institute of Health and Medical Research
Results and Problems in Cell Differentiation | Year: 2010

Neurotensin (NT) is synthesized as part of a larger precursor that also contains neuromedin N (NN), a six amino acid NT-like peptide. NT and NN are located in the C-terminal region of the precursor (pro-NT/NN) where they are flanked and separated by three Lys-Arg sequences. A fourth dibasic sequence is present in the middle of the precursor. Dibasics are the consensus sites recognized and cleaved by specialized endoproteases that belong to the family of proprotein convertases (PCs). In tissues that express pro-NT/NN, the three C-terminal Lys-Arg sites are differentially processed, whereas the middle dibasic is poorly cleaved. Processing gives rise mainly to NT and NN in the brain, NT and a large peptide with a C-terminal NN moiety (large NN) in the gut, and NT, large NN, and a large peptide with a C-terminal NT moiety (large NT) in the adrenals. Recent evidence indicates that PC1, PC2, and PC5-A are the prohormone convertases responsible for the processing patterns observed in the gut, brain, and adrenals, respectively. As NT, NN, large NT, and large NN are all endowed with biological activity, the evidence reviewed here supports the idea that posttranslational processing of pro-NT/NN in tissues may generate biological diversity of pathophysiological relevance. © 2010 Springer-Verlag Berlin Heidelberg.


Epaud R.,French Institute of Health and Medical Research
PloS one | Year: 2012

Insulin-like growth factors (IGF-I and -II) are pleiotropic regulators of somatic growth and development in vertebrate species. Endocrine and paracrine effects of both hormones are mediated by a common IGF type 1 receptor (IGF-1R). Lethal respiratory failure in neonatal IGF-1R knockout mice suggested a particular role for this receptor in pulmonary development, and we therefore investigated the consequences of IGF-1R inactivation in lung tissue. We first generated compound heterozygous mutant mice harboring a hypomorphic (Igf1r(neo)) and a null (Igf1r(-)) allele. These IGF-1R(neo/-) mice express only 22% of normal IGF-1R levels and are viable. In adult IGF-1R(neo/-) mice, we assessed lung morphology and respiratory physiology and found normal histomorphometric characteristics and normal breathing response to hypercapnia. We then generated homozygous IGF-1R knockout mutants (IGF-1R(-/-)) and analyzed their lung development during late gestation using histomorphometric and immunohistochemical methods. IGF-1R(-/-) embryos displayed severe lung hypoplasia and markedly underdeveloped diaphragms, leading to lethal neonatal respiratory distress. Importantly, IGF-1R(-/-) lungs from late gestation embryos were four times smaller than control lungs and showed markedly thickened intersaccular mesenchyme, indicating strongly delayed lung maturation. Cell proliferation and apoptosis were significantly increased in IGF-1R(-/-) lung tissue as compared with IGF-1R(+/+) controls. Immunohistochemistry using pro-SP-C, NKX2-1, CD31 and vWF as markers revealed a delay in cell differentiation and arrest in the canalicular stage of prenatal respiratory organ development in IGF-1R(-/-) mutant mice. We found that low levels of IGF-1R were sufficient to ensure normal lung development in mice. In contrast, complete absence of IGF-1R significantly delayed end-gestational lung maturation. Results indicate that IGF-1R plays essential roles in cell proliferation and timing of cell differentiation during fetal lung development.


Colnot C.,French Institute of Health and Medical Research
Tissue Engineering - Part B: Reviews | Year: 2011

One of the goals of bone tissue engineering is to design delivery methods for skeletal stem/progenitor cells to repair or replace bone. Although the materials used to retain cells play a central role in the quality of the constructs, the source of cells is key for bone regeneration. Bone marrow is the most common cell source, but other tissues are now being explored, such as the periosteum, fat, muscle, cord blood, and embryonic or induced pluripotent stem cells. The therapeutic effect of exogenous stem/progenitor cells is accepted, yet their contribution to bone repair is not well defined. The in vitro osteo-and/or chondrogenic potential of these skeletal progenitors do not necessarily predict their differentiation potential in vivo and their function may be affected by their ability to home correctly to bone. This review provides an overview of animal models used to test the efficacy of cell-based approaches. We examine the mechanisms of endogenous cell recruitment during bone repair and compare the role of local versus systemic cell recruitment. We discuss how the normal repair process can help define efficacious cell sources for bone tissue engineering and improve their methods of delivery. © 2011, Mary Ann Liebert, Inc.


Costet P.,French Institute of Health and Medical Research | Costet P.,Nantes University Hospital Center
Pharmacology and Therapeutics | Year: 2010

Recent guidelines in North America and Europe recommend lowering low density lipoprotein associated cholesterol (LDLC) to achieve optimal coronary heart disease risk reduction. Statins have been the therapy of choice and proven successful and relatively safe. However, we are now facing new challenges and it appears that additional or alternative drugs are urgently needed. This boosts research in the field, reopening old cases like other inhibitors of cholesterol synthesis or making attractive tools from the latest technologies like gene silencing by anti-sense oligonucleotides. LDLs are cholesterol-enriched lipoproteins stabilized by the hepatic apolipoprotein B100, and derived from TG rich very low density lipoprotein. This review focuses on the molecular pathways involved in plasma LDLC production and elimination, in particular cholesterol absorption and the hepatobiliary route, apoB100 and VLDL production, and LDL clearance via the LDL receptor. We will identify important or rate-limiting proteins (including Niemann-Pick C1-like 1 (NPC1L1), microsomal TG transfer protein (MTP), acyl-coenzyme A/cholesterol acyltransferase (ACAT), Acyl-CoA:diacylglycerol acyltransferases 2 (DGAT2), proprotein convertase subtilisin kexin type 9 (PCSK9)), and nuclear receptors (farnesoid X receptor (FXR), thyroid hormone receptor (TR)) that constitute interesting therapeutic targets. Numerous compounds already in use modulate these pathways, such as phytosterols, ezetimibe, bile acids sequestrants, niacin, and fibrates. Many pathways can be considered to lower LDLC, but the road has been paved with disappointments and difficulties. With new targets identified and diversification of the drugs, a new era for better LDLC management is plausible. © 2010 Elsevier Inc.


Tremblay R.E.,University College Dublin | Tremblay R.E.,University of Montreal | Tremblay R.E.,French Institute of Health and Medical Research
Journal of Child Psychology and Psychiatry and Allied Disciplines | Year: 2010

This paper reviews publications on developmental trajectories of disruptive behaviour (DB) problems (aggression, opposition-defiance, rule breaking, and stealing-vandalism) over the past decade. Prior to these studies two theoretical models had strongly influenced research on DB: social learning and disease onset. According to these developmental perspectives, children learn DB from their environment and onset of the disease is triggered by accumulated exposition to disruptive models in the environment, including the media. Most of the evidence came from studies of school age children and adolescents. Longitudinal studies tracing developmental trajectories of DB from early childhood onwards suggest an inversed developmental process. DB are universal during early childhood. With age, children learn socially acceptable behaviours from interactions with their environment. A 'disease' status is given to children who fail to learn the socially acceptable behaviours. The mechanisms that lead to deficits in using socially accepted behaviours are strongly intergenerational, based on complex genetic and environmental contributions, including epigenetic mechanisms. Prevention of these deficits requires early, intensive and long-term support to parents and child. Newly discovered epigenetic mechanisms suggest that intensive perinatal interventions will have impacts on numerous aspects of physical and mental health, including DB. This review also concludes that: a) subtypes of disruptive behaviours should not be aggregated because they have different developmental trajectories and require specific corrective interventions; b) the overt-covert and destructive- nondestructive dimensions appear the most useful to create DB subtypes; c) overt DB onset before covert DB because the latter require more brain maturation; d) DB subtype taxonomies are more useful for clinicians than developmental taxonomies because the latter are post mortem diagnoses and clinicians' retrospective information is unreliable; e) we need large-scale collaborative preventive experimental interventions starting during early pregnancy to advance knowledge on causes and prevention of DB problems. © 2010 The Author. Journal compilation © 2010 Association for Child and Adolescent Mental Health.


Mordon S.R.,French Institute of Health and Medical Research
Plastic and Reconstructive Surgery | Year: 2010

Background: Microvascular surgery has become an important method for reconstructing surgical defects resulting from trauma, tumors, or burns. The most important factor for successful free flap transfer is a well-executed anastomosis. This study was performed to review the authors' experience with a 1.9-μm diode laser in microsurgery, with special attention to outcomes and performance of the technique. Methods: Between January of 2005 and December of 2007, 27 patients underwent microsurgery with a 1.9-μm diode laser at the authors' institute. The patients had a mean age of 31 years (range, 2 to 59 years); 14 patients were women and 13 patients were men. This technique was used for digital replantations (n = 2) and for free flap transfer (n = 27). Causes of the defects were trauma (n = 14), tumor (n = 9), congenital (n = 2), burn (n = 1), infection (n = 1), arthritis (n = 1), and dog bite (n = 1). Laser-assisted microvascular anastomosis was performed with a 1.9-μm diode laser after placement of equidistant stitches. The following parameters were used: spot size, 400 μm; power, 125 mW; time depending on vessel size (0.8 to 1.8 mm); and fluence varying from 70 to 200 J/cm. Results: Three surgical revisions following hematoma and one rupture of the arterial anastomosis leading to a free deep inferior epigastric perforator flap necrosis resulting from high-dose radiotherapy before surgery occurred after laser-assisted microvascular anastomosis, accounting for an overall success rate of 96.6 percent. Conclusion: This study reports the numerous benefits of the technique: easier performance of vascular anastomosis with difficult access, decrease of reperfusion bleeding and complications, and a short learning curve. Copyright © 2010 by the American Society of Plastic Surgeons.


Courtois G.,French Institute of Health and Medical Research
Current topics in microbiology and immunology | Year: 2011

The IKK kinase complex is the core element of the NF-κB cascade. It is essentially made of two kinases (IKKα and IKKβ) and a regulatory subunit, NEMO/IKKγ. Additional components may exist, transiently or permanently, but their characterization is still uncertain. In this review, we will focus on the NEMO molecule, and describe the results which have been obtained, and the hypotheses which have been proposed, to explain how NEMO controls the activation of the IKK complex. NEMO is one of the very few non-redundant components of the NF-κB cascade, and the localization of the gene that encodes it on the X chromosome suggests it is likely to be the target of mutations leading to pathologies: this is indeed the case, and we will also present the current status of our knowledge regarding NEMO-associated pathologies.


Klatzmann D.,Paris-Sorbonne University | Klatzmann D.,French Institute of Health and Medical Research | Klatzmann D.,Biotherapy and Departement Hospitalo University Inflammation Immunopathology Biotherapy | Abbas A.K.,University of California at San Francisco
Nature Reviews Immunology | Year: 2015

Depletion of regulatory T (T Reg) cells in otherwise healthy individuals leads to multi-organ autoimmune disease and inflammation. This indicates that in a normal immune system, there are self-specific effector T cells that are ready to attack normal tissue if they are not restrained by T Reg cells. The data imply that there is a balance between effector T cells and T Reg cells in health and suggest a therapeutic potential of T Reg cells in diseases in which this balance is altered. Proof-of-concept clinical trials, now supported by robust mechanistic studies, have shown that low-dose interleukin-2 specifically expands and activates T Reg cell populations and thus can control autoimmune diseases and inflammation.


Mauger J.-P.,French Institute of Health and Medical Research | Mauger J.-P.,University Paris - Sud
Biology of the Cell | Year: 2012

The endoplasmic reticulum (ER) is the major Ca2+ store inside the cell. Its organisation in specialised subdomains allows the local delivery of Ca2+ to specific cell areas on stimulation. The nuclear envelope (NE), which is continuous with the ER, has a double role: it insulates the nucleoplasm from the cytoplasm and it stores Ca2+ around the nucleus. Furthermore, all the constituents of the signalling cascade leading to Ca2+ mobilisation are found in the NE; this allows the nuclear Ca2+ to be regulated autonomously. On the other hand, cytosolic Ca2+ transients can propagate within the nucleus via the nuclear pore complex. The variations in nuclear Ca2+ concentration are important for controlling gene transcription and progression in the cell cycle. Recent data suggest that invaginations of the NE modify the morphology of the nucleus and may affect Ca2+ dynamics in the nucleus and regulate transcriptional activity. © 2012 Soçiété Francaise des Microscopies and Société de Biologie Cellulaire de France.


Castera L.,French Institute of Health and Medical Research
Digestive Diseases | Year: 2015

Background: The prognosis and management of chronic liver diseases greatly depend on the amount and progression of liver fibrosis with the risk of developing cirrhosis. Liver biopsy, traditionally considered as the reference standard for the staging of fibrosis, has been challenged over the past decade by the development of novel noninvasive methodologies. Key Messages: Noninvasive methods rely on two different but complementary approaches: a 'biological' approach based on the dosage serum biomarkers, and a 'physical' approach based on the measurement of liver stiffness using transient elastography (TE). There are two clinically relevant endpoints for the staging of liver fibrosis: (1) significant fibrosis (indication for antiviral treatment in viral hepatitis B and C), and (2) cirrhosis (indication for screening of esophageal varices and hepatocellular carcinoma). TE (FibroScan), FibroTest and APRI have been the most extensively studied and validated methods, mainly in chronic hepatitis C. Combining two unrelated methods, such as TE and biomarkers, is an attractive approach that increases diagnostic performance and limits the drawback of both methodologies. TE appears to be an excellent tool for the early detection of cirrhosis with likely prognostic value in this setting. Thus far, however, it cannot replace upper endoscopy for screening of esophageal varices. The main limitation of TE in clinical practice is the impossibility of obtaining reliable liver stiffness measurements in around 20% of cases, mainly comprising obese patients. Conclusion: An increasing number of reliable noninvasive methods are now available that are widely used in clinical practice, mostly in viral hepatitis, resulting in a significant decrease in the need for liver biopsy. © 2015 S. Karger AG, Basel.


Pawlotsky J.-M.,Hopital Henri Mondor | Pawlotsky J.-M.,French Institute of Health and Medical Research
Gastroenterology | Year: 2014

Therapy for hepatitis C is undergoing a revolution. Several new drugs against the hepatitis C virus (HCV) have reached the market and many others, including direct-acting antivirals and host-targeted agents, are in phase II or III clinical development. All-oral, interferon-free combinations of drugs are expected to cure more than 90% of infections. A vast amount of data from clinical trials are presented regularly at international conferences or released to the press before peer-review, creating confusion in the viral hepatitis field. The goal of this review is to clarify the current stage of HCV therapy and drug development. This review describes the different classes of drugs and their mechanisms and properties, as well as treatment strategies in development, including those that are interferon-based and interferon-free. HCV treatment options that will be available in 2014-2015 are presented for each genotype. A number of unanswered questions and challenges remain, such as how to treat special populations, the role of ribavirin in interferon-free regimens, the role of HCV resistance in treatment failures, and how to best re-treat patients who failed on treatment. Strategic choices, cost issues, HCV screening, and improving access to care in resource-constrained areas also are discussed.


Bomont P.,French Institute of Health and Medical Research
Acta neuropathologica communications | Year: 2014

BACKGROUND: The BTB-KELCH protein Gigaxonin plays key roles in sustaining neuron survival and cytoskeleton architecture. Indeed, recessive mutations in the Gigaxonin-encoding gene cause Giant Axonal Neuropathy (GAN), a severe neurodegenerative disorder characterized by a wide disorganization of the Intermediate Filament network. Growing evidences suggest that GAN is a continuum with the peripheral neuropathy Charcot-Marie-Tooth diseases type 2 (CMT2). Sharing similar sensory-motor alterations and aggregation of Neurofilaments, few reports have revealed that GAN and some CMT2 forms can be misdiagnosed on clinical and histopathological examination. The goal of this study is to propose a new differential diagnostic test for GAN/CMT2. Moreover, we aim at identifying the mechanisms causing the loss-of-function of Gigaxonin, which has been proposed to bind CUL3 and substrates as part of an E3 ligase complex.RESULTS: We establish that determining Gigaxonin level constitutes a very valuable diagnostic test in discriminating new GAN cases from clinically related inherited neuropathies. Indeed, in a set of seven new families presenting a neuropathy resembling GAN/CMT2, only five exhibiting a reduced Gigaxonin abundance have been subsequently genetically linked to GAN. Generating the homology modeling of Gigaxonin, we suggest that disease mutations would lead to a range of defects in Gigaxonin stability, impairing its homodimerization, BTB or KELCH domain folding, or CUL3 and substrate binding. We further demonstrate that regardless of the mutations or the severity of the disease, Gigaxonin abundance is severely reduced in all GAN patients due to both mRNA and protein instability mechanisms.CONCLUSIONS: In this study, we developed a new penetrant and specific test to diagnose GAN among a set of individuals exhibiting CMT2 of unknown etiology to suggest that the prevalence of GAN is probably under-evaluated among peripheral neuropathies. We propose to use this new test in concert with the clinical examination and prior to the systematic screening of GAN mutations that has shown strong limitations for large deletions. Combining the generation of the structural modeling of Gigaxonin to an analysis of Gigaxonin transcripts and proteins in patients, we provide the first evidences of the instability of this E3 ligase adaptor in disease.


Bindea G.,French Institute of Health and Medical Research
Seminars in immunopathology | Year: 2011

Until now, the anatomic extent of tumor (TNM classification) has been, by far, the most important factor to predict the prognosis of colorectal cancer patients. However, in recent years, data collected from large cohorts of human cancers demonstrated that the immune contexture of the primary tumors is an essential prognostic factor for patients' disease-free and overall survival. Global analysis of tumor microenvironment showed that the nature, the functional orientation, the density, and the location of adaptive immune cells within distinct tumor regions influence the risk of relapse events. An immune classification of the patients was proposed based on the density and the immune cell location within the tumor. The immune classification has a prognostic value that is superior to the TNM classification, and tumor invasion is statistically dependent on the host immune reaction. Tumor and immunological markers predicted by systems biology methods are involved in the shaping of an efficient immune reaction and can serve as targets for novel therapeutic approaches. Thus, the strength of the immune reaction could advance our understanding of cancer evolution and have important consequences in clinical practice.


Rascol O.,French Institute of Health and Medical Research
European Journal of Neurology | Year: 2011

Intermittent or pulsatile dopamine-receptor stimulation is postulated to induce plastic changes in motor systems that are responsible for the development of motor fluctuations and dyskinesia, complicating long-term levodopa therapy of Parkinson's disease (PD). Continuous dopamine stimulation (CDS) is a concept that refers to the hypothesis that more continuous dopamine-receptor stimulation will reduce the risk of motor complications, particularly dyskinesias, and may also treat established dyskinesias. In line with this hypothesis, the intermittent administration of dopaminergic agents with short half-lives induce motor complications in animal models, whilst the continuous administration of the same compounds via mini-pumps substantially reduces such symptoms. Continuous drug delivery (CDD) strategies are therefore explored in clinical trials to prevent or manage motor complications. The early use of a dopamine agonist reduces the risk of motor fluctuations compared with levodopa. Conversely, the early combination of the catechol-O-methyltransferase inhibitor entacapone with levodopa has failed to demonstrate a comparable advantage. Outcomes of uncontrolled long-term studies of PD patients with motor complications treated for several months with subcutaneous continuous infusion of apomorphine or intraduodenal levodopa are compatible with CDS. New once-daily prolonged-release formulations of dopamine agonists have demonstrated antiparkinsonian efficacy in randomized trials conducted in early as well as advanced patients with PD. Once-daily administration is convenient and may improve compliance. Other theoretical advantages in terms of efficacy or tolerability deserve further exploration. © 2011 The Author(s). European Journal of Neurology © 2011 EFNS.


Chaput N.,French Institute of Health and Medical Research
Seminars in immunopathology | Year: 2011

To communicate, cells are known to release in their environment proteins which bind to receptors on surrounding cells. But cells also secrete more complex structures, called membrane vesicles, composed of a lipid bilayer with inserted transmembrane proteins, enclosing an internal content of hydrophilic components. Exosomes represent a specific subclass of such secreted membrane vesicles, which, despite having been described more than 20 years ago by two groups studying reticulocyte maturation, have only recently received attention from the scientific community. This renewed interest originated first from the description of exosome secretion by antigen-presenting cells, suggesting a potential role in immune responses, and very recently by the identification of the presence of RNA (both messenger and microRNA) in exosomes, suggesting a potential transfer of genetic information between cells. In this review, we will describe the conclusions of 20 years of studies on the immune properties of exosomes and the most recent advances on their roles and potential uses as markers or as therapeutic tools during pathologies, especially in cancer.


Vianey-Saban C.,French Institute of Health and Medical Research
Neuromuscular Disorders | Year: 2010

Disorders of muscle lipid metabolism may involve intramyocellular triglyceride degradation, carnitine uptake, long-chain fatty acids mitochondrial transport, or fatty acid β-oxidation. Three main diseases leading to permanent muscle weakness are associated with severe increased muscle lipid content (lipid storage myopathies): primary carnitine deficiency, neutral lipid storage disease and multiple acyl-CoA dehydrogenase deficiency. A moderate lipidosis may be observed in fatty acid oxidation disorders revealed by rhabdomyolysis episodes such as carnitine palmitoyl transferase II, very-long-chain acyl-CoA dehydrogenase, mitochondrial trifunctional protein deficiencies, and in recently described phosphatidic acid phosphatase deficiency. Respiratory chain disorders and congenital myasthenic syndromes may also be misdiagnosed as fatty acid oxidation disorders due to the presence of secondary muscle lipidosis. The main biochemical tests giving clues for the diagnosis of these various disorders are measurements of blood carnitine and acylcarnitines, urinary organic acid profile, and search for intracytoplasmic lipid on peripheral blood smear (Jordan's anomaly). Genetic analysis orientated by the results of biochemical investigation allows establishing a firm diagnosis. Primary carnitine deficiency and multiple acyl-CoA dehydrogenase deficiency may be treated after supplementation with carnitine, riboflavine and coenzyme Q10. New therapeutic approaches for fatty acid oxidation disorders are currently developed, based on pharmacological treatment with bezafibrate, and specific diets enriched in medium-chain triglycerides or triheptanoin. © 2010 Elsevier B.V.


Papagiakoumou E.,French Institute of Health and Medical Research | Papagiakoumou E.,University of Paris Descartes
Biology of the Cell | Year: 2013

Brain intricacies and the difficulty that scientists encounter in revealing its function with standard approaches such as electrical stimulation of neurons have led to the exploration of new tools that enable the study of neural circuits in a remote and non-invasive way. To this end, optogenetics has initialised a revolution for neuroscience in the last decade by enabling simultaneous monitoring and stimulation of specific neuronal populations in intact brain preparations through genetically targeted expression of light sensitive proteins and molecular photoswitches. In addition to ongoing molecular probe development and optimisation, novel optical techniques hold immense potential to amplify and diversify the utility of optogenetic methods. Importantly, by improving the spatio-temporal resolution of light stimulation, neural circuits can be photoactivated in patterns mimicking endogenous physiological processes. The following synopsis addresses the possibilities and limitations of optical stimulation methods applied to and developed for activation of neuronal optogenetic tools. Advances in molecular engineering and the bloom of optogenetics facilitated the realisation of studies towards the understanding of neural circuits function. To this direction, great effort has been made to also develop illumination tools that provide better specificity than standard wide-field illumination. Here, optical methods that have been used so far in optogenetics are reviewed and the challenges that need to satisfy are discussed.© 2013 Société Française des Microscopies and Société de Biologie Cellulaire de France. Published by John Wiley & Sons Ltd.


Asselah T.,French Institute of Health and Medical Research
Best Practice and Research: Clinical Gastroenterology | Year: 2012

Approximately 170 million people are infected with hepatitis C virus (HCV) worldwide. Sustained virological response (SVR) is equivalent to viral eradication and associated with a reduction in the risk of cirrhosis and hepatocellular carcinoma. The treatment for genotype 1 HCV chronic infection is the addition of a protease inhibitor (telaprevir or boceprevir) to the pegylated-interferon (PEG-IFN) plus ribavirin (RBV) regimen. Treatment of genotype 1 naïve chronic hepatitis C with PEG-IFN and ribavirin (RBV) for 48 weeks results in SVR in approximately 40% of patients. Retreatment of previous relapsers to PEG-IFN/RBV therapy with triple therapy, a protease inhibitor (telaprevir or boceprevir), plus PEG-IFN and RBV results in SVR in more than 70% of cases. However, retreatment of previous non-responders to PEG-IFN/RBV therapy with these triple therapies, results in SVR in less than 30% of cases. The aim of this review is to summarize results obtained with Boceprevir or Telaprevir triple therapy for prior HCV experienced patients (non-responders and relapsers). © 2012 Published by Elsevier Ltd.


Guenneau S.,Aix - Marseille University | Puvirajesinghe T.M.,French Institute of Health and Medical Research
Journal of the Royal Society Interface | Year: 2013

Here, we adapt the concept of transformational thermodynamics, whereby the flux of temperature is controlled via anisotropic heterogeneous diffusivity, for the diffusion and transport of mass concentration. The n-dimensional, time-dependent, anisotropic heterogeneous Fick's equation is considered, which is a parabolic partial differential equation also applicable to heat diffusion, when convection occurs, for example, in fluids. This theory is illustrated with finite-element computations for a liposome particle surrounded by a cylindrical multi-layered cloak in a water-based environment, and for a spherical multi-layered cloak consisting of layers of fluid with an isotropic homogeneous diffusivity, deduced from an effective medium approach. Initial potential applications could be sought in bioengineering. © 2013 The Author(s) Published by the Royal Society. All rights reserved.


Claperon A.,French Institute of Health and Medical Research
Clinics and research in hepatology and gastroenterology | Year: 2011

Scaffold proteins are defined by the presence of specific protein-binding domains (e.g. PDZ domains) that assemble several proteins into functional complexes. Thus, scaffolds are critical for spatio-temporal organization and for proper regulation of intracellular signalling upon specific stimulus. Identified 15years ago, NHERF scaffold proteins contain several PDZ modules and were initially viewed as "passive linkers" between transmembrane proteins and the cortical cytoskeleton underlying the plasma membrane. New NHERF-binding molecules involved in cell signalling have been recently identified. Thus, NHERFs are now viewed as "active" key players in regulating cellular functions. EBP50 and PDZK1, two members of the NHERF family, are highly expressed in the liver where they link receptors, channels, transporters and cytosolic components. This review aims to give an overview of the emerging functions of NHERF proteins in liver physiology. Copyright © 2011 Elsevier Masson SAS. All rights reserved.


Bost F.,French Institute of Health and Medical Research
Current opinion in oncology | Year: 2012

To focus on the potential role of metformin, a widely used antidiabetic drug, in cancer treatment. Epidemiological, preclinical and cellular studies have shown in the last 6 years that metformin exerts antitumoral properties. Here, we review the very last findings concerning metformin action in cancer. The results of the first clinical trials as well as the combined action of metformin and chemotherapeutics agents in vitro and in vivo will be discussed. Recent studies show that metformin could also regulate inflammation and, therefore, may play a role in tumor microenvironment. Finally, we will present the latest publications concerning the molecular mechanisms implicated in metformin action, especially the AMP-activated kinase-independent pathways. The numerous in-vitro and in-vivo studies warrant the ongoing clinical trials, which should definitively help us to determine if metformin could be used in cancer therapy.


Castera L.,French Institute of Health and Medical Research
Liver International | Year: 2014

Liver biopsy, which was traditionally considered to be the gold standard for the staging of fibrosis, has been challenged in the past decade by non-invasive techniques. These techniques rely on two distinct but complementary approaches: a 'biological' approach, based on the quantification of biomarkers of fibrosis in serum, and a 'physical' approach, based on the measurement of liver stiffness using elastography-based technologies. Advantages of serum biomarkers include their high applicability (>95%) and good reproducibility. However, as none are liver specific their results can be influenced by comorbid conditions (risk of false positive results with FibroTest® in patients with Gilbert's syndrome or with APRI in case of acute hepatitis). Transient elastograpy has the advantages of being a user's friendly procedure that can be performed at the bedside or in an outpatient clinic with high performance for detecting cirrhosis. However, its applicability is lower (80%) than that of serum biomarker (particularly in case of ascites, obesity and limited operator experience) with the risk of false positive results in case of ALT flares. Although these non-invasive methods were initially developed and validated in patients with chronic hepatitis C, they are now increasingly used in patients with hepatitis B, reducing the need for liver biopsy. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.


Trepo C.,French Institute of Health and Medical Research
Liver International | Year: 2014

Hepatitis has been a major plague of mankind. The history of the discovery of causative viruses is one of the most fascinating scientific adventures of this half century. Individualization of several types of hepatitis only emerged after world war two. Their identification has been associated with milestones which revolutionized medicine and public health. The discovery of HBV brought the first ever vaccine not prepared by tissue culture but initially directly from plasma and soon the first vaccine produced by genetic engineering. HBV vaccine proved to be the first "anti-cancer" vaccine by preventing hepatocellular carcinoma and practically eradicating it from childhood in Taiwan. Successful vaccines became also available for HAV and more recently HEV. The discovery of HCV in 1989 opened a new era since it was the first virus was identified by a direct molecular approach. Two billion people are infected with HBV and 350 million are chronic carriers of the virus. The extraordinary effectiveness of HBV vaccination was best illustrated in Taiwan and Singapore where in less than 2 decades HBs Ag carriers dropped from 9,1% to 2,7% and HCC from 27% to 17%. Successful development of nucleos(t)ides analogs make it now possible to fully control disease progression with a daily pill long term therapy. The progress in HCV therapy has been even more spectacular and successful treatment jumped from 6 % with interferon alone in 1986 to more than 80% in 2013 with triple combination therapies. Remarkably chronic hepatitis C is the only chronic disease which is curable. It will be soon possible to eradicate HCV infection with, an all oral, daily single pill (containing several molecules) for 3 to 6 months which will cure over 90% of patients. This unprecedented therapeutic victory benefiting hundred millions of people matches the triumphs over small pox, polio and tuberculosis. The next 10 years should undoubtedly witness cure or full control over all forms of acute and chronic hepatitis. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.


Neri C.,French Institute of Health and Medical Research
Frontiers in Pharmacology | Year: 2012

Studies in simple model organisms have yielded crucial insights into the genetic and molecular aspects of longevity. FOXO, which is most notable for its association with longevity, and its upstream regulators such as sirtuins have received particular attention in translational research because these genes modulate cell survival in several models of neurodegenerative diseases. There is a large amount of knowledge on the pathways that regulate FOXO activity and genes that may be regulated by FOXO. However, for the same reason that the FOXO network is a complex stress response system, its therapeutic potential to develop disease-modifying strategies requires further examination. Although the FOXO network contains druggable genes such as sirtuins and AMPK, whether they should be activated or inhibited and whether protection against the early or late phases of neuronal cell decline might require opposite therapeutic strategies remains unclear. Additionally, the mode of action of small compound molecules believed to act on FOXO network targets was questioned.This review recapitulates essential facts and questions about the promises of FOXO and its interactors in neurodegenerative disease. © 2012 Neri.


Defoort C.,French Institute of Health and Medical Research
Public health nutrition | Year: 2011

To determine the postprandial lipaemia response before and after intervention with healthy diets in the Medi-RIVAGE cohort of subjects with moderate risk factors of CVD. One hundred and thirty-five adults (fifty-two men and eighty-three women) followed either a Mediterranean-type (MED) diet or a low-fat American Heart Association-type diet in a parallel design for 3 months. At entry and after 3 months, lipids, glucose and insulin were measured in the fasting samples; TAG and apolipoprotein B48 (ApoB48; a marker of intestinally derived chylomicrons) levels were measured in the fasting and postprandial samples after a standard test meal. The MED diet only lowered (P < 0·028) fasting TAG and both diets reduced TAG and ApoB48 levels 5 h after the test meal. The overall 5 h postprandial ApoB48 response (area under curve (AUC)/incremental AUC) was lowered after both diets but this effect was more marked after the MED-diet intervention. Whatever the TAG level at entry, normo- and hyper TAG subjects showed a reduction in the postprandial ApoB48 levels after 3-month diets. BMI at entry did not impact the effect of diets given subjects with BMI < or >25 kg/m2 showed reduced postprandial ApoB48. Men and women displayed comparable postprandial changes after dietary challenges. A MED diet appears efficient to improve postprandial lipaemia, a recently acknowledged CVD risk, in men and women at moderate cardiovascular risk.


Deneux-Tharaux C.,French Institute of Health and Medical Research
Journal de Gynecologie Obstetrique et Biologie de la Reproduction | Year: 2012

Objective: To describe the prevalence of uterine scar and the risk of associated obstetrical complications and current modes of delivery in women with a previous cesarean. Method: Consultation of the Medline database, and of the National Perinatal Surveys data. Results: Previous cesarean is the main cause of uterine scar. In France, the cesarean rate increased from 15.5% in 1995 to 20.8% in 2010; as a consequence, the prevalence of previous cesarean also increased from 8 to 11% of parturients and from 14 to 19% of multiparas, between 1995 and 2010. Previous cesarean is, in developed countries, the main risk factor for uterine rupture, whose global incidence is estimated between 0.1 and 0.5% in parturients with previous cesarean. Women with previous cesarean also are at higher risk for abnormal placenta insertion, the strength of the association increasing with the number of previous cesareans: twice higher risk of placenta praevia and greater maternal morbidity associated with placenta praevia; major risk factor for placenta accreta in particular in women combining previous cesarean and placenta praevia. Modes of delivery in women with previous cesarean vary widely between countries. According to the 2010 National Perinatal Survey, in France, 51% have a cesarean before labor; among those with a trial of labor, 75% deliver vaginally; in total, 36.5% have a vaginal delivery. Conclusion: The prevalence of uterine scar is increasing, following the rise in cesarean rate. This condition is a risk factor for obstetrical complications in subsequent pregnancies. Women with multiple previous cesareans are particularly at risk. © 2012 Elsevier Masson SAS. All rights reserved.


Pawlotsky J.-M.,University Paris Est Creteil | Pawlotsky J.-M.,French Institute of Health and Medical Research
F1000 Biology Reports | Year: 2012

Approximately 120-130 million individuals are chronically infected with hepatitis C virus (HCV) worldwide, although it is curable by therapy.Until recently, treatment of chronic hepatitisCwas based on the combination of pegylated interferon-α and ribavirin. A number of models have been developed to study the HCV lifecycle and screen for potential HCV inhibitors. They led to the development of antiviral agents that specifically target a viral function (direct acting antivirals), and host-targeted agents that inhibit HCV replication. Direct acting antivirals in clinical development includeNS3-4A protease inhibitors (two of which, telaprevir and boceprevir, have recently been approved for treatment of HCV genotype 1 infection in combination with pegylated interferon-α and ribavirin), nucleoside/nucleotide analogue and non-nucleoside inhibitors of HCV RNA-dependent RNA polymerase, and NS5A inhibitors. Host-targeted agents include cyclophilin inhibitors. This article describes the direct acting antivirals and host-targeted agents that have recently been approved or have been tested in HCV-infected patients and discusses their two current paths of clinical development: with or without interferon-α. © 2012 Faculty of 1000 Ltd.


Blachier M.,University Paris Est Creteil | Leleu H.,University Paris Est Creteil | Peck-Radosavljevic M.,Medical University of Vienna | Valla D.-C.,French Institute of Health and Medical Research | Roudot-Thoraval F.,University Paris Est Creteil
Journal of Hepatology | Year: 2013

To survey the burden of liver disease in Europe and its causes 260 epidemiological studies published in the last five years were reviewed. The incidence and prevalence of cirrhosis and primary liver cancer are key to understand the burden of liver disease. They represent the end-stage of liver pathology and thus are indicative of the associated mortality. About 0.1% of Hungarian males will die of cirrhosis every year compared with 0.001% of Greek females. WHO estimate that liver cancer is responsible for around 47,000 deaths per year in the EU. Harmful alcohol consumption, viral hepatitis B and C and metabolic syndromes related to overweight and obesity are the leading causes of cirrhosis and primary liver cancer in Europe. Chronic hepatitis B affects 0.5-0.7% of the European population. In the last decade the prevalence of chronic hepatitis C was 0.13-3.26%. It is of great concern that about 90% of people in Europe infected by viral hepatitis are unaware of their status. Available data suggest the prevalence rate of NAFLD is 2-44% in the general European population (including obese children) and 42.6-69.5% in people with type 2 diabetes. Each of these four major causes of liver disease is amenable to prevention and treatment, reducing the burden of liver disease in Europe and saving lives. Further surveys are urgently needed to implement cost-effective prevention programmes and novel treatments to tackle this problem.


Moro C.,French Institute of Health and Medical Research | Lafontan M.,University Paul Sabatier
American Journal of Physiology - Heart and Circulatory Physiology | Year: 2013

Since the discovery of natriuretic peptides (NPs) by de Bold et al. in 1981, the cardiovascular community has been well aware that they exert potent effects on vessels, heart remodeling, kidney function, and the regulation of sodium and water balance. Who would have thought that NPs are also able to exert metabolic effects and contribute to an original cross talk between heart, adipose tissues, and skeletal muscle? The attention on the metabolic role of NPs was awakened in the year 2000 with the discovery that NPs exert potent lipolytic effects mediated by the NP receptor type A/cGMP pathway in human fat cells and that they contribute to lipid mobilization in vivo. In this review, we will discuss the biological effects of NPs on the main tissues involved in the regulation of energy metabolism (i.e., white and brown adipose tissues, skeletal muscle, liver, and pancreas). These recent results on NPs are opening a new chapter into the physiological properties and therapeutic usefulness of this family of hormones. © 2013 the American Physiological Society.


Lopez-Otin C.,University of Oviedo | Blasco M.A.,Telomeres and Telomerase Group | Partridge L.,Max Planck Institute for Biology of Ageing | Partridge L.,University College London | And 4 more authors.
Cell | Year: 2013

Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. This deterioration is the primary risk factor for major human pathologies, including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases. Aging research has experienced an unprecedented advance over recent years, particularly with the discovery that the rate of aging is controlled, at least to some extent, by genetic pathways and biochemical processes conserved in evolution. This Review enumerates nine tentative hallmarks that represent common denominators of aging in different organisms, with special emphasis on mammalian aging. These hallmarks are: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. A major challenge is to dissect the interconnectedness between the candidate hallmarks and their relative contributions to aging, with the final goal of identifying pharmaceutical targets to improve human health during aging, with minimal side effects. © 2013 Elsevier Inc.


Heisenberg C.-P.,Institute of Science and Technology Austria | Bellaiche Y.,French Institute of Health and Medical Research
Cell | Year: 2013

During development, mechanical forces cause changes in size, shape, number, position, and gene expression of cells. They are therefore integral to any morphogenetic processes. Force generation by actin-myosin networks and force transmission through adhesive complexes are two self-organizing phenomena driving tissue morphogenesis. Coordination and integration of forces by long-range force transmission and mechanosensing of cells within tissues produce large-scale tissue shape changes. Extrinsic mechanical forces also control tissue patterning by modulating cell fate specification and differentiation. Thus, the interplay between tissue mechanics and biochemical signaling orchestrates tissue morphogenesis and patterning in development. © 2013 Elsevier Inc.


Vainchenker W.,French Institute of Health and Medical Research | Vainchenker W.,Institute Gustave Roussy | Vainchenker W.,University Paris - Sud | Constantinescu S.N.,Ludwig Institute for Cancer Research
Oncogene | Year: 2013

The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is central to signaling by cytokine receptors, a superfamily of more than 30 transmembrane proteins that recognize specific cytokines, and is critical in blood formation and immune response. Many of those receptors transmit anti-apoptotic, proliferative and differentiation signals, and their expression and functions are critical for the formation of blood lineages. Several cancers, including blood malignancies, have been associated with constitutive activation of members of the STAT family, which normally require JAK-mediated tyrosine phosphorylation for transcriptional activation. More recently, human myeloproliferative neoplasms were discovered to be associated with a unique acquired somatic mutation in JAK2 (JAK2 V617F), rare exon 12 JAK2 mutations, or thrombopoietin receptor mutations that constitutively activate wild-type JAK2. Prompted by these observations, many studies have explored the possibility that JAKs, cytokine receptors, or other components of the JAK/STAT pathway are mutated or upregulated in several hematological malignancies. This has been observed in certain pediatric acute lymphoblastic leukemias and adult T-cell lymphoblastic leukemias, and overexpression of JAK2 seems to be important in Hodgkin lymphoma. Here we discuss the nature and respective contribution of mutations dysregulating the JAK/STAT pathway in hematological malignancies and present examples in which such mutations drive the disease, contribute to the phenotype, or provide a survival and proliferative advantage. JAK inhibitors are making their way into the therapeutic arsenal (for example, in myelofibrosis), and we discuss the possibility that other hematological diseases might benefit from treatment with these inhibitors in combination with other agents. © 2013 Macmillan Publishers Limited. All rights reserved 0950-9232/13.


Galy A.,French Institute of Health and Medical Research | Thrasher A.J.,University College London
Current Opinion in Allergy and Clinical Immunology | Year: 2011

Background: Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency (PID) characterized by micro-thrombocytopenia, recurrent infections, eczema, which is associated with a high incidence of auto-immunity and lymphoreticular malignancy. One of the first diseases to be successfully treated by allogeneic hematopoietic stem cell transplantation, WAS is currently the subject of several phase I/II gene therapy trials for patients without HLA-compatible donors. Purpose of Review: This article reviews the preclinical and clinical data leading to the development of gene therapy of WAS with lentiviral vectors. Recent Findings: A recent clinical trial using a conventional gammaretroviral vector has demonstrated the proof of principle of gene therapy in WAS, but has also highlighted a common limitation of the technology. Encouraging preclinical efficacy and safety results using refined lentiviral vectors, and the development of robust clinical-grade manufacturing processes have supported the initiation of several phase I/II new studies. Summary: WAS is amenable to hematopoietic stem cell gene therapy. New trials using lentiviral vectors are expected to improve efficacy and safety profiles. Beyond proof of principle, ongoing international efforts to coordinate trials of gene therapy for the WAS may also provide a model for the expedited development of new treatments for other rare diseases. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Clezardin P.,French Institute of Health and Medical Research
Anti-Cancer Agents in Medicinal Chemistry | Year: 2012

Bone is a common site of metastasis from advanced cancers, and metastasis to bone accounts for the majority of distant recurrences from breast and prostate cancers. Bone metastases are characterized by increased rates of bone turnover. Bisphosphonates are extensively used in the treatment of metastatic bone disease to reduce the rates of osteolysis and the risk of skeletal-related events. In addition, bisphosphonates have demonstrated direct and indirect anticancer potential in preclinical studies. These activities include induction of apoptosis, inhibition of invasion, synergistic cytotoxicity with chemotherapy agents, antiangiogenic properties, and modulation of immunologic activity against transformed cells. Notably, these activities of bisphosphonates are not limited to the bone microenvironment; indeed some effects are mediated on the cancer cells themselves. These preclinical data provide the rationale for the underlying potential clinical benefits from bisphosphonates (e.g., prevention of metastasis to bone and other sites in the early breast cancer setting and delayed disease progression in malignancies involving colonization of bone [e.g., multiple myeloma]). This review article summarizes the preclinical anticancer activities of bisphosphonates in various cancer types and evaluates their potential contributions to the recently demonstrated clinical effects. © 2012 Bentham Science Publishers.


Savagner P.,French Institute of Health and Medical Research
Annals of Oncology | Year: 2010

The epithelial-mesenchymal transition (EMT) describes a rapid and often reversible modulation of phenotype by epithelial cells. EMT was originally defined in the context of developmental stages, including heart morphogenesis, mesoderm and neural crest formation. Epithelial cells loosen cell-cell adhesion structures throughout EMT. They modulate their polarity, cytoskeleton organization and typically express vimentin filaments and downregulate cytokeratins. They become isolated, mobile and resistant to anoikis. The EMT at least superficially resembles the evolution from normal to transformed cell phenotype during carcinoma progression. The relevance of the concept of EMT in this context was indicated by in vitro models using transformed epithelial cells. Transduction pathways typical of embryogenic EMT in vivo were also found to be activated during cancer progression. More recently, it has been found that such pathways indicate an increased plasticity linked to cellular stemness and ability to generate tumors. However, in the absence of direct evidence, a number of oncologists and pathologists remain skeptical about applying the EMT concept to human tumor progression. Typically in the cancer field, EMT concept appears to be fully relevant in some situations, but the concept has to be adjusted in other situations to reflect tumor cell renewal and plasticity during carcinoma progression and metastasis. © The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Gubler M.-C.,French Institute of Health and Medical Research
Pediatric Nephrology | Year: 2014

Renal tubular dysgenesis (RTD) is a severe foetal disorder characterised by the absence or poor development of proximal tubules, early onset and persistent anuria (leading to oligohydramnios and the Potter sequence) and ossification defects of the skull. In most cases, early death occurs from pulmonary hypoplasia, anuria and refractory arterial hypotension. RTD may be acquired during foetal development or inherited as an autosomal recessive disease. Inherited RTD is genetically heterogeneous and linked to mutations in the genes encoding the major components of the renin-angiotensin system (RAS): angiotensinogen, renin, angiotensin-converting enzyme or angiotensin II receptor type 1. Mutations result in either the absence of production or lack of efficacy of angiotensin II. Secondary RTD has been observed in various situations, particularly in the donor twin of severe twin-to-twin transfusion syndrome, in foetuses affected with congenital haemochromatosis or in foetuses exposed to RAS blockers. All cases result in renal hypoperfusion. These examples illustrate the importance of a functional RAS in the maintenance of blood pressure and renal blood flow for humans during foetal life. The diagnosis of RTD in an anuric foetus with normal renal sonography results is important for the management of the foetus or neonate. Depending on the genetic or secondary cause of the disease, such findings can lead to genetic counselling or the prevention of recurrence in subsequent pregnancies. © 2013 IPNA.


Krisko A.,Mediterranean Institute for Life Sciences | Radman M.,Mediterranean Institute for Life Sciences | Radman M.,French Institute of Health and Medical Research
Cold Spring Harbor Perspectives in Biology | Year: 2013

The bacterium Deinococcus radiodurans is a champion of extreme radiation resistance that is accounted for by a highly efficient protection against proteome, but not genome, damage. A well-protected functional proteome ensures cell recovery from extensive radiation damage to other cellular constituents by molecular repair and turnover processes, including an efficient repair of disintegrated DNA. Therefore, cell death correlates with radiationinduced protein damage, rather than DNA damage, in both robust and standard species. From the reviewed biology of resistance to radiation and other sources of oxidative damage, we conclude that the impact of protein damage on the maintenance of life has been largely underestimated in biology and medicine. © 2013 Cold Spring Harbor Laboratory Press; all rights reserved.


de Donatis G.M.,French Institute of Health and Medical Research
Oncogene | Year: 2015

Enhancer of Zeste homologue 2 (EZH2) belongs to the polycomb repressive complex 2 and catalyzes the methylation of histone H3 lysine 27. These pivotal epigenetic marks are altered in many cancers, including melanoma, as a result of EZH2 overexpression. Here, we show that the non-canonical-NF-kB pathway accounts for most of the NF-kB activity in melanoma cells, in contrast to non-cancer cells. We identify the non-canonical-NF-kB pathway as a key regulator of EZH2 expression in melanoma. We show a striking correlation between NF-kB2 and EZH2 expression in human melanoma metastases. We demonstrate that inhibition of the non-canonical NF-kB pathway by targeting NF-kB2/p52 or the upstream kinase NIK restores the senescence program in melanoma cells through the decrease of EZH2. On the contrary, the overexpression of NF-kB2/p52 in normal human melanocytes prevents stress- and oncogene-induced senescence. Finally, we show in mouse models that the inhibition of the non-canonical NF-kB pathway restores senescence and induces a dramatic reduction in tumor growth compared with controls, thus providing potential drug targets for the re-induction of senescence in melanoma and other cancers where EZH2 is overexpressed.Oncogene advance online publication, 14 September 2015; doi:10.1038/onc.2015.331. © 2015 Macmillan Publishers Limited


Golmard L.,French Institute of Health and Medical Research
Oncogene | Year: 2015

BRCA1 and BRCA2 are the two major genes predisposing to breast and ovarian cancer. Whereas high de novo mutation rates have been demonstrated for several genes, only 11 cases of de novo BRCA1/2 mutations have been reported to date and the BRCA1/2 de novo mutation rate remains unknown. The present study was designed to fill this gap based on a series of 12 805 consecutive unrelated patients diagnosed with breast and/or ovarian cancer who met the inclusion criteria for BRCA1/2 gene analysis according to French guidelines. BRCA1/2 mutations were detected in 1527 (12%) patients, and three BRCA1 mutations and one BRCA2 mutation were de novo. The BRCA1/2 de novo mutation rate was estimated to be 0.3% (0.1%; 0.7%). Although rare, it may be useful to take the possibility of de novo BRCA1/2 mutation into account in genetic counseling of relatives and to improve the understanding of complex family histories of breast and ovarian cancers.Oncogene advance online publication, 1 June 2015; doi:10.1038/onc.2015.181. © 2015 Macmillan Publishers Limited


Monticelli L.,French Institute of Health and Medical Research
Methods in molecular biology (Clifton, N.J.) | Year: 2013

In this chapter we review the basic features and the principles underlying molecular mechanics force fields commonly used in molecular modeling of biological macromolecules. We start by summarizing the historical background and then describe classical pairwise additive potential energy functions. We introduce the problem of the calculation of nonbonded interactions, of particular importance for charged macromolecules. Different parameterization philosophies are then presented, followed by a section on force field validation. We conclude with a brief overview on future perspectives for the development of classical force fields.


Durandy A.,French Institute of Health and Medical Research | Kracker S.,University of Paris Descartes
Arthritis Research and Therapy | Year: 2012

Immunoglobulin class-switch recombination deficiencies (Ig-CSR-Ds) are rare primary immunodeficiencies characterized by defective switched isotype (IgG/IgA/IgE) production. Depending on the molecular defect in question, the Ig-CSR-D may be combined with an impairment in somatic hypermutation (SHM). Some of the mechanisms underlying Ig-CSR and SHM have been described by studying natural mutants in humans. This approach has revealed that T cell-B cell interaction (resulting in CD40-mediated signaling), intrinsic B-cell mechanisms (activation-induced cytidine deaminase-induced DNA damage), and complex DNA repair machineries (including uracil-N-glycosylase and mismatch repair pathways) are all involved in class-switch recombination and SHM. However, several of the mechanisms required for full antibody maturation have yet to be defined. Elucidation of the molecular defects underlying the diverse set of Ig-CSR-Ds is essential for understanding Ig diversification and has prompted better definition of the clinical spectrum of diseases and the development of increasingly accurate diagnostic and therapeutic approaches. © 2012 BioMed Central Ltd.


Maurice P.,French Institute of Health and Medical Research
Sub-cellular biochemistry | Year: 2012

Recent proteomic and biochemical evidence indicates that cellular -signaling is organized in protein modules. G protein-coupled receptors (GPCRs) are privileged entry points for extracellular signals that are transmitted through the plasma membrane into the cell. The adequate cellular response and signaling specificity is regulated by GPCR-associated protein modules. The composition of these modules is dynamic and might depend on receptor stimulation, the proteome of a given cellular context, the subcellular localization of receptor-associated modules, the formation of GPCR oligomers and the variation of expression levels of components of these modules under physiological, for example circadian rhythm, or pathological conditions. The current article will highlight the importance of GPCR-associated protein modules as a biochemical basis for signaling specificity.


Vandenesch F.,French Institute of Health and Medical Research
Frontiers in cellular and infection microbiology | Year: 2012

One key aspect of the virulence of Staphylococcus aureus lies in its ability to target the host cell membrane with a large number of membrane-damaging toxins and peptides. In this review, we describe the hemolysins, the bi-component leukocidins (which include the Panton Valentine leukocidin, LukAB/GH, and LukED), and the cytolytic peptides (phenol soluble modulins). While at first glance, all of these factors might appear redundant, it is now clear that some of these factors play specific roles in certain S. aureus life stages and diseases or target specific cell types or species. In this review, we present an update of the literature on toxin receptors and their cell type and species specificities. Furthermore, we review epidemiological studies and animal models illustrating the role of these membrane-damaging factors in various diseases. Finally, we emphasize the interplay of these factors with the host immune system and highlight all their non-lytic functions.


Spicuglia S.,French Institute of Health and Medical Research
Nucleus (Austin, Tex.) | Year: 2012

Gene-distal cis-regulatory sequences, such as enhancers, are key contributors of tissue-specific gene expression. In particular, enhancers can be located up to hundreds of kilobases from the promoters that they control, making their identification challenging. Thanks to the recent technological advances to map histone modifications and chromatin-associated factors genome-wide, several studies have begun to characterize chromatin signatures of active enhancers. Here, we discuss some of these results and how they provide new insights into the tissue-specific organization of enhancer repertoires.


Marie P.J.,French Institute of Health and Medical Research | Marie P.J.,University Paris Diderot
Journal of Bone and Mineral Research | Year: 2014

Age-related bone loss is in large part the consequence of senescence mechanisms that impact bone cell number and function. In recent years, progress has been made in the understanding of the molecular mechanisms underlying bone cell senescence that contributes to the alteration of skeletal integrity during aging. These mechanisms can be classified as intrinsic senescence processes, alterations in endogenous anabolic factors, and changes in local support. Intrinsic senescence mechanisms cause cellular dysfunctions that are not tissue specific and include telomere shortening, accumulation of oxidative damage, impaired DNA repair, and altered epigenetic mechanisms regulating gene transcription. Aging mechanisms that are more relevant to the bone microenvironment include alterations in the expression and signaling of local growth factors and altered intercellular communications. This review provides an integrated overview of the current concepts and interacting mechanisms underlying bone cell senescence during aging and how they could be targeted to reduce the negative impact of senescence in the aging skeleton. © 2014 American Society for Bone and Mineral Research. © 2014 American Society for Bone and Mineral Research.


Thornton S.N.,University of Lorraine | Thornton S.N.,French Institute of Health and Medical Research
Physiology and Behavior | Year: 2010

The constant supply of oxygen and nutriments to cells (especially neurons) is the role of the cardiovascular system. The constant supply of water (and sodium) for cardiovascular function is the role of thirst and sodium appetite and kidney function. This physiological regulation ensures that plasma volume and osmolality are maintained within set limits by initiating behaviour and release of hormones necessary to ingest and conserve water and sodium within the body. This regulation is separated into 2 parts; intracellular and extracellular (blood). An increased osmolality draws water from cells into the blood thus dehydrating specific brain osmoreceptors that stimulate drinking and release of anti diuretic hormone (ADH or vasopressin). ADH reduces water loss via lowered urine volume. Extracellular dehydration (hypovolaemia) stimulates specific vascular receptors that signal brain centres to initiate drinking and ADH release. Baro/volume receptors in the kidney participate in stimulating the release of the enzyme renin that starts a cascade of events to produce angiotensin II (AngII), which initiates also drinking and ADH release. This stimulates also aldosterone release which reduces kidney loss of urine sodium. Both AngII and ADH are vasoactive hormones that could work to reduce blood vessel diameter around the remaining blood. All these events work in concert so that the cardiovascular system can maintain a constant perfusion pressure, especially to the brain. Even if drinking does not take place ADH, AngII and aldosterone are still released. Furthermore, it has been observed that treatment of hypertension, obesity, diabetes and cancer can involve renin-AngII antagonists which could suggest that, in humans at least, there may be dysfunction of the thirst regulatory mechanism. © 2010 Elsevier Inc.


Bonnelye E.,French Institute of Health and Medical Research | Aubin J.E.,University of Toronto
Journal of Bone and Mineral Research | Year: 2013

Estrogen receptor-related receptor alpha (ERRα) is an orphan nuclear receptor with sequence homology to the estrogen receptors, ERα/β, but it does not bind estrogen. ERRα not only plays a functional role in osteoblasts but also in osteoclasts and chondrocytes. In addition, the ERRs, including ERRα, can be activated by coactivators such as peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC1α and β) and are implicated in adipogenesis, fatty acid oxidation, and oxidative stress defense, suggesting that ERRα - through its activity in bone resorption and adipogenesis - may regulate the insulin and leptin pathways and contribute to aging-related changes in bone and cartilage. In this review, we discuss data on ERRα and its cellular and molecular modes of action, which have broad implications for considering the potential role of this orphan receptor in cartilage and bone endocrine function, on whole-organism physiology, and in the bone aging process. © 2013 American Society for Bone and Mineral Research.


Tenaillon O.,French Institute of Health and Medical Research | Tenaillon O.,University Paris Diderot
Annual Review of Ecology, Evolution, and Systematics | Year: 2014

The accumulation of data on the genomic bases of adaptation has triggered renewed interest in theoretical models of adaptation. Among these models, Fisher's geometric model (FGM) has received a lot of attention over the past two decades. FGM is based on a continuous multidimensional phenotypic landscape, but it is mostly used for the emerging properties of individual mutation effects. Despite its apparent simplicity and limited number of parameters, FGM integrates a full model of mutation and epistatic interactions that allows the study of both beneficial and deleterious mutations and, subsequently, the fate of evolving populations. In this review, I present the different properties of FGM and the qualitative and quantitative support they have received from experimental evolution data. I then discuss how to estimate the different parameters of the model and outline some future directions to connect FGM and the molecular determinants of adaptation. © 2014 by Annual Reviews. All rights reserved.


Fisch C.,French Institute of Health and Medical Research | Dupuis-Williams P.,ESPCI ParisTech
Biology of the Cell | Year: 2011

Eukaryotic cilia and flagella performmotility and sensory functions which are essential for cell survival in protozoans, and to organism development and homoeostasis in metazoans. Their ultrastructure has been studied from the early beginnings of electron microscopy, and these studies continue to contribute to much of our understanding about ciliary biology. In the light of the progress made in the visualization of cellular structures over the last decade, we revisit the ultrastructure of cilia and flagella. We briefly describe the typical features of a 9+2 axoneme before focusing extensively on the transition zone, the ciliary necklace, the singlet zone, the ciliary cap and the ciliary crown. We discuss how the singlet zone is linked to sensory and/or motile function, the contribution of the ciliary crown to ovocyte and mucosal propulsion, and the relationship between the ciliary cap and microtubule growth and shortening, and its relation to ciliary beat. We further examine the involvement of the transition zone/the ciliary necklace in axonemal stabilization, autotomy and as a diffusion barrier. © The Authors Journal compilation. © 2011 Portland Press Limited.


Leviel V.,French Institute of Health and Medical Research | Leviel V.,University of Lyon
Journal of Neurochemistry | Year: 2011

Spontaneous and/or stimulated neural activity of the nigrostriatal dopamine (DA) pathway makes amines run out from the neurons. This DA dynamic follows a rather complex path, running in or out the terminals, and flushing or diffusing into the extracellular space. The location of this leakage is not limited to the axon terminals; it also occurs from the cell bodies and dendrites. This molecular release mechanism was, for a long time, considered as being produced, in part, by the exocytosis of previously stored vesicles. The DA carrier protein (DAT, DA transporter) embedded in the DA cell membrane is known to clear previously released amines through an inward DA influx. The DAT also appears to be an active vector of amine release. Particular local conditions and the presence of numerous psychostimulant substances are able to trigger an outward efflux of DA through the DAT. This process, delivering slowly large amounts of amine could play a major regulatory role in extracellular DA homeostasis. © 2011 International Society for Neurochemistry.


Pawlotsky J.-M.,University Paris Est Creteil | Pawlotsky J.-M.,French Institute of Health and Medical Research
Journal of Hepatology | Year: 2013

Summary Hepatitis C virus infection is a major health problem worldwide and no vaccine has yet been developed against this virus. In addition, currently approved pharmacotherapies achieve suboptimal cure rates and have side effects that result in non-compliance and premature treatment discontinuation. Significant research has been devoted to developing direct-acting antiviral agents that inhibit key viral functions. In particular, several novel drug candidates that inhibit the viral non-structural protein 5A (NS5A) have been demonstrated to possess high potency, pan-genotypic activity, and a high barrier to resistance. Clinical trials using combination therapies containing NS5A inhibitors have reported results that promise high cure rates and raise the possibility of developing interferon-free, all-oral regimens. © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.


Gourdy P.,Toulouse University Hospital Center | Gourdy P.,French Institute of Health and Medical Research
Best Practice and Research: Clinical Endocrinology and Metabolism | Year: 2013

The prevalence of diabetes mellitus is increasing dramatically worldwide, resulting in more and more women of reproductive age being affected by either type 1 or type 2 diabetes. Management of contraception is a major issue due to the specific risks associated with pregnancy and those potentially induced by hormonal contraceptives in diabetic women. This review emphasizes the urgent need to improve the use of contraception in women with diabetes. There is no consistent evidence that combined oral contraceptives significantly influence the risk of developing diabetes, even in women with a history of gestational diabetes. Furthermore, although data from specific studies remain sparse, no worsening effect has been reported in diabetic women, either in glycemic control or on the course of microvascular complications. Thus, the use of estroprogestive pills is now recognized as a safe and effective option for preconception care of women with uncomplicated diabetes. According to recent guidelines, these contraceptives must be avoided in case of associated cardiovascular risk factors, cardiovascular disease or severe microvascular complications such as nephropathy with proteinuria or active proliferative retinopathy. Prescription of combined hormonal contraception in type 2 diabetic women must also be considered with caution due to a frequent association with obesity and vascular risk factors which increase both thromboembolic and arterial risks. Thanks to their metabolic and vascular safety profile, progestin-only contraceptives, as well as non-hormonal methods, represent alternatives according to patient wishes. © 2012 Elsevier Ltd. All rights reserved.


Pawlotsky J.-M.,French Institute of Health and Medical Research
Nature Reviews Gastroenterology and Hepatology | Year: 2015

Treatment failure associated with HCV resistance to newly developed direct-acting antiviral agents is not an uncommon occurrence and poses a substantial problem to clinicians trying to re-treat patients who have failed available interferon-free treatments. A new study suggests that host-targeted agents are the way forward, but is this approach really feasible? © 2015 Macmillan Publishers Limited. All rights reserved.


Fainzang S.,French Institute of Health and Medical Research
Culture, Medicine and Psychiatry | Year: 2013

The concept of medicalization has given rise to considerable discussion in the social sciences, focusing especially on the extension of medicine's jurisdiction and its hold over our bodies through the reduction of social phenomena to individual biological pathologies. However, the process leading to medical treatment may start when individuals engage in self-medication and thus practice "self-medicalization." But, can we apply to this concept the same type of analysis as the first and see merely the individual's replication of the social control mechanisms to which he/she usually falls victim? This article aims to demonstrate that the medicalization individuals practice on themselves takes on a completely different meaning to that practiced by the medical profession. Empirical data collected in France show that self-medicalization, which may involve treating a problem medically when doctors believe it to be of a non-medical nature, can be an attempt by individuals to furnish a social explanation for their somatic problems and experiences. In this article, I examine the social and political significance of this phenomenon. © 2013 Springer Science+Business Media New York.


Werts C.,French Institute of Health and Medical Research
Chang Gung Medical Journal | Year: 2010

Leptospirosis is a widespread zoonosis caused by Leptospira interrogans, a pathogen transmitted by asymptomatic infected rodents. Leptospiral lipoproteins and lipopolysaccharide (LPS) have been shown to stimulate murine cells via Toll-like receptors (TLRs) 2 and 4. Host defense mechanisms remain obscure, although TLR4 has been associated with clearing Leptospira. In a recent study, we showed that in response to Leptospira infection, double (TLR2 and TLR4) knock-out (DKO) mice unexpectedly developed TLRindependent pro-inflammatory responses, and rapidly died from severe hepatic and renal failure. Subsequent analysis of chimeric and transgenic mice identified B-cells as the crucial lymphocyte subset responsible for the clearance of Leptospira, initially through the production of specific TLR4-dependent immunoglobulin M (IgM), directed against the LPS of Leptospira, and subsequently through specific IgG production, which is impaired in DKO mice. We also identified the protective, tissue-compartmentalized, TLR2/TLR4-mediated production of interferon-γ (IFN-γ) by B- and T-lymphocytes. Overall, our recent findings demonstrate that TLR2 and TLR4 both play a key role in the early control of leptospirosis, and constitute the first line of defense against Leptospira, confirming previous in vitro data showing that both LPS and lipoprotein play a crucial role in cell activation. However, if this first line of defense is by-passed, Leptospira can induce a deleterious inflammation in the target organs, and this does not rely on TLR activation.


Pantazis P.,ETH Zurich | Supatto W.,French Institute of Health and Medical Research
Nature Reviews Molecular Cell Biology | Year: 2014

With the advent of imaging probes and live microscopy, developmental biologists have markedly extended our understanding of the molecular and cellular details of embryonic development. To fully comprehend the complex mechanistic framework that forms the developing organism, quantitative studies with high fidelity in space and time are now required. We discuss how integrating established, newly introduced and future imaging tools with quantitative analysis will ensure that imaging can fulfil its promise to elucidate how new life begins. © 2014 Macmillan Publishers Limited.


Vanier M.T.,French Institute of Health and Medical Research
Orphanet Journal of Rare Diseases | Year: 2010

Niemann-Pick C disease (NP-C) is a neurovisceral atypical lysosomal lipid storage disorder with an estimated minimal incidence of 1/120 000 live births. The broad clinical spectrum ranges from a neonatal rapidly fatal disorder to an adult-onset chronic neurodegenerative disease. The neurological involvement defines the disease severity in most patients but is typically preceded by systemic signs (cholestatic jaundice in the neonatal period or isolated spleno- or hepatosplenomegaly in infancy or childhood). The first neurological symptoms vary with age of onset: delay in developmental motor milestones (early infantile period), gait problems, falls, clumsiness, cataplexy, school problems (late infantile and juvenile period), and ataxia not unfrequently following initial psychiatric disturbances (adult form). The most characteristic sign is vertical supranuclear gaze palsy. The neurological disorder consists mainly of cerebellar ataxia, dysarthria, dysphagia, and progressive dementia. Cataplexy, seizures and dystonia are other common features. NP-C is transmitted in an autosomal recessive manner and is caused by mutations of either the NPC1 (95% of families) or the NPC2 genes. The exact functions of the NPC1 and NPC2 proteins are still unclear. NP-C is currently described as a cellular cholesterol trafficking defect but in the brain, the prominently stored lipids are gangliosides. Clinical examination should include comprehensive neurological and ophthalmological evaluations. The primary laboratory diagnosis requires living skin fibroblasts to demonstrate accumulation of unesterified cholesterol in perinuclear vesicles (lysosomes) after staining with filipin. Pronounced abnormalities are observed in about 80% of the cases, mild to moderate alterations in the remainder ("variant" biochemical phenotype). Genotyping of patients is useful to confirm the diagnosis in the latter patients and essential for future prenatal diagnosis. The differential diagnosis may include other lipidoses; idiopathic neonatal hepatitis and other causes of cholestatic icterus should be considered in neonates, and conditions with cerebellar ataxia, dystonia, cataplexy and supranuclear gaze palsy in older children and adults. Symptomatic management of patients is crucial. A first product, miglustat, has been granted marketing authorization in Europe and several other countries for specific treatment of the neurological manifestations. The prognosis largely correlates with the age at onset of the neurological manifestations. © 2010 Vanier; licensee BioMed Central Ltd.


Mirouse V.,French National Center for Scientific Research | Billaud M.,French Institute of Health and Medical Research
FEBS Letters | Year: 2011

The LKB1 tumor suppressor kinase is an activator of the AMP-activated protein kinase (AMPK), a metabolic gauge that responds to variations of cellular energetic levels by favoring catabolic versus anabolic processes. Recent studies have provided substantial evidence that LKB1 and AMPK control cell polarity from invertebrates to mammals. This review examines how the LKB1-AMPK pathway, in conjunction with other positional signals, converts energy-sensing information into the activation of Myosin II to maintain epithelial-cell architecture but also to complete cell division. This molecular link between polarity and metabolism may constitute an ancient stress-response protective mechanism that was co-opted for tumor suppression during evolution. © 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.


Clezardin P.,French Institute of Health and Medical Research | Clezardin P.,University of Lyon
Breast Cancer Research | Year: 2011

Breast cancer is prone to metastasize to bone. Once metastatic cells are in the bone marrow, they do not, on their own, destroy bone. Instead, they alter the functions of bone-resorbing (osteoclasts) and bone-forming cells (osteoblasts), resulting in skeletal complications that cause pathological fractures and pain. In this review, we describe promising molecular bone-targeted therapies that have arisen from recent advances in our understanding of the pathogenesis of breast cancer bone metastases. These therapies target osteoclasts (receptor activator of nuclear factor kB ligand, integrin αvβ3, c-Src, cathepsin K), osteoblasts (dickkopf-1, activin A, endothelin A) and the bone marrow microenvironment (transforming growth factor β, bone morphogenetic proteins, chemokine CXCL-12 and its receptor CXCR4). The clinical exploitation of these bone-targeted agents will provide oncologists with novel therapeutic strategies for the treatment of skeletal lesions in breast cancer. © 2011 BioMed Central Ltd.


El Far O.,French Institute of Health and Medical Research | Seagar M.,Aix - Marseille University
Journal of Neurochemistry | Year: 2011

SNARE (soluble N-ethylmaleimide sensitive factor attachment protein receptors)-mediated exocytotic release of neurotransmitters is a key process in neuronal communication, controlled by a number of molecular interactions. A synaptic vesicle v-SNARE protein (VAMP2 or synaptobrevin), in association with two plasma membrane t-SNAREs (syntaxin 1 and SNAP25), assemble to form a protein complex that is largely accepted as the minimal membrane fusion machine. Acidification of the synaptic vesicle lumen by the large multi-subunit vacuolar proton pump (V-ATPase) is required for loading with neurotransmitters. Recent data demonstrate a direct interaction between the c-subunit of the V-ATPase and VAMP2 that appears to play a role at a late step in transmitter release. In this review, we examine evidence suggesting that the V0 membrane sector of the V-ATPase not only participates in proton pumping, but plays a second distinct role in neurosecretion, downstream of filling and close to vesicle fusion. © 2011 The Authors.


Probst A.V.,French Institute of Health and Medical Research | Almouzni G.,University Pierre and Marie Curie | Almouzni G.,French National Center for Scientific Research
Trends in Genetics | Year: 2011

Heterochromatin at pericentric satellites, characterized by a specific chromatin signature and chromocenter organization, is of paramount importance for genome function. Re-establishment of this organization after fertilization takes place in the context of genome-wide epigenetic reprogramming. We review how the asymmetry in histone variants and post-translational modifications between paternal and maternal genomes and their respective pericentric heterochromatin domains evolve during early cleavage stages in mouse. We draw a parallel between these data and the burst of pericentric satellite transcription that occurs concomitantly with the dynamic reorganization of the pericentric domains into chromocenters in two-cell stage embryos. Based on this new angle, we propose that a crucial developmental transition at the two-cell stage allows chromocenter formation by involving non-coding satellite transcripts to trigger specific chromatin changes. © 2011 Elsevier Ltd.


Kroemer G.,U848 | Kroemer G.,University of Paris Descartes | Kroemer G.,University Paris - Sud | Galluzzi L.,Institute Gustave Roussy | And 7 more authors.
Annual Review of Immunology | Year: 2013

Depending on the initiating stimulus, cancer cell death can be immunogenic or nonimmunogenic. Immunogenic cell death (ICD) involves changes in the composition of the cell surface as well as the release of soluble mediators, occurring in a defined temporal sequence. Such signals operate on a series of receptors expressed by dendritic cells to stimulate the presentation of tumor antigens to T cells. We postulate that ICD constitutes a prominent pathway for the activation of the immune system against cancer, which in turn determines the long-term success of anticancer therapies. Hence, suboptimal regimens (failing to induce ICD), selective alterations in cancer cells (preventing the emission of immunogenic signals during ICD), or defects in immune effectors (abolishing the perception of ICD by the immune system) can all contribute to therapeutic failure. We surmise that ICD and its subversion by pathogens also play major roles in antiviral immune responses. © Copyright 2013 by Annual Reviews. All rights reserved.


Turan B.,Ankara University | Vassort G.,French Institute of Health and Medical Research
Antioxidants and Redox Signaling | Year: 2011

Diabetes mellitus is a major risk factor for cardiovascular complications. Intracellular Ca 2+ release plays an important role in the regulation of muscle contraction. Sarcoplasmic reticulum Ca 2+ release is controlled by dedicated molecular machinery, composed of a complex of cardiac ryanodine receptors (RyR2s). Acquired and genetic defects in this complex result in a spectrum of abnormal Ca 2+ release phenotypes in heart. Cardiovascular dysfunction is a leading cause for mortality of diabetic individuals due, in part, to a specific cardiomyopathy, and to altered vascular reactivity. Cardiovascular complications result from multiple parameters, including glucotoxicity, lipotoxicity, fibrosis, and mitochondrial uncoupling. In diabetic subjects, oxidative stress arises from an imbalance between production of reactive oxygen and nitrogen species and capability of the system to readily detoxify reactive intermediates. To date, the etiology underlying diabetes-induced reductions in myocyte and cardiac contractility remains incompletely understood. However, numerous studies, including work from our laboratory, suggest that these defects stem in part from perturbation in intracellular Ca 2+ cycling. Since the RyR2s are one of the well-characterized redox-sensitive ion channels in heart, this article summarizes recent findings on redox regulation of cardiac Ca 2+ transport systems and discusses contributions of redox regulation to pathological cardiac function in diabetes. © 2011 Mary Ann Liebert, Inc.


MacIeira-Coelho A.,French Institute of Health and Medical Research
Biogerontology | Year: 2011

The capacity to regenerate cell compartments through cell proliferation is an important characteristic of many developed metazoan tissues. Pre- and post-natal development proceeds through the modifications occurring during cell division. Experiments with cultivated cells showed that cell proliferation originates changes in cell functions and coordinations that contribute to aging and senescence. The implications of the finite cell proliferation to aging of the organism is not the accumulation of cells at the end of their life cycle, but rather the drift in cell function created by cell division. Comparative gerontology shows that the regulation of the length of telomeres has no implications for aging. On the other hand there are interspecies differences in regard to the somatic cell division potential that seem to be related with the "plasticity" of the genome and with longevity, which should be viewed independently of the aging phenomenon. Telomeres may play a role in this plasticity through the regulation of chromosome recombination, and via the latter also in development. © 2011 Springer Science+Business Media B.V.


Nehlig A.,French Institute of Health and Medical Research
Biomarkers in Medicine | Year: 2011

The present review is devoted to application of MRI techniques to the epileptic brain and the search for potential biomarkers of epileptogenicity and/or epileptogenesis in rodents that could be translated to the clinic. Diffusion-weighted imaging reveals very early changes in water movements. T 2-weighted hypersignal indicates edema or gliosis within brain regions and is most often used along with histological assessment of neuronal loss. 31P magnetic resonance spectroscopy measures the energy reserve of the tissue while 1H spectroscopy assesses neuronal loss and mitochondrial dysfunction. 13C spectroscopy analyzes, separately, neuronal and astrocytic metabolism and interactions between the two cell types. Finally, diffusion tensor imaging and tractography have been applied to the study of plasticity and show a good coherence with circuit changes assessed by Timm staining. The potential of these techniques as reliable biomarkers of epileptogenesis is still disputed. At the moment, one study has provided a reliable temporal evolution of the T 2 signal, predicting epileptogenesis in 100% of the cases, and further imaging approaches based on the techniques described here are still needed to identify potential early imaging biomarkers of epileptogenicity and/or epileptogenesis. © 2011 Future Medicine Ltd.


Manel N.,French Institute of Health and Medical Research | Littman D.R.,New York University | Littman D.R.,Howard Hughes Medical Institute
Cell | Year: 2011

Two groups have identified SAMHD1, a protein encoded by an Aicardi-Goutires Syndrome susceptibility gene, as the factor that restricts infection of macrophages and dendritic cells with HIV-1. Here we discuss implications of this discovery for induction of antiviral protective immunity. © 2011 Elsevier Inc.


Gish R.,University of California at San Diego | Jia J.-D.,Capital Medical University | Locarnini S.,Victorian Infectious Diseases Reference Laboratory | Zoulim F.,French Institute of Health and Medical Research | Zoulim F.,Institut Universitaire de France
The Lancet Infectious Diseases | Year: 2012

Antiviral drug resistance is a crucial factor that frequently determines the success of long-term therapy for chronic hepatitis B. The development of resistance to nucleos(t)ide analogues has been associated with exacerbations in liver disease and increased risk of emergence of multidrug resistance. The selection of a potent nucleos(t)ide analogue with a high barrier to resistance as a first-line therapy, such as entecavir or tenofovir, provides the best chance of achieving long-term treatment goals and should be used wherever possible. The barrier to resistance of a given nucleos(t)ide analogue is influenced by genetic barrier, drug potency, patient adherence, pharmacological barrier, viral fitness, mechanism of action, and cross-resistance. In countries with limited health-care resources, the selection of a therapy with a high barrier to resistance is not always possible and alternative strategies for preventing resistance might be needed, although limited data are available to support these strategies. © 2012 Elsevier Ltd.


Barthelemy F.,French Institute of Health and Medical Research
Molecular medicine (Cambridge, Mass.) | Year: 2011

Dysferlinopathies are autosomal recessive disorders caused by mutations in the dysferlin (DYSF) gene, encoding the dysferlin protein. DYSF mutations lead to a wide range of muscular phenotypes, with the most prominent being Miyoshi myopathy (MM) and limb girdle muscular dystrophy type 2B (LGMD2B) and the second most common being LGMD. Symptoms generally appear at the end of childhood and, although disease progression is typically slow, walking impairments eventually result. Dysferlin is a modular type II transmembrane protein for which numerous binding partners have been identified. Although dysferlin function is only partially elucidated, this large protein contains seven calcium sensor C2 domains, shown to play a key role in muscle membrane repair. On the basis of this major function, along with detailed clinical observations, it has been possible to design various therapeutic approaches for dysferlin-deficient patients. Among them, exon-skipping and minigene transfer strategies have been evaluated at the preclinical level and, to date, represent promising approaches for clinical trials. This review aims to summarize the pathophysiology of dysferlinopathies and to evaluate the therapeutic potential for treatments currently under development.


Roingeard P.,French Institute of Health and Medical Research
Journal of Viral Hepatitis | Year: 2013

Hepatitis C virus (HCV) infection is closely associated with lipid metabolism defects throughout the viral lifecycle, with hepatic steatosis frequently observed in patients with chronic HCV infection. Hepatic steatosis is most common in patients infected with genotype 3 viruses, possibly due to direct effects of genotype 3 viral proteins. Hepatic steatosis in patients infected with other genotypes is thought to be mostly due to changes in host metabolism, involving insulin resistance in particular. Specific effects of the HCV genotype 3 core proteins have been observed in cellular models in vitro: mechanisms linked with a decrease in microsomal triglyceride transfer protein activity, decreases in the levels of peroxisome proliferator-activating receptors, increases in the levels of sterol regulatory element-binding proteins, and phosphatase and tensin homologue downregulation. Functional differences between the core proteins of genotype 3 viruses and viruses of other genotypes may reflect differences in amino acid sequences. However, bioclinical studies have failed to identify specific 'steatogenic' sequences in HCV isolates from patients with hepatic steatosis. It is therefore difficult to distinguish between viral and metabolic steatosis unambiguously, and host and viral factors are probably involved in both HCV genotype 3 and nongenotype 3 steatosis. © 2012 Blackwell Publishing Ltd.


Boulanger C.M.,French Institute of Health and Medical Research | Boulanger C.M.,University of Paris Descartes
Current Opinion in Nephrology and Hypertension | Year: 2010

Purpose of Review: To summarize the potential role of microparticles in hypertension and in cardiovascular diseases. Microparticles are submicron vesicles shed from the membrane in response to cell activation or apoptosis. Microparticles of different cellular origins are found in the plasma of healthy individuals and their circulating levels augment in patients with cardiovascular diseases. Recent Findings: Recent studies demonstrate that circulating levels of microparticles originating from endothelial cells, which represent a small fraction of the overall pool of plasma microparticles, augment with increased endothelial dysfunction in patients with cardiovascular diseases. Therefore, endothelial microparticles constitute an emerging surrogate marker of endothelial dysfunction, with potential prognostic value for major adverse events in patients with cardiovascular diseases. In addition, microparticles of endothelial and other cellular origins are also potential biological effectors in inflammation, vascular injury, angiogenesis and thrombosis. Summary: In summary, circulating endothelial microparticles may serve not only as an index of arterial damage but also as a trigger of vascular repair. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Sarrazy V.,French Institute of Health and Medical Research
Circulation Research | Year: 2016

RATIONALE:: Inflamed atherosclerotic plaques can be visualized by non-invasive PET-CT imaging with FDG, a glucose analog but the underlying mechanisms are poorly understood. OBJECTIVE:: Here, we directly investigated the role of Glut1-mediated glucose uptake in ApoE mouse model of atherosclerosis. METHODS AND RESULTS:: We first show that the enhanced glycolytic flux in atheromatous plaques of ApoE mice was associated with the enhanced metabolic activity of hematopoietic stem and multi-potential progenitors (HSPCs) and higher Glut1 expression in these cells. Mechanistically, the regulation of Glut1 in ApoE HSPCs was not due to alterations in hypoxia-inducible factor 1α (HIF1α) signaling or the oxygenation status of the bone marrow but was the consequence of the activation of the common β subunit of the granulocyte macrophage colony-stimulating factor/interleukin-3 receptor driving glycolytic substrate utilization by mitochondria. By transplanting BM from WT, Glut1, ApoE and ApoEGlut1 mice into hypercholesterolemic ApoE deficient mice, we found that Glut1 deficiency reversed ApoE HSPC proliferation and expansion, which prevented the myelopoiesis and accelerated atherosclerosis of ApoE mice transplanted with ApoE BM and resulted in reduced glucose uptake in the spleen and aortic arch of these mice. CONCLUSIONS:: We identified that Glut1 connects the enhanced glucose uptake in atheromatous plaques of ApoE mice with their myelopoiesis through regulation of HSPC maintenance and myelomonocytic fate and suggest Glut1 as potential drug target for atherosclerosis. © 2016 American Heart Association, Inc.


Michee S.,French Institute of Health and Medical Research
PloS one | Year: 2013

To characterize the effects of benzalkonium chloride (BAK) in THP-1 differentiated cells in vitro. Macrophages were obtained after differentiation of THP-1 cells, a human monocytic leukemia cell line. Macrophages were exposed for 24 h to 33 nM (10(-5)%) benzalkonium chloride (BAK), 10 nM dinitrochlorobenzene (DNCB), 100 ng/mL lipopolysaccharide (LPS), 5 ng/mL tumor necrosis factor alpha (TNF-α) or phosphate buffered saline (PBS) as controls. The expression of CD11b, CD11c, CD33 and CD54 was evaluated using immunohistochemistry and flow cytometry (FCM). Phagocytosis function was analyzed using carboxylate-modified fluorescent microspheres and quantified by FCM. Migration was evaluated in cocultures with conjunctival epithelial cells. Cytokine production was detected and quantified in culture supernatants using a human cytokine array. Stimulation of THP-1-derived macrophages with a low concentration of BAK increased CD11b and CD11c expression and decreased CD33. Macrophages exposed to BAK, LPS and TNF-α had increased phagocytosis. In contrast to LPS, BAK and TNF-α increased macrophage migration. Cytokines in supernatants of macrophages exposed to BAK revealed an increased release of CCL1, CCL4/MIP-1β, TNF-α, soluble CD54/ICAM-1 and IL-1β. In vitro, BAK has a direct stimulating effect on macrophages, increasing phagocytosis, cytokine release, migration and expression of CD11b and CD11c. Long-term exposure to low concentrations of BAK should be considered as a stimulating factor responsible for inflammation through macrophage activation.


Remen T.,French Institute of Health and Medical Research
BMC public health | Year: 2012

The natural history of occupational asthma (OA) is influenced by many determinants. This study aims to assess the combined roles of personal characteristics, including occupational exposure and nutritional habits, on the incidence of OA during the first years at work. A nested case-control study was conducted within a retrospective cohort of young workers in the bakery, pastry-making and hairdressing sectors. Cases were subjects diagnosed as 'confirmed' or 'probable' OA consecutively to a medical visit (N = 31). Controls were subjects without OA (N = 196). Atopy was defined after blood specific IgE analysis, based on the PhadiatopTM test. Occupational exposure was characterized by standardized questionnaires and diet patterns by a food frequency questionnaire. Among bakers and pastry-makers, only atopy is an independent risk factor of OA (OR = 10.07 95%CI [2.76 - 36.65]). Among hairdressers, several variables are associated with OA. Body mass index (unit OR = 1.24 [1.03 - 1.48]) and the score of exposure intensity (unit OR = 1.79 [1.05 - 3.05]) are independent predictors of OA, but the role of atopy is weak (OR = 4.94 [0.66 - 36.75]). Intake of vitamin A is higher among hairdressers cases (crude p = 0.002, adjusted p = 0.01 after control for body mass index and atopy); the same observation is made for vitamin D (crude p = 0.004, adjusted p = 0.01). This study suggests that the influence of several factors on the incidence of OA, including dietary vitamins, might vary across exposure settings.


Poupon R.,University Pierre and Marie Curie | Poupon R.,French Institute of Health and Medical Research
Journal of Hepatology | Year: 2010

Primary biliary cirrhosis (PBC) is a chronic inflammatory autoimmune disease that mainly targets the cholangiocytes of the interlobular bile ducts in the liver. The condition primarily affects middle-aged women. Without treatment, PBC generally progresses to cirrhosis and eventually liver failure over a period of 10-20 years. PBC is a rare disease with prevalence of less than 1/2000. PBC is thought to result from a combination of multiple genetic factors and superimposed environmental triggers. The contribution of the genetic predisposition is evidenced by the familial clustering. Several risk factors, including exposure to infectious agents and chemical xenobiotics, have been suggested. Ursodeoxycholic acid (UDCA) is currently the only FDA-approved medical treatment for PBC. When administered at doses of 13-15 mg/kg/day, a majority of patients with PBC have a normal life expectancy without additional therapeutic measures. One out of three patients does not adequately respond to UDCA therapy and may need additional medical therapy and/or liver transplantation. This review summarises current knowledge on the epidemiology, ethiopathogenesis, clinical, and therapeutic aspects of PBC. © 2010 European Association for the Study of the Liver.


Segura E.,French Institute of Health and Medical Research | Segura E.,University Pierre and Marie Curie | Villadangos J.A.,Walter and Eliza Hall Institute of Medical Research
Traffic | Year: 2011

Major histocompatibility complex class I (MHC I) presentation of exogenous antigens (cross-presentation) by dendritic cells (DC) is essential for CD8 T-cell immunity. Most cells use MHC I molecules to present peptides derived from endogenous proteins processed in the cytosol by the proteasome. The resulting peptides are translocated into the endoplasmic reticulum for loading onto MHC I molecules, and these complexes are then transported to the cell surface. In cross-presenting DC, these steps have been proposed to occur along two major tracks. In the 'endocytic' track, exogenous antigen processing and loading occur within endosomal compartments, using MHC I molecules recycled from the plasma membrane and transported back to the surface. In the 'cytosolic' track, antigens are translocated from endosomes to the cytosol, accessing the endogenous MHC I presentation pathway. This dichotomy now appears too simplistic. Some steps may occur in locations belonging to the endosomal track and others in the cytosolic track, or in hybrid compartments combining features of both. We propose a 'modular' view of cross-presentation, whereby processing, loading and MHC I transport represent modules that can occur in one or more locations. Cross-presentation of each MHC I-peptide complex may result from combining one or more options for each of these modules. © 2011 John Wiley & Sons A/S.


Alazet S.,University Claude Bernard Lyon 1 | Zimmer L.,CERMEP in Vivo Imaging | Zimmer L.,French Institute of Health and Medical Research | Billard T.,University Claude Bernard Lyon 1
Angewandte Chemie - International Edition | Year: 2013

Pin the tail on the alkyne: CF3S- or CF3CF 2S-alkynes can be simply and quickly obtained by mixing terminal alkynes with a trifluoromethanesulfenamide reagent. The reaction uses easy-to-handle reagents, and functions under mild conditions without activation by transition metals. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Chazaud B.,French Institute of Health and Medical Research | Chazaud B.,French National Center for Scientific Research | Chazaud B.,University of Paris Descartes
Immunobiology | Year: 2014

Macrophages, and more broadly inflammation, have been considered for a long time as bad markers of tissue homeostasis. However, if it is indisputable that macrophages are associated with many diseases in a deleterious way, new roles have emerged, showing beneficial properties of macrophages during tissue repair and regeneration. This discrepancy is likely due to the high plasticity of macrophages, which may exhibit a wide range of phenotypes and functions depending on their environment. Therefore, regardless of their role in immunity, macrophages play a myriad of roles in the maintenance and recovery of tissue homeostasis. They take a major part in the resolution of inflammation. They also exert various effects of parenchymal cells, including stem and progenitor cell, of which they regulate the fate. In the present review, few examples from various tissues are presented to illustrate that, beyond their specific properties in a given tissue, common features have been described that sustain a role of macrophages in the recovery and maintenance of tissue homeostasis. © 2013 Elsevier GmbH.


Pawlotsky J.-M.,University Paris Est Creteil | Pawlotsky J.-M.,French Institute of Health and Medical Research
Antiviral Research | Year: 2014

Hepatitis C virus (HCV) therapy is living a revolution. Host-targeted agents (HTAs) block HCV production by interacting with host cell components. Because they target conserved host proteins, not variable viral proteins, HTAs have the potential for pangenotypic antiviral activity and a high barrier to resistance. Only two HTAs have reached clinical development, including specific inhibitors of cyclophilin A peptidyl-prolyl cis/trans isomerase activity and antagonists of microRNA-122. Cyclophilin inhibitors have proven to be relatively well tolerated and can be confidently used as backbones of all-oral, interferon-free regimens. In addition, HTAs such as cyclophilin inhibitors offer opportunities for "panviral" approaches when they target mechanisms common to viruses of the same or different families. This article forms part of a symposium in Antiviral Research on "Hepatitis C: next steps toward global eradication." © 2014 Elsevier B.V. All rights reserved.


Petit-Topin I.,French Institute of Health and Medical Research
The Journal of steroid biochemistry and molecular biology | Year: 2014

The human progesterone receptor (PR) plays a key role in reproductive function in women. PR antagonists have numerous applications in female health care including regular and emergency contraception, and treatment of hormone-related pathological conditions such as breast cancer, endometriosis, and leiomyoma. The main factor limiting their long-term administration is the fact that they cross-bind to other oxo-steroid receptors. Ulipristal acetate (UPA), a highly potent PR antagonist, has recently come onto the market and is much more selective for PR than the other oxo-steroid receptors (androgen, AR, glucocorticoid, GR, and mineralocorticoid, MR receptors) and, remarkably, it displays lower GR-inactivating potency than RU486. We adopted a structural approach to characterizing the binding of UPA to the oxo-steroid receptors at the molecular level. We solved the X-ray crystal structure of the ligand-binding domain (LBD) of the human PR complexed with UPA and a peptide from the transcriptional corepressor SMRT. We used the X-ray crystal structure of the GR in its antagonist conformation to dock UPA within its ligand-binding cavity. Finally, we generated three-dimensional models of the LBD of androgen and mineralocorticoid receptors (AR and MR) in an antagonist conformation and docked UPA within them. Comparing the structures revealed that the network of stabilizing contacts between the UPA C11 aryl group and the LBD is responsible for its high PR antagonist potency. It also showed that it is the inability of UPA to contact Gln642 in GR that explains why it has lower potency in inactivating GR than RU486. Finally, we found that the binding pockets of AR and MR are too small to accommodate UPA, and allowed us to propose that the extremely low sensitivity of MR to UPA is due to inappropriate interactions with the C11 substituent. All these findings open new avenues for designing new PR antagonist compounds displaying greater selectivity. Copyright © 2014 Elsevier Ltd. All rights reserved.


Dierick F.,French Institute of Health and Medical Research
Circulation Research | Year: 2016

RATIONALE:: Pulmonary arterial hypertension (PAH) is characterized by vascular remodeling and neomuscularization. PW1 progenitor cells can differentiate into smooth muscle cells (SMC) in vitro. OBJECTIVE:: To determine the role of pulmonary PW1 progenitor cells in vascular remodeling characteristic of PAH. METHODS AND RESULTS:: We investigated their contribution during chronic hypoxia (CH)-induced vascular remodeling in Pw1 mouse expressing β-galactosidase in PW1 cells and in differentiated cells derived from PW1 cells. PW1 progenitor cells are present in the perivascular zone in rodent and human control lungs. Using progenitor markers, three distinct myogenic PW1 cell populations were isolated from the mouse lung of which two were significantly increased after 4 days of CH. The number of proliferating pulmonary PW1 cells and the proportion of β-gal vascular SMC were increased, indicating a recruitment of PW1 cells and their differentiation into vascular SMC during early CH-induced neomuscularization. CXCR4 inhibition using AMD3100 prevented PW1 cells differentiation into SMC but did not inhibit their proliferation. Bone marrow transplantation experiments showed that the newly formed β-gal SMC were not derived from circulating bone marrow-derived PW1 progenitor cells, confirming a resident origin of the recruited PW1 cells. The number of pulmonary PW1 cells was also increased in rats after monocrotaline (MCT) injection. In the human PAH lung, PW1-expressing cells were observed in large numbers in remodeled vascular structures. CONCLUSIONS:: These results demonstrate the existence of a novel population of resident SMC progenitor cells expressing PW1 and participating in PH-associated vascular remodeling. © 2016 American Heart Association, Inc.


Mathern G.W.,University of California at Los Angeles | Beninsig L.,Epilepsia | Nehlig A.,French Institute of Health and Medical Research
Epilepsia | Year: 2015

Summary Objective From May 20 to September 1 2014, Epilepsia conducted an online survey seeking opinions about the use of medical marijuana and cannabidiol (CBD) for people with epilepsy. This study reports the findings of that poll. Methods The survey consisted of eight questions. Four questions asked if there were sufficient safety and efficacy data, whether responders would advise trying medical marijuana in cases of severe refractory epilepsy, and if pharmacologic grade compounds containing CBD should be available. Four questions addressed occupation, geographic region of residence, if responders had read the paper, and if they were International League Against Epilepsy/International Bureau for Epilepsy (ILAE/IBE) members. Results Of 776 who started or completed the survey, 58% were patients from North America, and 22% were epileptologists and general neurologists from Europe and North America. A minority of epileptologists and general neurologists said that there were sufficient safety (34%) and efficacy (28%) data, and 48% would advise using medical marijuana in severe cases of epilepsy. By comparison, nearly all patients and the public said there were sufficient safety (96%) and efficacy (95%) data, and 98% would recommend medical marijuana in cases of severe epilepsy. General physicians, basic researchers, nurses, and allied health professions sided more with patients, saying that there were sufficient safety (70%) and efficacy (71%) data, and 83% would advise using marijuana in severe cases. A majority (78%) said there should be pharmacologic grade compounds containing CBD, and there were no differences between specialists, general medical personal, and patients and the public. Significance This survey indicates that there is a wide disparity in opinion on the use of medical marijuana and CBD in the treatment of people with epilepsy, which varied substantially, with fewer medical specialists supporting its use compared with general medical personal, and patients and the public. © Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.


Lagarrigue M.,French Institute of Health and Medical Research
Molecular & cellular proteomics : MCP | Year: 2011

Matrix-assisted laser desorption/ionization (MALDI) molecular imaging technology attracts increasing attention in the field of biomarker discovery. The unambiguous correlation between histopathology and MALDI images is a key feature for success. MALDI imaging mass spectrometry (MS) at high definition thus calls for technological developments that were established by a number of small steps. These included tissue and matrix preparation steps, dedicated lasers for MALDI imaging, an increase of the robustness against cell debris and matrix sublimation, software for precision matching of molecular and microscopic images, and the analysis of MALDI imaging data using multivariate statistical methods. The goal of these developments is to approach single cell resolution with imaging MS. Currently, a performance level of 20-μm image resolution was achieved with an unmodified and commercially available instrument for proteins detected in the 2-16-kDa range. The rat testis was used as a relevant model for validating and optimizing our technological developments. Indeed, testicular anatomy is among the most complex found in mammalian bodies. In the present study, we were able to visualize, at 20-μm image resolution level, different stages of germ cell development in testicular seminiferous tubules; to provide a molecular correlate for its well established stage-specific classification; and to identify proteins of interest using a top-down approach and superimpose molecular and immunohistochemistry images.


Dauvilliers Y.A.,French Institute of Health and Medical Research | Laberge L.,University of Quebec at Chicoutimi
Sleep Medicine Reviews | Year: 2012

Myotonic dystrophy type 1 (DM1), or Steinert's disease, is the most common adult-onset form of muscular dystrophy. DM1 also constitutes the neuromuscular condition with the most significant sleep disorders including excessive daytime sleepiness (EDS), central and obstructive sleep apneas, restless legs syndrome (RLS), periodic leg movements in wake (PLMW) and periodic leg movements in sleep (PLMS) as well as nocturnal and diurnal rapid eye movement (REM) sleep dysregulation. EDS is the most frequent non-muscular complaint in DM1, being present in about 70-80% of patients. Different phenotypes of sleep-related problems may mimic several sleep disorders, including idiopathic hypersomnia, narcolepsy without cataplexy, sleep apnea syndrome, and periodic leg movement disorder. Subjective and objective daytime sleepiness may be associated with the degree of muscular impairment. However, available evidence suggests that DM1-related EDS is primarily caused by a central dysfunction of sleep regulation rather than by sleep fragmentation, sleep-related respiratory events or periodic leg movements. EDS also tends to persist despite successful treatment of sleep-disordered breathing in DM1 patients. As EDS clearly impacts on physical and social functioning of DM1 patients, studies are needed to identify the best appropriate tools to identify hypersomnia, and clarify the indications for polysomnography (PSG) and multiple sleep latency test (MSLT) in DM1. In addition, further structured trials of assisted nocturnal ventilation and randomized trials of central nervous system (CNS) stimulant drugs in large samples of DM1 patients are required to optimally treat patients affected by this progressive, incurable condition. © 2012 Elsevier Ltd.


Nava C.,French Institute of Health and Medical Research
Translational psychiatry | Year: 2012

The striking excess of affected males in autism spectrum disorders (ASD) suggests that genes located on chromosome X contribute to the etiology of these disorders. To identify new X-linked genes associated with ASD, we analyzed the entire chromosome X exome by next-generation sequencing in 12 unrelated families with two affected males. Thirty-six possibly deleterious variants in 33 candidate genes were found, including PHF8 and HUWE1, previously implicated in intellectual disability (ID). A nonsense mutation in TMLHE, which encodes the e-N-trimethyllysine hydroxylase catalyzing the first step of carnitine biosynthesis, was identified in two brothers with autism and ID. By screening the TMLHE coding sequence in 501 male patients with ASD, we identified two additional missense substitutions not found in controls and not reported in databases. Functional analyses confirmed that the mutations were associated with a loss-of-function and led to an increase in trimethyllysine, the precursor of carnitine biosynthesis, in the plasma of patients. This study supports the hypothesis that rare variants on the X chromosome are involved in the etiology of ASD and contribute to the sex-ratio disequilibrium.


Le Bousse-Kerdiles M.-C.,French Institute of Health and Medical Research
Fibrogenesis and Tissue Repair | Year: 2012

Primary Myelofibrosis (PMF) is a chronic myeloproliferative neoplasm characterized by a clonal myeloproliferation and a myelofibrosis. The concomitant presence of neoangiogenesis and osteosclerosis suggests a deregulation of medullar stem cell niches in which hematopoietic stem cells are engaged in a constant crosstalk with their stromal environment. Despite the recently discovered mutations including the JAK2Val617Fmutation, the primitive molecular event responsible for the clonal hematopoietic proliferation is still unknown. We propose that the "specificity" of the pathological process that caracterizes PMF results from alterations in the cross talk between hematopoietic and stromal cells. These alterations contribute in creating a abnormal microenvironment that participates in the maintenance of the neoplasic clone leading to a misbalance disfavouring normal hematopoiesis; in return or simultaneously, stromal cells constituting the niches are modulated by hematopoietic cells resulting in stroma dysfunctions. Therefore, PMF is a remarkable "model" in which deregulation of the stem cell niche is of utmost importance for the disease development. A better understanding of the crosstalk between stem cells and their niches should imply new therapeutic strategies targeting not only intrinsic defects in stem cells but also regulatory niche-derived signals and, consequently, hematopoietic cell proliferation. © 2012 Le Bousse-Kerdilès; licensee BioMed Central Ltd.


Deneux-Tharaux C.,French Institute of Health and Medical Research
Obstetrics and Gynecology | Year: 2011

Objective: To identify factors associated with severity of postpartum hemorrhage among characteristics of women and their delivery, the components of initial postpartum hemorrhage management, and the organizational characteristics of maternity units. Methods: This population-based cohort study included women with postpartum hemorrhage due to uterine atony after vaginal delivery in 106 French hospitals between December 2004 and November 2006 (N=4,550). Severe postpartum hemorrhage was defined by a peripartum change in hemoglobin of 4 g/dL or more. A multivariable logistic model was used to identify factors independently associated with postpartum hemorrhage severity. Results: Severe postpartum hemorrhage occurred in 952 women (20.9%). In women with postpartum hemorrhage, factors independently associated with severity were: primiparity; previous postpartum hemorrhage; previous cesarean delivery; cervical ripening; prolonged labor; and episiotomy; and delay in initial care for postpartum hemorrhage. Also associated with severity was 1) administration of oxytocin more than 10 minutes after postpartum hemorrhage diagnosis: 10-20 minutes after, proportion with severe postpartum hemorrhage 24.6% compared with 20.5%, adjusted OR 1.38, 95% CI 1.03-1.85; more than 20 minutes after, 31.8% compared with 20.5%, adjusted OR 1.86, CI 1.45-2.38; 2) manual examination of the uterine cavity more than 20 minutes after (proportion with severe postpartum hemorrhage 28.2% versus 20.7%, adjusted OR 1.83, 95% CI 1.42-2.35); 3) call for additional assistance more than 10 minutes after (proportion with severe postpartum hemorrhage 29.8% versus 24.8%, adjusted OR 1.61, 95% CI 1.23-2.12 for an obstetrician, and 35.1% compared with 29.9%, adjusted OR 1.51, 95% CI 1.14-2.00 for an anesthesiologist); 4) and delivery in a public non-university hospital. Epidural analgesia was found to be a protective factor against severe blood loss in women with postpartum hemorrhage. Conclusion: Aspects of labor, delivery, and their management; delay in initial care; and place of delivery are independent risk factors for severe blood loss in women with postpartum hemorrhage caused by atony. © 2010 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins.


Mattout J.,French Institute of Health and Medical Research | Mattout J.,University of Lyon
Frontiers in Human Neuroscience | Year: 2012

A number of recent studies have put human subjects in true social interactions, with the aim of better identifying the psychophysiological processes underlying social cognition. Interestingly, this emerging Neuroscience of Social Interactions (NSI) field brings up challenges which resemble important ones in the field of Brain-Computer Interfaces (BCI). Importantly, these challenges go beyond common objectives such as the eventual use of BCI and NSI protocols in the clinical domain or common interests pertaining to the use of online neurophysiological techniques and algorithms. Common fundamental challenges are now apparent and one can argue that a crucial one is to develop computational models of brain processes relevant to human interactions with an adaptive agent, whether human or artificial. Coupled with neuroimaging data, such models have proved promising in revealing the neural basis and mental processes behind social interactions. Similar models could help BCI to move from well-performing but offline static machines to reliable online adaptive agents.This emphasizes a social perspective to BCI, which is not limited to a computational challenge but extends to all questions that arise when studying the brain in interaction with its environment. © 2012 Mattout.


Dumontet C.,French Institute of Health and Medical Research | Dumontet C.,UniversiteLyon 1 | Jordan M.A.,University of California at Santa Barbara
Nature Reviews Drug Discovery | Year: 2010

Microtubules are dynamic filamentous cytoskeletal proteins composed of tubulin and are an important therapeutic target in tumour cells. Agents that bind to microtubules have been part of the pharmacopoeia of anticancer therapy for decades and until the advent of targeted therapy, microtubules were the only alternative to DNA as a therapeutic target in cancer. The screening of a range of botanical species and marine organisms has yielded promising new antitubulin agents with novel properties. In the current search for novel microtubule-binding agents, enhanced tumour specificity, reduced neurotoxicity and insensitivity to chemoresistance mechanisms are the three main objectives. © 2010 Macmillan Publishers Limited. All rights reserved.


Fainzang S.,French Institute of Health and Medical Research
Drug Safety | Year: 2014

Background: The practice of self-medication is exemplary in raising the question of medicinal uses and risks. In contrast to the biomedical or pharmacological view of self-medication, the anthropological approach looks to understand the logics that underpin it. Objective: Therefore, I wished to question how users choose the medicines they take and how they construct the modalities of their use. However, not only are the users conscious of the risks associated with pharmaceutical use, they even devise strategies that specifically aim to reduce these risks. Based on research carried out in France on how people use medicines in the context of self-medication, I examined the strategies they adopt in order to reduce the risks connected with such use. Method: This study relies on qualitative research. It combines interviews with users and anthropological observation, both conducted at the participants' homes, to reveal their uses, their decisions, their hesitations and the precautions they take regarding their medicines. Results: The logics underpinning the management of risks associated with medicinal consumption are varied. Thus we find quantitative and qualitative logics, in virtue of which users choose to limit their medicines depending on the number of different medicines or on their intrinsic qualities. Their choices hinge on a logic of cumulation and a logic of identity, where, in the former, users seek to increase or reduce their medicinal consumption to augment the efficacy of a medicine or, in the latter case, they aim to reduce the risks in relation to their personal characteristics. In the same way, the perception of risk that underpins consumption practices is organised according to the notions of risk in itself and risk for oneself, where risk is either considered to be inherent to the medicine or to be linked to the incompatibility between a given substance and a person's body. Managing risk is thus done in parallel to managing efficacy, where a balance is sought between maximising the latter and minimising the former. This either leads patients to limit the consumption of medicines because of their adverse effects, or, on the contrary, to consume them precisely for these effects. Risk reduction strategies often consist of verifying, experimenting with, and personalising treatments. Conclusion: Although users sometimes resort to practices that do not comply with biomedical recommendations, they do so in order to attain the values and exigencies of biomedicine as regards the validation or personalisation of treatments. However irrational and peculiar these practices may appear, the mechanisms on which they are based do not necessarily break away from medical recommendations. Therefore, anthropologically speaking, we cannot oppose good and bad practices in terms of medicinal uses, since what health professionals would consider to be bad practices are thought by patients to be in keeping with good use. © 2014 Springer International Publishing.


Ravaud A.,Bordeaux University Hospital Center | Ravaud A.,French Institute of Health and Medical Research | Schmidinger M.,Medical University of Vienna
Annals of Oncology | Year: 2013

There are now a range of effective targeted agents available for the first-and second-line treatment of advanced renal cell carcinoma (RCC). However, patients with advanced RCC have varied responses to therapy; some experience long-term responses while others may not respond, or even progress rapidly. Characteristics or markers that could be used to determine which patients will benefit most from which agent may enable us to select the optimal treatment of each individual patient, thereby improving efficacy and avoiding unnecessary toxic effects. These characteristics may be at the cellular or genetic level. Alternatively, the occurrence of adverse events may act as surrogate markers of a drug's on treatment activity, enabling prediction of outcomes during treatment. Recently, it has been suggested that during some targeted therapy for advanced RCC, the occurrence of specific adverse events, such as hypertension, hypothyroidism, hand-foot syndrome or fatigue/asthenia, may be associated with improved efficacy. This article reviews the evidence supporting clinical biomarkers in patients with advanced RCC receiving targeted agents. We also consider how these clinical biomarkers may affect the future management of patients with advanced RCC. © The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Joutel A.,French Institute of Health and Medical Research | Joutel A.,University Paris Diderot
BioEssays | Year: 2011

Small vessel diseases (SVDs) of the brain are the leading cause of vascular cognitive impairment and a major contributor to stroke in the human adult, however, their pathogenesis is poorly understood. Dominant mutations in NOTCH3 cause CADASIL, one of the most prevalent inherited cerebral SVDs. The disease gene encodes a transmembrane receptor primarily expressed in smooth muscle cells of small arteries and pericytes of brain capillaries. Pathogenic mutations alter the number of cysteine residues in the extracellular domain of NOTCH3, leading to its abnormal accumulation in the vessels of patients. Mice lacking NOTCH3 have revealed a critical role for NOTCH3 in the elaboration of small arteries. Despite being incomplete disease models, transgenic mice expressing CADASIL-associated NOTCH3 mutations, have provided important insights into specific aspects of CADASIL pathogenesis, including the functional significance of disease-linked mutations and the earliest pathological events that initiate brain lesions. In this paper, I provide a critical overview of these studies. Moreover, I discuss future directions and further work that needs to be done. Copyright © 2011 WILEY Periodicals, Inc.


Besson D.,French Institute of Health and Medical Research
Molecular & cellular proteomics : MCP | Year: 2011

Expression profiles represent new molecular tools that are useful to characterize the successive steps of tumor progression and the prediction of recurrence or chemotherapy response. In this study, we have used quantitative proteomic analysis to compare different stages of colorectal cancer. A combination of laser microdissection, OFFGEL separation, iTRAQ labeling, and MALDI-TOF/TOF MS was used to explore the proteome of 28 colorectal cancer tissues. Two software packages were used for identification and quantification of differentially expressed proteins: Protein Pilot and iQuantitator. Based on ∼1,190,702 MS/MS spectra, a total of 3138 proteins were identified, which represents the largest database of colorectal cancer realized to date and demonstrates the value of our quantitative proteomic approach. In this way, individual protein expression and variation have been identified for each patient and for each colorectal dysplasia and cancer stage (stages I-IV). A total of 555 proteins presenting a significant fold change were quantified in the different stages, and this differential expression correlated with immunohistochemistry results reported in the Human Protein Atlas database. To identify a candidate biomarker of the early stages of colorectal cancer, we focused our study on secreted proteins. In this way, we identified olfactomedin-4, which was overexpressed in adenomas and in early stages of colorectal tumors. This early stage overexpression was confirmed by immunohistochemistry in 126 paraffin-embedded tissues. Our results also indicate that OLFM4 is regulated by the Ras-NF-κB2 pathway, one of the main oncogenic pathways deregulated in colorectal tumors.


Fontaine B.,French Institute of Health and Medical Research
Handbook of Clinical Neurology | Year: 2013

Muscle channelopathies and related disorders are neuromuscular disorders predominantly of genetic origin which are caused by mutations in ion channels or genes that play a role in muscle excitability. They include different forms of periodic paralysis which are characterized by acute and reversible attacks of muscle weakness concomitant to changes in blood potassium levels. These disorders may also present as distinguishable myotonic syndromes (slowed muscle relaxation) which have in common lack of involvement of dystrophic changes of the muscle, in contrast to dystrophia myotonica. Recent advances have been made in the diagnosis of these different disorders, which require, in addition to a careful clinical evaluation, detailed EMG and molecular study. Although these diseases are rare, they deserve attention since patients may benefit from drugs which can dramatically improve their condition. Patients may have atypical presentations, sometimes life-threatening, which may delay a proper diagnosis, mostly in the first months of life. The creation of specialized reference centers in the Western world has greatly benefited the proper recognition of these neuromuscular diseases. © 2013 Elsevier B.V.


Beuers U.,Tytgat Institute for Liver and Intestinal Research | Trauner M.,Medical University of Vienna | Jansen P.,Tytgat Institute for Liver and Intestinal Research | Poupon R.,French Institute of Health and Medical Research
Journal of Hepatology | Year: 2015

Cholestasis is an impairment of bile formation/flow at the level of the hepatocyte and/or cholangiocyte. The first, and for the moment, most established medical treatment is the natural bile acid (BA) ursodeoxycholic acid (UDCA). This secretagogue improves, e.g. in intrahepatic cholestasis of pregnancy or early stage primary biliary cirrhosis, impaired hepatocellular and cholangiocellular bile formation mainly by complex post-transcriptional mechanisms. The limited efficacy of UDCA in various cholestatic conditions urges for development of novel therapeutic approaches. These include nuclear and membrane receptor agonists and BA derivatives. The nuclear receptors farnesoid X receptor (FXR), retinoid X receptor (RXR), peroxisome proliferator-activated receptor α (PPARα), and pregnane X receptor (PXR) are transcriptional modifiers of bile formation and at present are under investigation as promising targets for therapeutic interventions in cholestatic disorders. The membrane receptors fibroblast growth factor receptor 4 (FGFR4) and apical sodium BA transporter (ASBT) deserve attention as additional therapeutic targets, as does the potential therapeutic agent norUDCA, a 23-C homologue of UDCA. Here, we provide an overview on established and future promising therapeutic agents and their potential molecular mechanisms and sites of action in cholestatic diseases. © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.


Idee J.-M.,Research and Innovation Division | Guiu B.,French Institute of Health and Medical Research
Critical Reviews in Oncology/Hematology | Year: 2013

Hepatocellular carcinoma (HCC) remains a major public health problem. Transarterial chemoembolization (TACE) is recognized as the standard of care for patients with unresectable, asymptomatic, noninvasive and multinodular HCC. This procedure is based on percutaneous administration of a cytotoxic drug emulsified with Lipiodol followed by embolization of the tumour-feeding arteries. The standard procedure involves Lipiodol, an oily contrast medium which consists of a mixture of long-chain di-iodinated ethyl esters of poppy seed fatty acids. The aim of this review is to discuss the physical properties, tumour uptake behaviour and drug delivery effects of Lipiodol, the parameters influencing tumour uptake and future prospects.Lipiodol has a unique place in TACE as it combines three specific characteristics: drug delivery, transient and plastic embolization and radiopacity properties. Substantial heterogeneity in the physicochemical characteristics of Lipiodol/cytotoxic agent emulsions might reduce the efficacy of this procedure and justifies the current interest in Lipiodol for drug delivery. © 2013 Elsevier Ireland Ltd.


Rubinstein E.,French Institute of Health and Medical Research | Rubinstein E.,University Paris - Sud
Biochemical Society Transactions | Year: 2011

Tetraspanins compose a family of structurally related molecules with four transmembrane domains. A total of 33 tetraspanins are present in the human genome, and tetraspanins are also found in plants and certain fungi. A well-known property of tetraspanins is their ability to interact with one another and many other surface proteins, which led to the suggestion that they organize a network of molecular interaction referred to as the 'tetraspanin web', and that they play a role in membrane compartmentalization. Recent studies of the dynamics of these molecules provided important new information that helped refining the models of this 'web'. Several genetic studies in mammals and invertebrates have demonstrated key physiological roles for some of the tetraspanins, in particular in immune response, sperm-egg fusion, photoreceptor function and the normal function of certain epitheliums or vascular development. However, in several examples, the phenotypes of tetraspanin-knockout mice are relatively mild or restricted to a particular organ, despite a wide tissue distribution. ©The Authors Journal compilation ©2011 Biochemical Society.


Heard E.,French Institute of Health and Medical Research
Cold Spring Harbor perspectives in biology | Year: 2011

The sex chromosomes play a highly specialized role in germ cell development in mammals, being enriched in genes expressed in the testis and ovary. Sex chromosome abnormalities (e.g., Klinefelter [XXY] and Turner [XO] syndrome) constitute the largest class of chromosome abnormalities and the commonest genetic cause of infertility in humans. Understanding how sex-gene expression is regulated is therefore critical to our understanding of human reproduction. Here, we describe how the expression of sex-linked genes varies during germ cell development; in females, the inactive X chromosome is reactivated before meiosis, whereas in males the X and Y chromosomes are inactivated at this stage. We discuss the epigenetics of sex chromosome inactivation and how this process has influenced the gene content of the mammalian X and Y chromosomes. We also present working models for how perturbations in sex chromosome inactivation or reactivation result in subfertility in the major classes of sex chromosome abnormalities.


Castanier C.,French Institute of Health and Medical Research | Arnoult D.,University Paris - Sud
Biochimica et Biophysica Acta - Molecular Cell Research | Year: 2011

Viruses have developed a battery of distinct strategies to overcome the very sophisticated defense mechanisms of the infected host. Throughout the process of pathogen-host co-evolution, viruses have therefore acquired the capability to prevent host cell apoptosis because elimination of infected cells via apoptosis is one of the most ancestral defense mechanism against infection. Conversely, induction of apoptosis may favor viral dissemination as a result of the dismantlement of the infected cells. Mitochondria have been long recognized for their key role in the modulation of apoptosis but more recently, mitochondria have been shown to serve as a crucial platform for innate immune signaling as illustrated by the identification of MAVS. Thus, it is therefore not surprising that this organelle represents a recurrent target for viruses, aiming to manipulate the fate of the infected host cell or to inhibit innate immune response. In this review, we highlight the viral proteins that are specifically targeted to the mitochondria to subvert host defense. This article is part of a Special Issue entitled Mitochondria: the deadly organelle. © 2010 Elsevier B.V.


Brozzoli C.,Karolinska Institutet | Ehrsson H.H.,Karolinska Institutet | Farne A.,French Institute of Health and Medical Research
Neuroscientist | Year: 2014

When interacting with objects and other people, the brain needs to locate our limbs and the relevant visual information surrounding them. Studies on monkeys showed that information from different sensory modalities converge at the single cell level within a set of interconnected multisensory frontoparietal areas. It is largely accepted that this network allows for multisensory processing of the space surrounding the body (peripersonal space), whose function has been linked to the sensory guidance of appetitive and defensive movements, and localization of the limbs in space. In the current review, we consider multidisciplinary findings about the processing of the space near the hands in humans and offer a convergent view of its functions and underlying neural mechanisms. We will suggest that evolution has provided the brain with a clever tool for representing visual information around the hand, which takes the hand itself as a reference for the coding of surrounding visual space. We will contend that the hand-centered representation of space, known as perihand space, is a multisensory-motor interface that allows interaction with the objects and other persons around us. © 2013 The Author(s).


Chedotal A.,French Institute of Health and Medical Research | Chedotal A.,Paris-Sorbonne University | Chedotal A.,French National Center for Scientific Research
Trends in Neurosciences | Year: 2014

Commissural neurons project their axons across the midline of the nervous system to contact neurons on the opposite side. Although their existence has been known for more than a century, the function of brain commissures, as well as their diversity and evolutionary advantage, are far from understood. Recent genetic studies in mammals have led to the identification of subsets of commissural neurons, which, in the hindbrain and spinal cord, control the tuning and bilateral coordination of locomotion. The molecular mechanisms and transcriptional programs which specify axonal laterality during development are also now being elucidated. Finally, new studies have confirmed that axonal laterality is plastic and that facilitating the commissural sprouting of axon collaterals might influence functional recovery after brain injury. © 2014 Elsevier Ltd.


Jacquet P.O.,University of Bologna | Jacquet P.O.,French Institute of Health and Medical Research | Avenanti A.,University of Bologna
Cerebral Cortex | Year: 2015

Watching others grasping and using objects activates an action observation network (AON), including inferior frontal (IFC), anterior intraparietal (AIP), and somatosensory cortices (S1). Yet, causal evidence of the differential involvement of such AON sensorimotor nodes in representing high- and low-level action components (i.e., end-goals and grip type) is meager. To address this issue, we used transcranial magnetic stimulation-adaptation (TMS-A) during 2 novel action perception tasks. Participants were shown adapting movies displaying a demonstrator performing goal-directed actions with a tool, using either power or precision grips. They were then asked to match the end-goal (Goal-recognition task) or the grip (Grip-recognition task) of actions shown in test pictures to the adapting movies. TMS was administered over IFC, AIP, or S1 during presentation of test pictures. Virtual lesion-like effects were found in the Grip-recognition task where IFC stimulation induced a general performance decrease, suggesting a critical role of IFC in perceiving grips. In the Goal-recognition task, IFC and S1 stimulation differently affected the processing of "adapted" and "nonadapted" goals. These "state-dependent" effects suggest that the overall goal of seen actions is encoded into functionally distinct and spatially overlapping neural populations in IFC-S1 and such encoding is critical for recognizing and understanding end-goals. © 2013 The Author.


Favier J.,French Institute of Health and Medical Research | Amar L.,Assistance Publique Hopitaux de Paris | Gimenez-Roqueplo A.-P.,University of Paris Descartes
Nature Reviews Endocrinology | Year: 2015

Paragangliomas and phaeochromocytomas are neuroendocrine tumours whose pathogenesis and progression are very strongly influenced by genetics. A germline mutation in one of the susceptibility genes identified so far explains â 1/440% of all cases; the remaining 60% are thought to be sporadic cases. At least one-third of these sporadic tumours contain a somatic mutation in a predisposing gene. Genetic testing, which is indicated in every patient, is guided by the clinical presentation as well as by the secretory phenotype and the immunohistochemical characterization of the tumours. The diagnosis of an inherited form drives clinical management and tumour surveillance. Different 'omics' profiling methods have provided a neat classification of these tumours in accordance with their genetic background. Transcriptomic studies have identified two main molecular pathways that underlie development of these tumours, one in which the hypoxic pathway is activated (cluster 1) and another in which the MAPK and mTOR (mammalian target of rapamycin) signalling pathways are activated (cluster 2). DNA methylation profiling has uncovered a hypermethylator phenotype in tumours related to SDHx genes (a group of genes comprising SDHA, SDHB, SDHC, SDHD and SDHAF2) and revealed that succinate acts as an oncometabolite, inhibiting 2-oxoglutarate-dependent dioxygenases, such as hypoxia-inducible factor prolyl-hydroxylases and histone and DNA demethylases. 'Omics' data have suggested new therapeutic targets for patients with a malignant tumour. In the near future, new 'omics'-based tests are likely to be transferred into clinical practice with the goal of establishing personalized medical management for affected patients. © 2015 Macmillan Publishers Limited. All rights reserved.


The increasing Internet coverage and the widespread use of digital devices offer the possibility to develop new digital surveillance systems potentially capable to provide important aid to epidemiological and public health monitoring and research. In France, a new nationwide surveillance system for influenza-like illness, GrippeNet.fr, was introduced since the 2011/2012 season based on an online participatory mechanism and open to the general population. We evaluate the recruitment and participation of users to the first pilot season with respect to similar efforts in Europe to assess the feasibility of establishing a participative network of surveillance in France. We further investigate the representativeness of the GrippeNet.fr population along a set of indicators on geographical, demographic, socio-economic and health aspects. Participation was widespread in the country and with rates comparable to other European countries with partnered projects running since a longer time. It was not representative of the general population in terms of age and gender, however all age classes were represented, including the older classes (65+ years old), generally less familiar with the digital world, but considered at high risk for influenza complications. Once adjusted on demographic indicators, the GrippeNet.fr population is found to be more frequently employed, with a higher education level and vaccination rate with respect to the general population. A similar propensity to commute for work to different regions was observed, and no significant difference was found for asthma and diabetes. Results show the feasibility of the system, provide indications to inform adjusted epidemic analyses, and highlight the presence of specific population groups that need to be addressed by targeted communication strategies to achieve a higher representativeness in the following seasons.


Ikeda Y.,GCOE Research Group | Ikeda Y.,French Institute of Health and Medical Research
Plant and Cell Physiology | Year: 2012

Genomic imprinting is an epigenetic phenomenon found in mammals and flowering plants that leads to differential allelic gene expression depending on their parent of origin. In plants, genomic imprinting primarily occurs in the endosperm, and it is associated with seed development. The imprinted expression is driven by the epigenetic memory programmed in each lineage of female and male germlines. Several imprinted genes have been identified based on genetic studies in maize and Arabidopsis. Recent advances in genome-wide analyses made it possible to identify multiple imprinted genes including many nuclear proteins, such as transcription factors and chromatin-related proteins in different plant species. Some of these genes are conserved in Arabidopsis, rice and maize, but many are species specific. Genome-wide analyses also clarified the regulation mechanism of imprinted genes orchestrated by DNA methylation and histone methylation marks. Additionally, genetic analyses using Arabidopsis revealed new regulatory factors of DNA demethylation and imprinting and shed light on the more precise mechanisms. © 2012 The Author.


Jardin F.,French Institute of Health and Medical Research | Figeac M.,Lille 2 University of Health and Law
Current Opinion in Oncology | Year: 2013

PURPOSE OF REVIEW: The crucial role of microRNAs (miRNAs) in major biological processes and cancer development has been extensively described. Some stage-specific miRNAs are involved in B-cell differentiation, from the naïve B-cell stage through germinal center maturation. Assuming that lymphoma cells are derived from B cells at different stages of maturation, miRNAs can be considered as both specific markers and putative target genes. Here, we review the most salient recent publications in this field, highlighting the clinical and therapeutic value of miRNAs in lymphomas. RECENT FINDINGS: miRNA array-based experiments have indicated that almost all mature lymphoid malignancies can be characterized by a distinct miRNA profile. Recent works have highlighted the crucial roles of miR-155 and miR-17-92 in the pathogeneses of diffuse large B-cell lymphoma and mantle cell lymphoma, respectively, indicating that they represent promising target genes. Novel mechanisms of miRNA deregulation have also been reported, including recurrent somatic mutations, MYC-driven miRNA repression, and cross-talk with other cells in the microenvironment. SUMMARY: In experimental models, some lymphomas are considered to be addicted to the sustained expression of targetable oncomiRs, such as miR-155 and miR-21. However, despite these results, which provide considerable information regarding lymphoma pathogenesis, the integration of miRNA analysis for lymphoma diagnosis or treatment in daily practice remains challenging. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Parks S.K.,University of Nice Sophia Antipolis | Chiche J.,French Institute of Health and Medical Research | Pouyssegur J.,University of Nice Sophia Antipolis | Pouyssegur J.,Center Scientifique Of Monaco
Nature Reviews Cancer | Year: 2013

Intense interest in the 'Warburg effect' has been revived by the discovery that hypoxia-inducible factor 1 (HIF1) reprogrammes pyruvate oxidation to lactic acid conversion; lactic acid is the end product of fermentative glycolysis. The most aggressive and invasive cancers, which are often hypoxic, rely on exacerbated glycolysis to meet the increased demand for ATP and biosynthetic precursors and also rely on robust pH-regulating systems to combat the excessive generation of lactic and carbonic acids. In this Review, we present the key pH-regulating systems and synthesize recent advances in strategies that combine the disruption of pH control with bioenergetic mechanisms. We discuss the possibility of exploiting, in rapidly growing tumours, acute cell death by 'metabolic catastrophe'. © 2013 Macmillan Publishers Limited. All rights reserved.


Benmerah A.,French Institute of Health and Medical Research | Benmerah A.,French National Center for Scientific Research | Benmerah A.,University of Paris Descartes
Current Opinion in Cell Biology | Year: 2013

Cilia are fascinating highly conserved organelles shared by very different organisms from unicellular eukaryotes to vertebrates where they are involved in motility and sensory functions. In vertebrates, the function of the primary cilium, a unique nonmotile cilium found at the surface of most cell types during development, remained mysterious during 40 years until its crucial function in the control of key signaling cascades during development and its involvement in complex genetic disorders now called ciliopathies were uncovered. Recent studies have focused on a specific membrane domain found at the base of primary cilia in most cell types which was already mentioned in the first descriptions of these cilia but did not raise much interest during 50 years. This membrane domain, the 'ciliary pocket', also found at the base of some motile cilia, may act as a platform for cilia-associated vesicular trafficking and as an interface with the actin cytoskeleton but also likely in additional important functions which remain to be discovered. © 2012 Elsevier Ltd.


Potier M.-C.,French Institute of Health and Medical Research
Molecular neurodegeneration | Year: 2014

BACKGROUND: It is suspected that excess of brain cholesterol plays a role in Alzheimer's disease (AD). Membrane-associated cholesterol was shown to be increased in the brain of individuals with sporadic AD and to correlate with the severity of the disease. We hypothesized that an increase of membrane cholesterol could trigger sporadic AD early phenotypes.RESULTS: We thus acutely loaded the plasma membrane of cultured neurons with cholesterol to reach the 30% increase observed in AD brains. We found changes in gene expression profiles that are reminiscent of early AD stages. We also observed early AD cellular phenotypes. Indeed we found enlarged and aggregated early endosomes using confocal and electron microscopy after immunocytochemistry. In addition amyloid precursor protein vesicular transport was inhibited in neuronal processes, as seen by live-imaging. Finally transient membrane cholesterol loading lead to significantly increased amyloid-β42 secretion.CONCLUSIONS: Membrane cholesterol increase in cultured neurons reproduces most early AD changes and could thus be a relevant model for deciphering AD mechanisms and identifying new therapeutic targets.


Mithieux G.,French Institute of Health and Medical Research | Mithieux G.,University Claude Bernard Lyon 1 | Mithieux G.,University of Lyon
Trends in Endocrinology and Metabolism | Year: 2013

The neural sensing of nutrients during food digestion plays a key role in the regulation of hunger. Recent data have emphasized that the extrinsic gastrointestinal nervous system is preponderant in this phenomenon and in its translation to the control of food intake by the central nervous system (CNS). Nutrient sensing by the extrinsic gastrointestinal nervous system may account for the satiation induced by food lipids, the satiety initiated by food protein, and for the rapid benefits of gastric bypass surgeries on both glucose and energy homeostasis. Thus, this recent knowledge provides novel examples of the mechanisms that control food intake and body weight, and this might pave the way for future approaches to the prevention and/or treatment of obesity. © 2013 Elsevier Ltd.


Martin S.G.,University of Lausanne | Arkowitz R.A.,University of Nice Sophia Antipolis | Arkowitz R.A.,French National Center for Scientific Research | Arkowitz R.A.,French Institute of Health and Medical Research
FEMS Microbiology Reviews | Year: 2014

Polarization is a fundamental cellular property, which is essential for the function of numerous cell types. Over the past three to four decades, research using the best-established yeast systems in cell biological research, Saccharomyces cerevisiae (or budding yeast) and Schizosaccharomyces pombe (or fission yeast), has brought to light fundamental principles governing the establishment and maintenance of a polarized, asymmetric state. These two organisms, though both ascomycetes, are evolutionarily very distant and exhibit distinct shapes and modes of growth. In this review, we compare and contrast the two systems. We first highlight common cell polarization pathways, detailing the contribution of Rho GTPases, the cytoskeleton, membrane trafficking, lipids, and protein scaffolds. We then contrast the major differences between the two organisms, describing their distinct strategies in growth site selection and growth zone dimensions and compartmentalization, which may be the basis for their distinct shapes. © 2013 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved.


Simons C.,University of Queensland | Simons C.,Garvan Institute of Medical Research | Simons C.,Acibadem University | Simons C.,University of Liege | And 4 more authors.
Nature genetics | Year: 2015

Temple-Baraitser syndrome (TBS) is a multisystem developmental disorder characterized by intellectual disability, epilepsy, and hypoplasia or aplasia of the nails of the thumb and great toe. Here we report damaging de novo mutations in KCNH1 (encoding a protein called ether à go-go, EAG1 or KV10.1), a voltage-gated potassium channel that is predominantly expressed in the central nervous system (CNS), in six individuals with TBS. Characterization of the mutant channels in both Xenopus laevis oocytes and human HEK293T cells showed a decreased threshold of activation and delayed deactivation, demonstrating that TBS-associated KCNH1 mutations lead to deleterious gain of function. Consistent with this result, we find that two mothers of children with TBS, who have epilepsy but are otherwise healthy, are low-level (10% and 27%) mosaic carriers of pathogenic KCNH1 mutations. Consistent with recent reports, this finding demonstrates that the etiology of many unresolved CNS disorders, including epilepsies, might be explained by pathogenic mosaic mutations.


Crow Y.J.,French Institute of Health and Medical Research | Crow Y.J.,University of Paris Pantheon Sorbonne | Crow Y.J.,University of Manchester
Current Opinion in Immunology | Year: 2015

The concept of grouping Mendelian disorders associated with an up-regulation of type I interferon has only recently been suggested. Here we discuss the progress being made in the delineation and understanding of this novel set of inborn errors of immunity, the human type I interferonopathies. © 2014 Elsevier Ltd.


Chanson P.,French Institute of Health and Medical Research
Neuroendocrinology | Year: 2016

Treatment of acromegaly aims to correct (or prevent) tumor compression of surrounding tissues by excising the disease-causing lesion and reduce growth hormone (GH) and IGF-1 levels to normal values. When surgery (the usual first-line treatment) fails to correct GH/IGF-1 hypersecretion, medical treatment with dopamine agonists (DAs; particularly cabergoline) or somatostatin analogs (SAs) can be used. The GH receptor antagonist pegvisomant is helpful in patients who are totally or partially resistant to SAs and can be given in association with both SAs and/or DAs. Thanks to this multistep therapeutic strategy, adequate hormonal disease control is achieved in most patients, giving them normal life expectancy. Comorbidities associated with acromegaly generally improve after treatment, but persistent sequelae may nonetheless impair quality of life. © 2015 S. Karger AG, Basel. All rights reserved.


Eichel C.A.,French Institute of Health and Medical Research
Circulation Research | Year: 2016

RATIONALE:: Mechanisms underlying membrane protein localization are crucial in the proper function of cardiac myocytes. The main cardiac sodium channel, NaV1.5, carries the sodium current (INa) which provides a rapid depolarizing current during the upstroke of the action potential. While enriched in the intercalated disc (ID), NaV1.5 is present in different membrane domains in myocytes and interacts with several partners. OBJECTIVE:: To test the hypothesis that the Membrane-Associated GUanylate Kinase (MAGUK) protein Calcium/calmodulin-dependent Serine protein Kinase (CASK) interacts with and regulates NaV1.5 in cardiac myocytes. METHODS AND RESULTS:: Immunostaining experiments showed that CASK localizes at lateral membranes (LM) of cardiac myocytes, in association with dystrophin. Whole-cell patch clamp showed that CASK-silencing increases INa in vitro. In vivo CASK knockdown similarly increased INa recorded in freshly isolated myocytes. Pull-down experiments revealed that CASK directly interacts with the C-terminus of NaV1.5. CASK silencing reduces syntrophin expression without affecting NaV1.5 and dystrophin expression levels. Total Internal Reflection Fluorescence microscopy (TIRFm) and biotinylation assays showed that CASK silencing increased the surface expression of NaV1.5 without changing mRNA levels. Quantification of NaV1.5 expression at the LM and ID revealed that the LM pool only was increased upon CASK silencing. The protein transport inhibitor brefeldin-A prevented INa increase in CASK-silenced myocytes. During atrial dilation/remodeling, CASK expression was reduced but its localization unchanged. CONCLUSION:: This study constitutes the first description of an unconventional MAGUK protein, CASK, which directly interacts with NaV1.5 channel and controls its surface expression at the LM by regulating ion channel trafficking. © 2016 American Heart Association, Inc.


Chalker D.L.,Washington University in St. Louis | Meyer E.,French Institute of Health and Medical Research | Mochizuki K.,Austrian Academy of Sciences
Cold Spring Harbor Perspectives in Biology | Year: 2013

Research using ciliates revealed early examples of epigenetic phenomena and continues to provide novel findings. These protozoans maintain separate germline and somatic nuclei that carry transcriptionally silent and active genomes, respectively. Examining the differences in chromatin within distinct nuclei of Tetrahymena identified histone variants and established that transcriptional regulators act by modifying histones. Formation of somatic nuclei requires both transcriptional activation of silent chromatin and large-scale DNA elimination. This somatic genome remodeling is directed by homologous RNAs, acting with an RNA interference (RNAi)-related machinery. Furthermore, the content of the parental somatic genome provides a homologous template to guide this genome restructuring. The mechanisms regulating ciliate DNA rearrangements reveal the surprising power of homologous RNAs to remodel the genome and transmit information transgenerationally. © 2013 Cold Spring Harbor Laboratory Press; all rights reserved.


Zappala G.,Behavioral Neurology Unit | Thiebaut de Schotten M.,Kings College London | Thiebaut de Schotten M.,French Institute of Health and Medical Research | Eslinger P.J.,Penn State Hershey Medical Center
Cortex | Year: 2012

Traumatic brain injury (TBI) is a leading cause of death in the young population and long-term disability in relation to pervasive cognitive-behavioural disturbances that follow frontal lobe damage. To date, emphasis has been placed primarily on the clinical correlates of frontal cortex damage, whilst identification of the contribution of subjacent white matter lesion is less clear. Our poor understanding of white matter pathology in TBI is primarily due to the low sensitivity of conventional neuroimaging to identify pathological changes in less severe traumatic injury and the lack of methods to localise white matter pathology onto individual frontal lobe connections. In this paper we focus on the potential contribution of diffusion tensor imaging (DTI) to TBI. Our review of the current literature supports the conclusion that DTI is particularly sensitive to changes in the microstructure of frontal white matter, thus providing a valuable biomarker of the severity of traumatic injury and prognostic indicator of recovery of function. Furthermore we propose an atlas approach to TBI to map white matter lesions onto individual tracts. In the cases presented here we showed a direct correspondence between the clinical manifestations of the patients and the damage to specific white matter tracts. We are confident that in the near future the application of DTI to TBI will improve our understanding of the complex and heterogeneous clinical symptomatology which follows a TBI, especially mild and moderate head injury, which still represents 70-80% of all clinical population. © 2011 Elsevier Srl.


Vignot S.,French Institute of Health and Medical Research
Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2013

Characterization of the genomic changes that drive an individual patient's disease is critical in management of many cancers. In patients with non-small-cell lung cancer (NSCLC), obtaining tumor samples of sufficient size for genomic profiling on recurrence is often challenging. We undertook this study to compare genomic alterations identified in archived primary tumors from patients with NSCLC with those identified in metachronous or synchronous metastases. Primary and matched metastatic tumor pairs from 15 patients were analyzed by using a targeted next-generation sequencing assay in a Clinical Laboratory Improvement Amendments laboratory. Genomic libraries were captured for 3,230 exons in 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer and sequenced to high coverage. Among 30 tumors, 311 genomic alterations were identified of which 63 were known recurrent (32 in primary tumor, 31 in metastasis) and 248 were nonrecurrent (likely passenger). TP53 mutations were the most frequently observed recurrent alterations (12 patients). Tumors harbored two or more (maximum four) recurrent alterations in 10 patients. Comparative analysis of recurrent alterations between primary tumor and matched metastasis revealed a concordance rate of 94% compared with 63% for likely passenger alterations. This high concordance suggests that for the purposes of genomic profiling, use of archived primary tumor can identify the key recurrent somatic alterations present in matched NSCLC metastases and may provide much of the relevant genomic information required to guide treatment on recurrence.


Coulouarn C.,French Institute of Health and Medical Research | Clement B.,University of Rennes 1
Journal of Hepatology | Year: 2014

Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the most common types of primary tumors in the liver. Although major advances have been made in understanding the cellular and molecular mechanisms underlying liver carcinogenesis, HCC and ICC are still deadly cancers worldwide waiting for innovative therapeutic options. Growing evidence from the literature highlight the critical role of the tumor cell microenvironment in the pathogenesis of cancer diseases. Thus, targeting the microenvironment, particularly the crosstalk between tumor cells and stromal cells, has emerged as a promising therapeutic strategy. This strategy would be particularly relevant for liver cancers which frequently develop in a setting of chronic inflammation and microenvironment remodeling associated with hepatic fibrosis and cirrhosis, such processes in which hepatic stellate cells (HSC) greatly contribute. This review brings a genomic point of view on the alterations of the cellular microenvironment in liver cancers, particularly the stromal tissue within tumor nodules, emphasizing the importance of the crosstalk between tumor cells and stromal cells, notably activated HSC, in tumor onset and progression. Furthermore, potential therapeutic modalities of targeting the stroma and HSC are discussed. © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.


Dumaz N.,French Institute of Health and Medical Research
Small GTPases | Year: 2011

BRAF and RAS are often mutated in cutaneous melanoma and both mutations stimulate the MAPK pathway. However the biological consequences of BRAF and NRAS mutations are different because when RAS is mutated in melanoma, cells use CRAF rather than BRAF to activate MEK/ERK. The mechanism of this BRAF to CRAF isoform switching in response to oncogenic RAS has recently been described. Activation of the MAPK pathway, which results from a mutation of NRAS, induces phosphorylation of BRAF on serine 151 by ERK which prevents its binding to NRAS. To circumvent this negative feedback inhibition of BRAF, melanoma cells containing a mutation of RAS use CRAF to activate MEK/ERK. However, because the cAMP pathway in melanocytes constitutively inhibits CRAF, RAF isoform switching in melanoma is accompanied by an inhibition of the cAMP pathway. This inhibition is due to an increase in phosphodiesterase activity, which degrades cAMP thereby preventing inhibition of CRAF by PKA. These data highlight the importance of CRAF downstream of oncogenic Ras in tumor development. © 2011 Landes Bioscience.


Bechet D.,University of Lorraine | Mordon S.R.,French Institute of Health and Medical Research | Guillemin F.,University of Lorraine | Barberi-Heyob M.A.,University of Lorraine
Cancer Treatment Reviews | Year: 2014

The poor outcome of primary malignant brain tumours is predominantly due to local invasion and local recurrence and their prognosis is highly dependent on the degree of resection. They have no border and, at best, a marginal zone that remains invisible to the surgeon. Photodynamic therapy (PDT) appears to be an interesting modality to fill the need for a targeted treatment that may reduce recurrence and extend survival with minimal side effects.In this review, we summarize the different technologies of brain tumour PDT employed such as interstitial PDT, and PDT-associated surgical resection, describing new light delivery devices. The role of dosimetry - one of the key factors behind successful brain tumour PDT - is discussed. This can be achieved by integrating results from in vivo studies. In this context, the development of new therapeutic photosensitizer delivery systems is also an area of significant research interest. Multifunctionality can be engineered into a single nanoplatform to provide tumour-specific detection, treatment, and follow-up. Such multitasking systems appear to be complementary to conventional technologies. © 2012 Elsevier Ltd.


Bensaude O.,French Institute of Health and Medical Research
Transcription | Year: 2011

This review first discusses ways in which we can evaluate transcription inhibition, describe changes in nuclear structure due to transcription inhibition, and report on genes that are paradoxically stimulated by transcription inhibition. Next, it summarizes the characteristics and mechanisms of commonly used inhibitors: α-amanitin is highly selective for RNAP II and RNAP III but its action is slow, actinomycin D is fast but its selectivity is poor, CDK9 inhibitors such as DRB and flavopiridol are fast and reversible but many genes escape transcription inhibition. New compounds, such as triptolide, are fast and selective and able to completely arrest transcription by triggering rapid degradation of RNAP II. © 2011 Landes Bioscience.


Ma E.,CEA Saclay Nuclear Research Center | Hyrien O.,French Institute of Health and Medical Research | Goldar A.,CEA Saclay Nuclear Research Center
Nucleic Acids Research | Year: 2012

Recent studies of eukaryotic DNA replication timing profiles suggest that the time-dependent rate of origin firing, I(t), has a universal shape, which ensures a reproducible replication completion time. However, measurements of I(t) are based on population averages, which may bias the shape of the I(t) because of imperfect cell synchrony and cell-to-cell variability. Here, we measure the population-averaged I(t) profile from synchronized Saccharomyces cerevisiae cells using DNA combing and we extract the single-cell I(t) profile using numerical deconvolution. The single cell I(t) and the population-averaged I(t) extracted from DNA combing and replication timing profiles are similar, indicating a genome scale invariance of the replication process, and excluding cell-to-cell variability in replication time as an explanation for the shape of I(t). The single cell I(t) correlates with fork density in wild-type cells, which is specifically loosened in late S phase in the clb5Δ mutant. A previously proposed numerical model that reproduces the wild-type I(t) profile, could also describe the clb5Δ mutant I(t) once modified to incorporate the decline in CDK activity and the looser dependency of initiation on fork density in the absence of Clb5p. Overall, these results suggest that the replication forks emanating from early fired origins facilitate origin firing in later-replicating regions. © 2011 The Author(s).


Asselah T.,French Institute of Health and Medical Research
Journal of Hepatology | Year: 2010

Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Dongliang Ge, Jacques Fellay, Alexander J. Thompson, Jason S. Simon, Kevin V. Shianna, Thomas J. Urban, Erin L. Heinzen, Ping Qiu, Arthur H. Bertelsen, Andrew J. Muir, Mark Sulkowski, John G. McHutchison, David B. Goldstei. Abstract reprinted by permission from Macmillan Publishers Ltd: Nature 200;461(7262):399-401. copyright 2009. Abstract: Chronic infection with hepatitis C virus (HCV) affects 170 million people worldwide and is the leading cause of cirrhosis in North America. Although the recommended treatment for chronic infection involves a 48-week course of peginterferon-2b (PegIFN-2b) or -2a (PegIFN-2a) combined with ribavirin (RBV), it is well known that many patients will not be cured by treatment, and that patients of European ancestry have a significantly higher probability of being cured than patients of African ancestry. In addition to limited efficacy, treatment is often poorly tolerated because of side effects that prevent some patients from completing therapy. For these reasons, identification of the determinants of response to treatment is a high priority. Here we report that a genetic polymorphism near the IL28B gene, encoding interferon-3 (IFN-3), is associated with an approximately twofold change in response to treatment, both among patients of European ancestry (P = 1.06 10-25) and African-Americans (P = 2.06 10-30). Because the genotype leading to better response is in substantially greater frequency in European than African populations, this genetic polymorphism also explains approximately half of the difference in response rates between African-Americans and patients of European ancestry. © 2010.


King J.R.,French Institute of Health and Medical Research
Philosophical transactions of the Royal Society of London. Series B, Biological sciences | Year: 2014

Subliminal perception studies have shown that one can objectively discriminate a stimulus without subjectively perceiving it. We show how a minimalist framework based on Signal Detection Theory and Bayesian inference can account for this dissociation, by describing subjective and objective tasks with similar decision-theoretic mechanisms. Each of these tasks relies on distinct response classes, and therefore distinct priors and decision boundaries. As a result, they may reach different conclusions. By formalizing, within the same framework, forced-choice discrimination responses, subjective visibility reports and confidence ratings, we show that this decision model suffices to account for several classical characteristics of conscious and unconscious perception. Furthermore, the model provides a set of original predictions on the nonlinear profiles of discrimination performance obtained at various levels of visibility. We successfully test one such prediction in a novel experiment: when varying continuously the degree of perceptual ambiguity between two visual symbols presented at perceptual threshold, identification performance varies quasi-linearly when the stimulus is unseen and in an 'all-or-none' manner when it is seen. The present model highlights how conscious and non-conscious decisions may correspond to distinct categorizations of the same stimulus encoded by a high-dimensional neuronal population vector.


Yip S.-C.,Fox Chase Cancer Center | Cottere S.,French Institute of Health and Medical Research | Chernoff J.,Fox Chase Cancer Center
Journal of Cell Science | Year: 2012

Protein tyrosine phosphatase (PTP)1B is an abundant non-transmembrane enzyme that plays a major role in regulating insulin and leptin signaling. Recently, we reported that PTP1B is inhibited by sumoylation, and that sumoylated PTP1B accumulates in a perinuclear distribution, consistent with its known localization in the endoplasmic reticulum (ER) and the contiguous outer nuclear membrane. Here, we report that, in addition to its localization at the ER, PTP1B also is found at the inner nuclear membrane, where it is heavily sumoylated. We also find that PTP1B interacts with emerin, an inner nuclear membrane protein that is known to be tyrosine phosphorylated, and that PTP1B expression levels are inversely correlated with tyrosine phosphorylation levels of emerin. PTP1B sumoylation greatly increases as cells approach mitosis, corresponding to the stage where tyrosine phosphorylation of emerin is maximal. In addition, expression of a non- sumoylatable mutant of PTP1B greatly reduced levels of emerin tyrosine phosphorylation. These results suggest that PTP1B regulates the tyrosine phosphorylation of a key inner nuclear membrane protein in a sumoylation- and cell-cycle-dependent manner. © 2012.


Carvalho F.A.,Clermont University | Carvalho F.A.,French Institute of Health and Medical Research | Aitken J.D.,Georgia State University | Vijay-Kumar M.,Georgia State University | Gewirtz A.T.,Georgia State University
Annual Review of Physiology | Year: 2012

The well-being of the intestine and its host requires that this organ execute its complex function amid colonization by a large and diverse microbial community referred to as the gut microbiota. A myriad of interacting mechanisms of mucosal immunity permit the gut to corral the microbiota in such a way as to maximize the benefits and to minimize the danger of living in close proximity to this large microbial biomass. Toll-like receptors and Nod-like receptors, collectively referred to as pattern recognition receptors (PRRs), recognize a variety of microbial components and, hence, play a central role in governing the interface between host and microbiota. This review examines mechanisms by which PRR-microbiota interactions are regulated so as to allow activation of host defense when necessary while preventing excessive inflammation, which can have a myriad of negative consequences for the host. Analysis of published studies performed in human subjects and a variety of murine disease models reveals the central theme that PRRs play a key role in maintaining a healthful stable relationship between the intestine and its microbiota. In contrast, although select genetic ablations of PRR signaling may protect against some chronic diseases, the overriding theme of studies performed to date is that perturbations of PRR-microbiota interactions are more likely to promote disease states associated with inflammation. Copyright © 2012 by Annual Reviews. All rights reserved.


Antherieu S.,French Institute of Health and Medical Research
Toxicology in vitro : an international journal published in association with BIBRA | Year: 2012

The HepaRG cell line is the first human cell line able to differentiate in vitro into mature hepatocyte-like cells. Our main objective within the framework of the EEC-LIINTOP project was to optimize the use of this cell line for drug metabolism and toxicity studies, especially after repeat treatments. The main results showed that differentiated HepaRG cells: (i) retained their drug metabolism capacity (major CYPs, phase 2 enzymes, transporters and nuclear receptors) and responsiveness to prototypical inducers at relatively stable levels for several weeks at confluence. The levels of several functions, including some CYPs such as CYP3A4, were dependent on the addition of dimethyl sulfoxide in the culture medium; (ii) sustained the different types of chemical-induced hepatotoxicity, including steatosis, phospholipidosis and cholestasis, after acute and/or repeat treatment with reference drugs. In particular, drug-induced vesicular steatosis was demonstrated in vitro for the first time. In conclusion, our results from the LIINTOP project, together with other studies reported concomitantly or more recently in the literature, support the conclusion that the metabolically competent human HepaRG cells represent a surrogate to primary human hepatocytes for investigating drug metabolism parameters and both acute and chronic effects of xenobiotics in human liver. Copyright © 2012 Elsevier Ltd. All rights reserved.


Ben-Ari Y.,French Institute of Health and Medical Research
Neuroscience | Year: 2014

The developing brain is talkative but its language is not that of the adult. Most if not all voltage and transmitter-gated ionic currents follow a developmental sequence and network-driven patterns differ in immature and adult brains. This is best illustrated in studies engaged almost three decades ago in which we observed elevated intracellular chloride (Cl-)i levels and excitatory GABA early during development and a perinatal excitatory/inhibitory shift. This sequence is observed in a wide range of brain structures and animal species suggesting that it has been conserved throughout evolution. It is mediated primarily by a developmentally regulated expression of the NKCC1 and KCC2 chloride importer and exporter respectively. The GABAergic depolarization acts in synergy with N-methyl-d-aspartate (NMDA) receptor-mediated and voltage-gated calcium currents to enhance intracellular calcium exerting trophic effects on neuritic growth, migration and synapse formation. These sequences can be deviated in utero by genetic or environmental insults leading to a persistence of immature features in the adult brain. This "neuroarcheology" concept paves the way to novel therapeutic perspectives based on the use of drugs that block immature but not adult currents. This is illustrated notably with the return to immature high levels of chloride and excitatory actions of GABA observed in many pathological conditions. This is due to the fact that in the immature brain a down regulation of KCC2 and an up regulation of NKCC1 are seen. Here, I present a personal history of how an unexpected observation led to novel concepts in developmental neurobiology and putative treatments of autism and other developmental disorders. Being a personal account, this review is neither exhaustive nor provides an update of this topic with all the studies that have contributed to this evolution. We all rely on previous inventors to allow science to advance. Here, I present a personal summary of this topic primarily to illustrate why we often fail to comprehend the implications of our own observations. They remind us - and policy deciders - why Science cannot be programed, requiring time, and risky investigations that raise interesting questions before being translated from bench to bed. Discoveries are always on sideways, never on highways. © 2014 The Author.


Nordmann P.,French Institute of Health and Medical Research | Nordmann P.,University of Fribourg
Medecine et Maladies Infectieuses | Year: 2014

Bacterial resistance to antibiotics has become a major source of concern for public health. Enterobacteriaceae are among the most common human pathogens, causing community-acquired as well as hospital-acquired infections. Carbapenem-resistant Enterobacteriaceae have been increasingly reported worldwide since their first identification more than 20years ago. Three main classes of carbapenemases have been identified: Ambler classA beta-lactamase (KPC), classB (metallo-enzymes), and classD (OXA-48 type). Klebsiella pneumoniae carbapenemases (KPC) was first reported in the United States in the late 1990s and since then worldwide, with a marked endemicity in the United States, Greece, and now Italy. Carbapenemase NDM-1 (New Delhi metallo-beta-lactamase-1) is one of the most recently reported metallo-enzymes. It has spread widely in the Indian sub-continent and now worldwide. Carbapenemases of the oxacillinase-48 type (OXA-48) have been identified mostly in Mediterranean and southern European countries with a rapid spread. An early and quick identification of carbapenemase-producing infected patients, but also of carriers, is mandatory to prevent the spread of these highly resistant pathogens. The early identification of carriers and implementing of cohorting strategies is the only means to prevent nosocomial outbreaks caused by carbapenemase, with very few, if any, therapeutic options. © 2013 Elsevier Masson SAS.


Roubaud-Baudron C.,French Institute of Health and Medical Research
Neurobiology of aging | Year: 2012

Recent case-control studies reported an association between H. pylori infection and Alzheimer's disease (AD). Our aim was to compare cognitive impairment, neuroinflammation, and cerebrovascular lesion load in a group of AD patients according to their H. pylori status. For the 53 AD patients included, we assessed: clinical data (vascular comorbidities and cognitive assessment), biological data (especially fibrinogen, homocysteine levels, apolipoprotein E4 genotype; cerebrospinal fluid [CSF] total tau protein [Tau], phospho-tau(181) protein [pTau(181)]), and amyloid beta peptide levels, serum/CSF-cytokines (interleukin [IL]-1β, IL-6, IL-8, tumor necrosis factor [TNF]-α) and pepsinogen I/pepsinogen II (PgI/PgII) ratio, and cerebrovascular lesion load (magnetic resonance imaging [MRI] fluid-attenuated inversion recovery [FLAIR] with the Fazekas and Schmidt scale). H. pylori infection was diagnosed by enzyme-linked immunosorbent assay (ELISA) and immunoblot test. H. pylori infection was associated with a decreased Mini Mental State Examination (MMS) (p = 0.024), and higher CSF pTau(181) (p = 0.014) and tau (p = 0.021) levels. A decreased PgI/II ratio (i.e., an increased gastric atrophy) was associated with the infection (p = 0.005). Homocysteine levels were positively correlated to Fazekas score (r = 0.34; p = 0.032) and to H. pylori immunoglobulin (Ig)G levels (r = 0.44; p = 0.001). Higher CSF cytokine levels (IL-8, p = 0.003; TNF-α, p = 0.019) were associated with the infection, but systemic inflammation results were controversial. Finally, in multivariate analysis, a lower MMSE score (odds ratio [OR], 0.83 [0.72-0.97]; p = 0.017), plasma IL-1β level (OR, 0.31 [0.11-0.87]; p = 0.025), an increased gastric atrophy, i.e., a lower PgI/PgII ratio (OR, 0.63 [0.43-0.93]; p = 0.020) were still associated with the infection. AD patients infected by H. pylori tended to be more cognitively impaired. Studies are needed to attest to the impact of H. pylori infection on AD course, especially on cerebrovascular lesions and neuroinflammation. Copyright © 2012 Elsevier Inc. All rights reserved.


Merino M.M.,University of Bern | Rhiner C.,University of Bern | Lopez-Gay J.M.,University of Bern | Lopez-Gay J.M.,French Institute of Health and Medical Research | And 3 more authors.
Cell | Year: 2015

Viable yet damaged cells can accumulate during development and aging. Although eliminating those cells may benefit organ function, identification of this less fit cell population remains challenging. Previously, we identified a molecular mechanism, based on "fitness fingerprints" displayed on cell membranes, which allows direct fitness comparison among cells in Drosophila. Here, we study the physiological consequences of efficient cell selection for the whole organism. We find that fitness-based cell culling is naturally used to maintain tissue health, delay aging, and extend lifespan in Drosophila. We identify a gene, azot, which ensures the elimination of less fit cells. Lack of azot increases morphological malformations and susceptibility to random mutations and accelerates tissue degeneration. On the contrary, improving the efficiency of cell selection is beneficial for tissue health and extends lifespan. © 2015 The Authors.


Reme T.,French Institute of Health and Medical Research
Bioinformatics (Oxford, England) | Year: 2013

Despite huge prognostic promises, gene expression-based survival assessment is rarely used in clinical routine. Main reasons include difficulties in performing and reporting analyses and restriction in most methods to one high-risk group with the vast majority of patients being unassessed. The present study aims at limiting these difficulties by (i) mathematically defining the number of risk groups without any a priori assumption; (ii) computing the risk of an independent cohort by considering each patient as a new patient incorporated to the validation cohort and (iii) providing an open-access Web site to freely compute risk for every new patient. Using the gene expression profiles of 551 patients with multiple myeloma, 602 with breast-cancer and 460 with glioma, we developed a model combining running log-rank tests under controlled chi-square conditions and multiple testing corrections to build a risk score and a classification algorithm using simultaneous global and between-group log-rank chi-square maximization. For each cancer entity, we provide a statistically significant three-group risk prediction model, which is corroborated with publicly available validation cohorts. In constraining between-group significances, the risk score compares favorably with previous risk classifications. Risk assessment is freely available on the Web at https://gliserv.montp.inserm.fr/PrognoWeb/ for personal or test data files. Web site implementation in Perl, R and Apache.


Scoazec J.Y.,French Institute of Health and Medical Research
Journal of visceral surgery | Year: 2013

Incidentally discovered cystic tumors of the pancreas (CTP) are an increasingly frequent entity. It is essential to differentiate lesions whose malignant potential is either nil or negligible (pseudocyst, serous cystadenoma, simple cysts) from lesions with intermediate malignant potential (intraductal papillary mucinous tumor of the pancreas [IPMN] involving the secondary ducts, cystic endocrine tumor) or those with high malignant potential (mucinous cystadenoma, solid pseudopapillary tumors and IPMN involving the main pancreatic duct). The approach to defining malignant potential is based on diagnostic CT scan, magnetic resonance imaging (MRI), and endoscopic ultrasound (EUS), often complemented by EUS-guided cyst puncture for biochemical and cytological analysis of cyst fluid. Surgery for diagnostic purposes should be avoided because of its significant morbidity. For pseudocysts, simple cysts and serous cystadenomas, abstention is the general rule. Resection, preserving as much pancreatic parenchyma as possible, is the rule for IPMN involving the main pancreatic duct, mucinous cystadenomas, solid and pseudopapillary tumors, and cystic endocrine tumors. Resection is rarely indicated at the outset for IPMN involving secondary pancreatic ducts; morphologic observation is the general rule and preventive excision may be indicated secondarily. Good collaboration between surgeons, radiologists and endosonographists is necessary for optimal management of CTP. Copyright © 2013. Published by Elsevier Masson SAS.


Lartigue L.,French Institute of Health and Medical Research | Faustin B.,University of Bordeaux Segalen
International Journal of Biochemistry and Cell Biology | Year: 2013

Higher vertebrates have developed protective mechanisms that can detect stress-induced agents expressed during infection, stress or cellular damage. Innate sensing of these agents by Pattern Recognition Receptors enables downstream adaptive immunity to be primed, thereby mediating the body's appropriate response. Mitochondria, known as the cell powerhouse, have recently emerged as crucial regulators of the innate immune response to both pathogen infections and cell stress in various cell types unrestricted to immune cells. These highly dynamic organelles host numerous innate immune signaling modulators, of which some are directly linked to oxidative phosphorylation capacity and its control of oxidative stress. Therefore, mitochondrial bioenergetics is tightly connected to innate immunity and the extent of the immune response. In this short review, we shed light on how this bacteria "within" orchestrates innate immune responses at different levels by promoting a cellular metabolic reprogramming necessary to enhance energy synthesis, and the release of host danger signals to alert subsequent cytosolic immune signaling cascades. © 2013 Elsevier Ltd. All rights reserved.


Guguen-Guillouzo C.,French Institute of Health and Medical Research
Methods in molecular biology (Clifton, N.J.) | Year: 2010

In vitro hepatocyte models represent very useful systems in both fundamental research and various application areas. Primary hepatocytes appear as the closest model for the liver in vivo. However, they are phenotypically unstable, have a limited life span and in addition, exhibit large interdonor variability when of human origin. Hepatoma cell lines appear as an alternative but only the HepaRG cell line exhibits various functions, including major cytochrome P450 activities, at levels close to those found in primary hepatocytes. In vitro hepatocyte models have brought a substantial contribution to the understanding of the biochemistry, physiology, and cell biology of the normal and diseased liver and in various application domains such as xenobiotic metabolism and toxicity, virology, parasitology, and more generally cell therapies. In the future, new well-differentiated hepatocyte cell lines derived from tumors or from either embryonic or adult stem cells might be expected and although hepatocytes will continue to be used in various fields, these in vitro liver models should allow marked advances, especially in cell-based therapies and predictive and mechanistic hepatotoxicity of new drugs and other chemicals. All models will benefit from new developments in throughput screening based on cell chips coupled with high-content imaging and in toxicogenomics technologies.


Castellana D.,French Institute of Health and Medical Research
Thrombosis research | Year: 2010

Thrombotic complications have been documented in patients with cancer, and associated with tumor progression. Cancer patients have an increased level of circulating submicrometric (0.1-1 microm) membrane fragments termed microvesicles (MV) or microparticles. Variations in MV levels and phenotypes make them relevant pathogenic markers of thrombotic disorders and vascular damage. MV are released from the plasma membrane of activated or apoptotic cells, and are considered efficient effectors of the hemostatic or thrombotic responses. They are mostly characterized by the presence of procoagulant phospholipids at their surface and eventually that of tissue factor depending on the cells they originate from. These procoagulant entities allow them to initiate and propagate thrombotic reactions within the blood vessels. MV are also recognized as proximal or remote mediators of cell-to-cell communication. The mechanisms through which MV interact with target cells remain unclear although a number of studies suggest involvement of MV-cell fusion and/or ligand-receptor interactions. It has however to be emphasized that MV do not necessarily elicit deleterious responses. This review focuses on the role of MV in cancer-associated thrombosis.


Chedotal A.,French Institute of Health and Medical Research
Cold Spring Harbor perspectives in biology | Year: 2010

The mammalian brain is the most complex organ in the body. It controls all aspects of our bodily functions and interprets the world around us through our senses. It defines us as human beings through our memories and our ability to plan for the future. Crucial to all these functions is how the brain is wired in order to perform these tasks. The basic map of brain wiring occurs during embryonic and postnatal development through a series of precisely orchestrated developmental events regulated by specific molecular mechanisms. Below we review the most important features of mammalian brain wiring derived from work in both mammals and in nonmammalian species. These mechanisms are highly conserved throughout evolution, simply becoming more complex in the mammalian brain. This fascinating area of biology is uncovering the essence of what makes the mammalian brain able to perform the everyday tasks we take for granted, as well as those which give us the ability for extraordinary achievement.


Mkaddem S.B.,French Institute of Health and Medical Research
Oncotarget | Year: 2010

Ischemia-reperfusion injury induces intense inflammatory response and tissue damages resulting from the capacity of endogenous constituents called damageassociated molecular patterns (DAMPs) released by damaged or necrotic cells, to activate signaling pathways mediated by receptors of the innate immune systems. Among them, two members of the Toll-like receptors (TLR) family, TLR2 and TLR4 have been shown to play key roles in the induction of inflammatory response and cell apoptosis in a variety of ischemic tissues. The oxidative stress injury caused by I/R injury has been attributed to the activation of MAP kinase pathways, including those of ERK, JNK and p38. Here, we summarise recent findings concerning the role of the protein phosphatase 5 involved in the selective regulation of TLR2-mediated ERK1/2 signaling and the identification of the key role of the non-phagocytic NADPH oxidase 4 producing reactive oxygen species in the control of TLR4-mediated apoptosis in murine models of renal I/R injury and in post-hypoxic kidney tubule cells. The identification of molecules signaling involved in the ER stress-induced apoptotic signaling cascade may therefore represent potential targets to prevent the induction of apoptosis in hypoxic tissues.


Laurent S.,University of Paris Descartes | Laurent S.,French Institute of Health and Medical Research | Schlaich M.,Baker IDI Heart and Diabetes Institute | Esler M.,Baker IDI Heart and Diabetes Institute
The Lancet | Year: 2012

Successful treatment of hypertension is difficult despite the availability of several classes of antihypertensive drug, and the value of strategies to combat the effect of adverse lifestyle behaviours on blood pressure. In this paper, we discuss two promising therapeutic alternatives for patients with resistant hypertension: novel drugs, including new pharmacological classes (such as vasopeptidase inhibitors and aldosterone synthase inhibitors) and new molecules from present pharmacological classes with additional properties in blood-pressure or metabolism pathways; and new procedures and devices, including stimulation of arterial baroreceptors and catheter-based renal denervation. Although several pharmacological targets have been discovered with promising preclinical results, the clinical development of novel antihypertensive drugs has been more difficult and less productive than expected. The effectiveness and safety of new devices and procedures should be carefully assessed in patients with resistant hypertension, thus leading to a new era of outcome trials and evidence-based guidelines.


Billard C.,French Institute of Health and Medical Research | Billard C.,University Pierre and Marie Curie
Oncotarget | Year: 2014

Chronic lymphocytic leukemia (CLL) is characterized by a typical defect in apoptosis and is still an incurable disease. Numerous apoptosis inducers have been described. These synthetic compounds and natural products (mainly derived from plants) display antileukemic properties in vitro and in vivo and some have even been tested in the clinic in CLL. They act through several different mechanisms. Most of them involve proteins of the Bcl-2 family, which are the key regulators in triggering the mitochondrial pathway of caspase-dependent apoptosis. Thus, the Mcl-1/Noxa axis appeared as a target. Here I overview natural and synthetic apoptosis inducers and their mechanisms of action in CLL cells. Opportunities for developing novel, apoptosis-based therapeutics are presented.


Selosse M.-A.,CNRS Systematics, Biodiversity and Evolution Institute | Bessis A.,French Institute of Health and Medical Research | Pozo M.J.,CSIC - Experimental Station of El Zaidin
Trends in Microbiology | Year: 2014

The functional similarity between root and gut microbiota, both contributing to the nutrition and protection of the host, is often overlooked. A central mechanism for efficient protection against pathogens is defense priming, the preconditioning of immunity induced by microbial colonization after germination or birth. Microbiota have been recruited several times in evolution as developmental signals for immunity maturation. Because there is no evidence that microbial signals are more relevant than endogenous ones, we propose a neutral scenario for the evolution of this dependency: any hypothetic endogenous signal can be lost because microbial colonization, reliably occurring at germination or birth, can substitute for it, and without either positive selection or the acquisition of new functions. Dependency of development on symbiotic signals can thus evolve by contingent irreversibility. © 2014 Elsevier Ltd.


Gachet C.,French Institute of Health and Medical Research | Gachet C.,University of Strasbourg
Journal of Thrombosis and Haemostasis | Year: 2015

The current standard care for acute coronary syndromes is dual antiplatelet therapy combining the COX1 inhibitor aspirin with a drug targeting the P2Y12 receptor, together with anticoagulation during and after early revascularization by percutaneous intervention. In very high-risk patients, glycoprotein (GP) IIb/IIIa antagonists may also be used. Secondary prevention of ischemic events requires dual antiplatelet therapy for several months followed by lifelong low-dose aspirin. The duration of treatment and the drugs to combine nevertheless remain matters of debate and the focus of ongoing research. Despite great progress, there is still room for improved efficacy and this could involve new targets for both antiplatelet drugs (like the thrombin receptor PAR1) and anticoagulants. However, improved efficacy is offset by an increased risk of bleeding. Stroke patients are still waiting for better treatment, their bleeding risk being particularly high. New targets including the collagen receptor, glycoprotein VI (GPVI), and the GPIb-von Willebrand factor axis, governing platelet interaction with the diseased vessel wall, should enable us to complete the armamentarium of antiplatelet drugs. © 2015 International Society on Thrombosis and Haemostasis.


Pawlotsky J.-M.,University Paris Est Creteil | Pawlotsky J.-M.,French Institute of Health and Medical Research
Seminars in Liver Disease | Year: 2014

The development of new models and tools has led to the discovery and clinical development of a large number of new anti-hepatitis C virus (HCV) drugs, including direct-acting antivirals and host-targeted agents. Surprisingly, curing HCV infection appears to be easy with these new drugs, provided that a potent drug combination with a high barrier to resistance is used. HCV infection cure rates can be optimized by combining drugs with synergistic antiviral effects, tailoring treatment duration to the patients' needs, and/or using ribavirin. Two HCV drugs have been approved in 2011-telaprevir and boceprevir, both first-wave, first-generation NS3-4A protease inhibitors, two others in 2013/2014-simeprevir, a second-wave, first-generation NS3-4A protease inhibitor, and sofosbuvir, a nucleotide analogue inhibitor of the viral polymerase. Numerous other drugs have reached phase II or III clinical development. From 2015 and onwards, interferon-containing regimens will disappear, replaced by interferon-free regimens yielding infection cure rates over 90%. These therapies will raise new issues, including the need for broad-scale screening and access to care. © 2014 by Thieme Medical, Inc.


Sullivan R.,University of Quebec | Saez F.,French Institute of Health and Medical Research
Reproduction | Year: 2013

Mammalian spermatozoa are unique cells in many ways, and the acquisition of their main function, i.e. fertilization capacity, is a multistep process starting in the male gonad and ending near the female egg for the few cells reaching this point. Owing to the unique character of this cell, the molecular pathways necessary to achieve its maturation also show some specific characteristics. One of the most striking specificities of the spermatozoon is that its DNA is highly compacted after the replacement of histones by protamines, making the classical processes of transcription and translation impossible. The sperm cells are thus totally dependent on their extracellular environment for their protection against oxidative stress, for example, or for the molecular changes occurring during the transit of the epididymis; the first organ in which post-testicular maturation takes place. The molecular mechanisms underlying sperm maturation are still largely unknown, but it has been shown in the past three decades that extracellular vesicles secreted by the male reproductive tract are involved in this process. This review will examine the roles played by two types of naturally occurring extracellular vesicles, epididymosomes and prostasomes, secreted by the epididymis and the prostate respectively. We will also describe how the use of artificial vesicles, liposomes, contributed to the study of male reproductive physiology. © 2013 Society for Reproduction and Fertility.


Pessayre D.,French Institute of Health and Medical Research
Handbook of Experimental Pharmacology | Year: 2010

Mitochondrial dysfunction is a major mechanism of liver injury. A parent drug or its reactive metabolite can trigger outer mitochondrial membrane permeabilization or rupture due to mitochondrial permeability transition. The latter can severely deplete ATP and cause liver cell necrosis, or it can instead lead to apoptosis by releasing cytochrome c, which activates caspases in the cytosol. Necrosis and apoptosis can trigger cytolytic hepatitis resulting in lethal fulminant hepatitis in some patients. Other drugs severely inhibit mitochondrial function and trigger extensive microvesicular steatosis, hypoglycaemia, coma, and death. Milder and more prolonged forms of drug-induced mitochondrial dysfunction can also cause macrovacuolar steatosis. Although this is a benign liver lesion in the short-term, it can progress to steatohepatitis and then to cirrhosis. Patient susceptibility to drug-induced mitochondrial dysfunction and liver injury can sometimes be explained by genetic or acquired variations in drug metabolism and/or elimination that increase the concentration of the toxic species (parent drug or metabolite). Susceptibility may also be increased by the presence of another condition, which also impairs mitochondrial function, such as an inborn mitochondrial cytopathy, β-oxidation defect, certain viral infections, pregnancy, or the obesity-associated metabolic syndrome. Liver injury due to mitochondrial dysfunction can have important consequences for pharmaceutical companies. It has led to the interruption of clinical trials, the recall of several drugs after marketing, or the introduction of severe black box warnings by drug agencies. Pharmaceutical companies should systematically investigate mitochondrial effects during lead selection or preclinical safety studies. © 2010 Springer-Verlag Berlin Heidelberg.


Gregoire M.,French Institute of Health and Medical Research
Cell Adhesion and Migration | Year: 2010

Malignant pleural mesothelioma (MPM) is a rare malignancy of the pleura with a very poor prognosis. Treatments evaluated for malignant mesothelioma, including chemotherapy, radiotherapy and surgery are of limited efficacy. However, the fact that the tumors of some patients with MPM regress spontaneously or respond to immunotherapy suggests that the immune system may respond to MPM under some circumstances. In this respect, animal studies have demonstrated immunoreactivity of MPM to different immunotherapies. In the case of MPM, several clinical studies have demonstrated a correlation between the presence of a lymphocyte infiltrate and a better prognosis and humoral response directed against specific antigens related to tumor. Thus, MPM immunotherapy is undoubtedly a highly promising but also very challenging approach to the treatment of this disease that has slipped through the defense lines of the immune system. This article reviews past and recent developments of the clinical strategies that concern immunotherapy of mesothelioma. © 2010 Landes Bioscience.


MacIeira-Coelho A.,French Institute of Health and Medical Research
Biogerontology | Year: 2010

The post-mitotic cell reached by normal cell populations after serial divisions has been regarded as the hallmark of cell senescence. It was proposed that this non-dividing cell is a mechanism of protection against malignant transformation and different approaches have been used to induce the post-mitotic state. There are contradictions and paradoxes between the concepts and the data, which are described herein. There are also contradictions between data from different laboratories that attempted to identify the mechanisms leading to the post-mitotic cell. The contradictions are bypassed with the claim that there are different pathways to cell senescence. The contradictions and the differences between the data should be explained before these phenomena can be understood.


Charbord P.,French Institute of Health and Medical Research
Human Gene Therapy | Year: 2010

This review describes the historical emergence of the concept of bone marrow mesenchymal stem cells (MSCs), summarizing data on Wolf and Trentin's hematopoietic inductive microenvironment; Dexter's hematopoiesis-supportive stromal cells; Friedenstein's osteogenic cells; and Pittenger's trilineal osteoblastic, chondrocytic, and adipocytic precursors; to finally introduce the specific bone marrow mesenchymal stem cells with differentiation potential to four lineages (mesenchymal and vascular smooth muscle lineages), and stromal and immunomodulatory capacities. Two points are the object of detailed discussion. The first point envisions the stem cell attributes (multipotentiality, self-renewal, tissue regeneration, population heterogeneity, plasticity, and lineage priming) compared with that of the paradigmatic hematopoietic stem cell. In the second point, we discuss the possible existence of bone marrow cells with greater differentiation potential, eventually pluripotential cells. The latter point raises the issues of cell fusion, reprogramming, or selection under nonstandardized conditions of rare populations of neuroectodermal origin, or of cells that had undergone mesenchymal-to-epithelial transition. In the last section, we review data on MSC senescence and possible malignant transformation secondary to extensive culture, gene transfer of telomerase, or mutations such as leading to Ewing's sarcoma. The set of data leads to the conclusion that bone marrow MSCs constitute a specific adult tissue stem cell population. The multiple characteristics of this stem cell type account for the versatility of the mechanisms of injured tissue repair. Although MSC administration may be extremely useful in a number of clinical applications, their transplantation is not without risks that must not be overlooked when developing cell therapy protocols. © Mary Ann Liebert, Inc. 2010.


Chaouat G.,French Institute of Health and Medical Research
Journal of Reproductive Immunology | Year: 2013

This review summarises an invited talk presented at the 2012 ESRI/ASRI meeting in Hamburg, concerning current views of inflammation in pregnancy, which is timely given that the effects of a local injury in the uterus acts to favour implantation. Recalling that inflammation can be good (it is useful and necessary for implantation), bad (in implantation failure, RSA) and ugly (at the extreme, endometriosis is associated with pain and infertility) leads to consideration of its status in pregnancy. Its role in implantation and the fact that pregnancy maintains some aspects of inflammation throughout, leads to revision of not only concepts of immunosuppression and the Th1/Th2 paradigm, but also the feto-maternal relationship as seen since Medawar's hypotheses were advanced. This is examined from an evolutionary perspective, which should lead to further review of our perception of uterine NK cells, and the emergence of Treg cells to control some aspects of adaptive immunity, which appeared long after placentation. © 2012 Elsevier Ireland Ltd.


Ben Abdelwahed R.,French Institute of Health and Medical Research
Investigative ophthalmology & visual science | Year: 2013

Primary cerebral lymphoma (PCL) and primary intraocular lymphoma (PIOL) belong to the systemic diffuse large B-cell lymphoma family and are characterized by the presence of CD20(+) lymphoma B cells in the brain or the eye. These highly aggressive malignancies have a poor prognosis and no specific therapy. The presence of effector immune cells in the damaged brain and vitreous suggests that treatment with anti-human CD20 (hCD20) monoclonal antibodies might be effective. We developed murine models of PCL and PIOL to assess the intracerebral and intraocular antitumor effect of ublituximab, a promising glycoengineered anti-hCD20 mAb with a high affinity for FcγRIIIa (CD16) receptors. The murine lymphoma B-cell line A20.IIA-GFP-hCD20 (H-2(d)) was injected into the right cerebral striatum or the vitreous of immunocompetent adult BALB/c mice (H-2(d)). Four to 7 days later, ublituximab was injected intracerebrally or intravitreously into the tumor site. Rituximab was the reference compound. Survival was monitored for injected mice; histopathological and flow cytometric analyses were performed to study tumor growth and T-cell infiltration. Single doses of ublituximab, injected intracerebrally or intravitreously, had a marked antitumor effect, more pronounced than that obtained with the same dose of rituximab in these conditions. The reduction in tumor cells was correlated with an increased proportion of CD8(+) T cells. This efficacy was observed only against lymphoma B cells expressing hCD20. These in vivo results confirm the potential of the glycoengineered anti-hCD20 mAb ublituximab as an innovative therapeutic approach to treat primary central nervous system lymphoma and other B-cell lymphomas.


Marie P.J.,French Institute of Health and Medical Research
Bone | Year: 2010

Recent progress has been made in our understanding of the functional role of the seven-transmembrane-spanning extracellular calcium-sensing receptor (CaSR) in bone cells. Both in vitro and in vivo data indicate that the CaSR is a physiological regulator of bone cell metabolism. The CaSR regulates the recruitment, differentiation and survival of osteoblasts and osteoclasts through activation of multiple CaSR-mediated intracellular signaling pathways in bone cells. This raises the possibility that the bone CaSR could potentially be targeted by allosteric modulators, either agonists (calcimimetics) or antagonists (calcilytics) to control bone remodeling. The therapeutic potential of CaSR agonists or antagonists in bone cells is however hampered by their effects on the CaSR in nonskeletal tissues. Rather, direct targeting of the bone CaSR may be of potential interest for the treatment of bone diseases. Targeting the bone CaSR using a bone-seeking CaSR agonist offers a potential mean to modulate bone cell metabolism. The development of drugs that preferentially target the CaSR and possibly other cation-sensing receptors in bone cells may thus be helpful for the treatment of osteoporosis. © 2009 Elsevier Inc.


Bafeta A.,French Institute of Health and Medical Research
BMJ (Clinical research ed.) | Year: 2013

To examine whether network meta-analyses, increasingly used to assess comparative effectiveness of healthcare interventions, follow the key methodological recommendations for reporting and conduct of systematic reviews. Methodological systematic review of reports of network meta-analyses. Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Medline, and Embase, searched from inception to 12 July 2012. All network meta-analyses comparing clinical efficacy of three or more interventions based on randomised controlled trials, excluding meta-analyses with an open loop network of three interventions. We assessed the reporting of general characteristics and key methodological components of the systematic review process using two composite outcomes. For some components, if reporting was adequate, we assessed their conduct quality. Of 121 network meta-analyses covering a wide range of medical areas, 100 (83%) assessed pharmacological interventions and 11 (9%) non-pharmacological interventions; 56 (46%) were published in journals with a high impact factor. The electronic search strategy for each database was not reported in 88 (73%) network meta-analyses; for 36 (30%), the primary outcome was not clearly identified. Overall, 61 (50%) network meta-analyses did not report any information regarding the assessment of risk of bias of individual studies, and 103 (85%) did not report any methods to assess the likelihood of publication bias. Overall, 87 (72%) network meta-analyses did not report the literature search, searched only one database, did not search other sources, or did not report an assessment of risk of bias of individual studies. These methodological components did not differ by publication in a general or specialty journal or by public or private funding. Essential methodological components of the systematic review process-conducting a literature search and assessing risk of bias of individual studies-are frequently lacking in reports of network meta-analyses, even when published in journals with high impact factors.


Nordmann P.,French Institute of Health and Medical Research
Medecine/Sciences | Year: 2010

Clinically-significant Gram-negative species remain mostly Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii. Carbapenem molecules are often the last resort for treating infections due to multidrug resistant isolates. In Enterobacteriaceae, resistance to carbapenems may result from combined mechanisms of resistance associating ß-lactamases with weak (if any) intrinsic carbapenemase activity and decreased outer membrane permeability, or from true carbapenemases. KPC-type enzymes (partially inhibited by clavulanic acid) have been identified mostly in Klebsiella pneumoniae, first in bacteria identified in the USA and then worldwide, and in many enterobacterial species. Carbapenem-hydrolyzing ß-lactamases (CHBL) could be also metallo-ß-lactamases (VIM, IMP, NDM-1, etc.) mostly in hospital-acquired K. pneumoniae. One of the latest reported CHBL in Enterobacteriaceae is OXA-48, identified mostly in Mediterranean countries. All these carbapenemase producers are difficult to detect in a clinical laboratory and may be the source of multidrug resistance leading to a therapeutic dead end. Whereas the main mechanism of resistance to imipenem in P. aeruginosa remains due to a modification of the outer membrane protein OprD, the landscape of CHBL in P. aeruginosa expanding worldwide is made of KPC, GES-related enzymes and metallo-ß-lactamases (IMP, VIM, etc.). These enzymes are involved in multidrug resistance strains as a source of nosocomial outbreaks. In Acinetobacter baumannii, KPC and metallo-ß-lactamases have been identified. However, the most frequent CHBL are oxacillinases (OXA-23, OXA-40, OXA-58, OXA-143) which are specific to that species. Novel carbapenemases are continuously being identified worldwide with exchange of the resistance genes between Enterobacteriaceae, P. aeruginosa and A. baumannii.


Yuan J.,Harvard University | Kroemer G.,French Institute of Health and Medical Research | Kroemer G.,Institute Gustave Roussy | Kroemer G.,University of Paris Descartes
Genes and Development | Year: 2010

A canonical regulatory pathway involving the members of the Bcl-2 and caspase families has been established to regulate developmental apoptosis in nematodes and flies. However, mutant mice that have major deficiencies in this apoptosis pathway show only relatively minor developmental defects. Recent revelations indicate that multiple mechanisms are involved in regulating cell death during mammalian development, tissue homeostasis, and pathological cell loss. Here, we critically evaluate the evidence demonstrating the existence of alternative cell death mechanisms, including apoptosis of lower organisms in the absence of canonical apoptosis mediators, autophagic cell death, necroptosis, elimination by shedding, keratinocyte death by cornification, and cell-cell cannibalism by entosis. The physiological relevance of alternative cell death mechanisms as primary and backup mechanisms is discussed. © 2010 by Cold Spring Harbor Laboratory Press.


McLaughlin V.V.,University of Michigan | Shah S.J.,Northwestern University | Souza R.,University of Sao Paulo | Humbert M.,University Paris - Sud | Humbert M.,French Institute of Health and Medical Research
Journal of the American College of Cardiology | Year: 2015

Pulmonary hypertension (PH) is common and may result from a number of disorders, including left heart disease, lung disease, and chronic thromboembolic disease. Pulmonary arterial hypertension (PAH) is an uncommon disease characterized by progressive remodeling of the distal pulmonary arteries, resulting in elevated pulmonary vascular resistance and, eventually, in right ventricular failure. Over the past decades, knowledge of the basic pathobiology of PAH and its natural history, prognostic indicators, and therapeutic options has exploded. A thorough evaluation of a patient is critical to correctly characterize the PH. Cardiac studies, including echocardiography and right heart catheterization, are key elements in the assessment. Given the multitude of treatment options currently available for PAH, assessment of risk and response to therapy is critical in long-term management. This review also underscores unique situations, including perioperative management, intensive care unit management, and pregnancy, and highlights the importance of collaborative care of the PAH patient through a multidisciplinary approach. © 2015 American College of Cardiology Foundation.


Le Meur N.,EHESP | Le Meur N.,French Institute of Health and Medical Research
Current Opinion in Biotechnology | Year: 2013

Recent advances in miniaturization and automation of technologies have enabled cell-based assay high-throughput screening, bringing along new challenges in data analysis. Automation, standardization, reproducibility have become requirements for qualitative research. The Bioconductor community has worked in that direction proposing several R packages to handle high-throughput data including flow cytometry (FCM) experiment. Altogether, these packages cover the main steps of a FCM analysis workflow, that is, data management, quality assessment, normalization, outlier detection, automated gating, cluster labeling, and feature extraction. Additionally, the open-source philosophy of R and Bioconductor, which offers room for new development, continuously drives research and improvement of theses analysis methods, especially in the field of clustering and data mining. This review presents the principal FCM packages currently available in R and Bioconductor, their advantages and their limits. © 2012 Elsevier Ltd.


Hovnanian A.,French Institute of Health and Medical Research | Hovnanian A.,Imagine Institute for Genetic Diseases | Hovnanian A.,University of Paris Pantheon Sorbonne
Cell and Tissue Research | Year: 2013

Netherton syndrome (NS) is a rare autosomal recessive skin disease with severe skin inflammation and scaling, a specific hair shaft defect and constant allergic manifestations. NS is caused by loss-of-function mutations in SPINK5 (serine protease inhibitor of kazal type 5) encoding LEKTI-1 (lympho-epithelial kazal type related inhibitor type 5) expressed in stratified epithelia. In vitro and in vivo studies in murine models and in NS patients have cast light on the pathogenesis of the disease and shown that LEKTI deficiency results in unopposed kallikrein-related peptidase 5 (KLK5) and KLK7 activities and to the overactivity of a new epidermal protease, elastase 2 (ELA2). Two main cascades initiated by KLK5 activity have emerged. One results in desmoglein 1 degradation and desmosome cleavage leading to stratum corneum detachment. KLK5 also activates KLK7 and ELA2, which contribute to a defective skin barrier. This facilitates allergen and microbe penetration and generates danger signals leading to caspase 1 activation and the production of active interleukin-1β. In parallel, KLK5 activates a specific cascade of allergy and inflammation by activating protease-activated receptor-2 (PAR-2) receptors. PAR-2 activation triggers the production of the major pro-Th2 cytokine TSLP (thymic stromal lymphopoietin) and several inflammatory cytokines, including tumour necrosis factor-α. Levels of thymus and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC) also contribute to allergy in a PAR-2-independent manner. Patient investigations have confirmed these abnormalities and revealed a wide spectrum of disease expression, sometimes associated with residual LEKTI expression. These results have demonstrated that the tight regulation of epidermal protease activity is essential for skin homeostasis and identified new targets for therapeutic intervention. They also provide a link with atopic dermatitis through deregulated protease activity, as recently supported by functional studies of the E420K LEKTI variant. © Springer-Verlag Berlin Heidelberg 2013.


Rome S.,French Institute of Health and Medical Research
Clinical Biochemistry | Year: 2013

MicroRNAs (miRNAs) are a class of evolutionary conserved non-coding RNAs of 19-22 nucleotides that function as negative regulators of gene expression. Originally discovered in C. elegans, miRNAs regulate fundamental cellular processes in diverse organisms, including the control of metabolic pathways involved in fat metabolism, adipocyte differentiation, energy homeostasis, glucose-stimulated insulin secretion and inflammation. Several miRNAs have been identified as having a physiological role in tissues in which type 2 diabetes (T2DM) complications occur (liver, pancreas, adipose tissue and skeletal muscle). In addition, previous studies in animal models or in human tissues have demonstrated altered expression of microRNAs in insulin-sensitive tissues of T2DM patients suggesting a potential role for these small RNA molecules in the complications associated with the diabetic condition. However all these data assume that miRNAs reside and elicit their regulatory action within the producing cells. However, studies in the last 5. years have demonstrated that miRNAs are not only found intracellularly, but are also detectable outside cells, including in various body fluids. This phenomenon raises questions about the biological functions of such extracellular miRNAs. The aim of the present review is to summarize the current knowledge of the impact of extracellular miRNAs on the development of obesity-associated T2DM, and its related complications including endothelial and vascular smooth muscle cell dysfunction. It also considers the possible use of blood miRNAs as biomarkers for the detection of T2DM, classification of the disease and detection of associated pathologies. © 2013 The Canadian Society of Clinical Chemists.


Kiliaan A.J.,Donders Institute for Brain | Arnoldussen I.A.C.,Donders Institute for Brain | Gustafson D.R.,New York University | Gustafson D.R.,French Institute of Health and Medical Research
The Lancet Neurology | Year: 2014

Being overweight or obese, as measured with body-mass index or central adiposity (waist circumference), and the trajectory of body-mass index over the life course have been associated with brain atrophy, white matter changes, disturbances of blood-brain barrier integrity, and risk of all-cause late-onset dementia and Alzheimer's disease. This observation leads us to question what it is about body-mass index that is associated with health of the brain and dementia risk. If high body-mass index and central adiposity represent an increase in adipose tissue, then the endocrine function of adipose tissue, mediated by adipose tissue hormones and adipokines, could be a clue to mechanisms that underlie the association with dementia and Alzheimer's disease. Hundreds of adipokines have been identified, creating a complexity that is a challenge to simplify. Nonetheless, adipokines are being investigated in association with clinical dementia outcomes, and with imaging-based measures of brain volume, structure, and function in human beings and in preclinical models of clinical dementia. © 2014 Elsevier Ltd.


Sermet-Gaudelus I.,French Institute of Health and Medical Research
European Respiratory Review | Year: 2013

Cystic fibrosis (CF) is an autosomal recessive lethal disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that encodes for CFTR, an epithelial cell-surface expressed protein responsible for the transport of chloride (Cl-). Gating mutations associated with defective conductance can be modulated by CFTR potentiators. Ivacaftor is a CFTR potentiator approved for the treatment of CF patients <6 yrs of age with at least one copy of the G551D-CFTR mutation. Herein, the clinical trial development programme for ivacaftor will be reviewed, including two pivotal studies in adolescents/adults and in children. These studies report sustained improvements in lung function and sweat chloride concentrations, and a reduction in pulmonary exacerbations over a 48-week treatment period. In the era of personalised medicine, ivacaftor offers an effective and well-tolerated treatment for the clinical management of CF patients with the G551D mutation. A long-term, open-label study will report the effects of ivacaftor over a further 48 weeks. © ERS 2013.


Hebert-Chatelain E.,French Institute of Health and Medical Research
International Journal of Biochemistry and Cell Biology | Year: 2013

Mitochondria produce the most part of the energy used by the cells. This energetic production occurs through the oxidative phosphorylation (OXPHOS) process. Mitochondrial functions such as OXPHOS need to be tightly regulated to respect the needs of cells. Phosphorylation of mitochondrial proteins now appears as a major regulation pathway of mitochondrial functions. Several kinases and phosphatases are specifically targeted to mitochondria where they modulate mitochondrial functions. However, we still poorly understand the extent of tyrosine phosphorylation events on mitochondrial metabolism. Among the tyrosine-kinases observed in mitochondria, Src kinases emerge as key players. In the past years, several mitochondrial proteins were shown to be substrates of Src kinases. Notably, these kinases can impact greatly OXPHOS and apoptosis. Important regulators of Src kinases activity are also observed in mitochondria. The aim of this review is to summarize the recent findings on how overall mitochondrial tyrosine phosphorylation events and more specifically Src kinases can influence mitochondrial functions. The different mechanisms of Src kinases regulation and translocation into mitochondria will be also discussed. This article is part of a Directed Issue entitled: Bioenergetic dysfunction, adaptation and therapy. © 2012 Elsevier Ltd.


Itzykson R.,French Institute of Health and Medical Research
Blood | Year: 2013

Genomic studies in chronic myeloid malignancies, including myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS), and MPN/MDS, have identified common mutations in genes encoding signaling, epigenetic, transcription, and splicing factors. In the present study, we interrogated the clonal architecture by mutation-specific discrimination analysis of single-cell-derived colonies in 28 patients with chronic myelomonocytic leukemias (CMML), the most frequent MPN/MDS. This analysis reveals a linear acquisition of the studied mutations with limited branching through loss of heterozygosity. Serial analysis of untreated and treated samples demonstrates a dynamic architecture on which most current therapeutic approaches have limited effects. The main disease characteristics are early clonal dominance, arising at the CD34(+)/CD38(-) stage of hematopoiesis, and granulomonocytic differentiation skewing of multipotent and common myeloid progenitors. Comparison of clonal expansions of TET2 mutations in MDS, MPN, and CMML, together with functional invalidation of TET2 in sorted progenitors, suggests a causative link between early clonal dominance and skewed granulomonocytic differentiation. Altogether, early clonal dominance may distinguish CMML from other chronic myeloid neoplasms with similar gene mutations.


CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) play a critical role in the maintenance of immune tolerance. Intravenous immunoglobulin (IVIg), a therapeutic preparation of normal pooled human IgG, expands Tregs in various experimental models and in patients. However, the cellular and molecular mechanisms by which IVIg expands Tregs are relatively unknown. As Treg expansion in the periphery requires signaling by antigen-presenting cells such as dendritic cells (DCs) and IVIg has been demonstrated to modulate DC functions, we hypothesized that IVIg induces distinct signaling events in DCs that subsequently mediate Treg expansion. We demonstrate that IVIg expands Tregs via induction of cyclooxygenase (COX)-2-dependent prostaglandin E2 (PGE2) in human DCs. However, costimulatory molecules of DCs such as programmed death ligands, OX40 ligand, and inducible T-cell costimulator ligands were not implicated. Inhibition of PGE2 synthesis by COX-2 inhibitors prevented IVIg-mediated Treg expansion in vitro and significantly diminished IVIg-mediated Treg expansion in vivo and protection from disease in experimental autoimmune encephalomyelitis model. IVIg-mediated COX-2 expression, PGE2 production, and Treg expansion were mediated in part via interaction of IVIg and F(ab')2 fragments of IVIg with DC-specific intercellular adhesion molecule-3-grabbing nonintegrin. Our results thus uncover novel cellular and molecular mechanism by which IVIg expands Tregs.


Benyamina A.,French Institute of Health and Medical Research
International Journal of General Medicine | Year: 2014

Aim: Project Access France was a national survey designed to provide real-world observations on the status of opioid dependence treatment in France.Methods: The views of physicians (n=100), patients (n=130), and out-of-treatment opioid users (n=33) were collected via interviews and questionnaires.Results: Physicians reported being moderately satisfied with treatment programs in their area (rating 6.9 out of 10). Most physicians (82%) reported being concerned about misuse and diversion of medication-assisted treatment (MAT) medications and 50% identified psychosocial/behavioral counseling as the key change that would most improve patient care. Among patients, the mean number of previous MAT episodes was low (1.5); 78% reported that it was easy to access a doctor to undergo MAT; 14% reported regularly or sometimes using heroin; misuse and diversion were reported in 15% and 39% of patients, respectively; and 57% of patients were not receiving psychosocial help. Out-of-treatment opioid users reported using drugs on a regular basis (42% regularly used heroin) and cited ‘not wanting to give up drugs completely’ as the most frequent reason for staying out of MAT.Conclusion: This survey highlights a number of positive features of the open-access, GP-based treatment model for opioid dependence in France. Challenges remain with regard to continu. © 2014 Benyamina.


Fournier A.,French Institute of Health and Medical Research
Menopause International | Year: 2010

The current evaluation of the benefit/risk ratio associated with menopausal hormone therapy (MHT) use is largely based on clinical trials which investigated the effects of oral treatments.Would MHT with transdermal estrogens be associated with a more favourable benefit/risk ratio? We reviewed the available epidemiologic evidence on that question. Epidemiologic studies were considered if they provided risk estimates of conditions which carry an important weight among menopausal women, and for which epidemiologic evidence of a possible link with MHT use is convincing: cardiovascular diseases, breast cancer, diabetes, colorectal cancer and hip fracture. We did not include studies with only surrogate measures. We found that the available information on the potential impact of the route of administration of MHT on the risk of our selected outcomes is limited. To date, epidemiologic data suggest that it has no impact on the risk of breast cancer and hip fracture. Results on the risk of coronary heart disease and colorectal cancer are inconsistent. Studies on stroke and diabetes risk are too few to allow meaningful conclusions. There is a suggestion that transdermal MHT may be less deleterious than oral MHTregarding venous thromboembolism which needs to be confirmed. The issue of the route of administration of MHT should remain an active area of research as part of an attempt to identify treatment modalities that would have the least potential for exerting adverse effects.


Chapman M.J.,French Institute of Health and Medical Research
Atherosclerosis Supplements | Year: 2011

Atherogenic dyslipidemia is characterised by high levels of triglycerides, low levels of high-density lipoprotein-cholesterol (HDL-C), and moderate to marked elevations in low-density lipoprotein-cholesterol (LDL-C) concentrations; such dyslipidemia is further characterised by high apolipoprotein B (apoB): apolipoprotein A1 (apoA1) ratios. Numerous clinical trials have demonstrated that statins are effective in lowering LDL-C and reducing cardiovascular (CV) risk in people with dyslipidemia. However, the most effective treatments should target all of the key atherogenic features, rather than LDL-C alone. Pitavastatin is a new member of the statin class whose distinct pharmacological features translate into a broad spectrum of action on both apoB-containing and apoA1-containing lipoprotein components of the atherogenic lipid profile. The efficacy and safety of this statin has been demonstrated by a large clinical development programme conducted both in Japanese and Caucasian populations. Phase III and IV studies in a wide range of patients with primary hypercholesterolemia or combined dyslipidemia showed that 12 weeks' treatment with pitavastatin l-4 mg was well tolerated, significantly improved lipid profiles (including LDL-C, TG, and HDL-C levels) and increased the EAS-/NCEP ATP Ill-recommended LDL-C target attainment rate to a similar or greater degree as comparable doses of atorvastatin, simvastatin, or pravastatin. Results were similar across all patient groups and were generally sustained after 52 weeks of treatment. However, whereas the effects of atorvastatin and simvastatin on HDL-C levels remained constant over the long term, pitavastatin-treated patients experienced progressive and maintained elevations in HDL-C, ultimately increasing by up to 14.3% vs. initial baseline. In this context, it is significant that the in vitro studies of Yamashita et al. [J Atheroscler Thromb 2010;17:436-51] have shown pitavastatin to be distinguished by its potent stimulation of apoA1 production in hepatocyte-like cells. These findings suggest that pitavastatin may be highly efficacious in raising levels of lipid-poor apoA1 particles, which are known to be highly active in ABCA1-mediated cellular cholesterol efflux, an observation which is pertinent to the excessive accumulation of cholesterol in macrophage foam cells of the atherosclerotic plaque. Indeed, the intravascular remodelling and maturation of lipid-poor apoA1 particles is known to drive flux of apoA1, cholesterol and phospholipid through the HDL pathway. It is equally relevant that pitavastatin therapy has been shown to be efficacious in markedly reducing coronary atheroma volume in acute coronary syndrome patients in the JAPAN-ACS trial, a therapeutic effect which may be linked to its impact on apoA1/HDL metabolism and function. Overall, Phase III and IV studies demonstrate that pitavastatin 1-4 mg is well tolerated, attenuates the atherogenic lipid profile and increases LDL-C target attainment rates with a similar or greater efficacy to comparable doses of atorvastatin, simvastatin and pravastatin. Furthermore, pitavastatin may be particularly beneficial in high-risk patients with elevated concentrations of TG-rich lipoproteins and low levels of HDL-C, and in whom the atheroprotective function of HDL particles is typically defective; significantly, such patients typically exhibit persistent, residual cardiometabolic risk even when LDL-C is at goal. In this context, it is relevant that such patient groups cover a wide spectrum of metabolic diseases, including metabolic syndrome, type 2 diabetes, coronary disease, familial and non-familial forms of hypercholesterolemia, auto-immune diseases such as rheumatoid arthritis and lupus, renal disease and some forms of hepatic insufficiency. © 2011 Elsevier Ireland Ltd.


Fabre A.C.,French Institute of Health and Medical Research
Hepatology (Baltimore, Md.) | Year: 2010

A major atheroprotective functionality of high-density lipoproteins (HDLs) is to promote "reverse cholesterol transport" (RCT). In this process, HDLs mediate the efflux and transport of cholesterol from peripheral cells and its subsequent transport to the liver for further metabolism and biliary excretion. We have previously demonstrated in cultured hepatocytes that P2Y(13) (purinergic receptor P2Y, G protein-coupled, 13) activation is essential for HDL uptake but the potential of P2Y(13) as a target to promote RCT has not been documented. Here, we show that P2Y(13)-deficient mice exhibited a decrease in hepatic HDL cholesterol uptake, hepatic cholesterol content, and biliary cholesterol output, although their plasma HDL and other lipid levels were normal. These changes translated into a substantial decrease in the rate of macrophage-to-feces RCT. Therefore, hallmark features of RCT are impaired in P2Y(13)-deficient mice. Furthermore, cangrelor, a partial agonist of P2Y(13), stimulated hepatic HDL uptake and biliary lipid secretions in normal mice and in mice with a targeted deletion of scavenger receptor class B type I (SR-BI) in liver (hypomSR-BI-knockout(liver)) but had no effect in P2Y(13) knockout mice, which indicate that P2Y(13)-mediated HDL uptake pathway is independent of SR-BI-mediated HDL selective cholesteryl ester uptake. CONCLUSION: These results establish P2Y(13) as an attractive novel target for modulating RCT and support the emerging view that steady-state plasma HDL levels do not necessarily reflect the capacity of HDL to promote RCT.


Pellestor F.,Laboratory of Chromosomal Genetics | Pellestor F.,French Institute of Health and Medical Research
Human Reproduction | Year: 2014

The recent discovery of a new kind of massive chromosomal rearrangement, baptized chromothripsis (chromo for chromosomes, thripsis for shattering into pieces), greatly modifies our understanding of molecular mechanisms implicated in the repair of DNA damage and the genesis of complex chromosomal rearrangements. Initially described in cancers, and then in constitutional rearrangements, chromothripsis is characterized by the shattering of one (or a few) chromosome(s) segments followed by a chaotic reassembly of the chromosomal fragments, occurring during one unique cellular event. The diversity and the high complexity of chromothripsis events raise questions about their origin, their ties to chromosome instability and their impact in pathology. Several causative mechanisms, involving abortive apoptosis, telomere erosion, mitotic errors, micronuclei formation and p53 inactivation, have been proposed. The remarkable point is that all these mechanisms have been identified in the field of human reproduction as causal factors for reproductive failures and chromosomal abnormalities. Consequently, it seems important to consider this unexpected catastrophic phenomenon in the context of fertilization and early embryonic development in order to discuss its potential impact on human reproduction. © 2014 The Author.


Polentes J.,French Institute of Health and Medical Research
Cell transplantation | Year: 2012

Human induced pluripotent stem cells (hiPSCs) are a most appealing source for cell replacement therapy in acute brain lesions. We evaluated the potential of hiPSC therapy in stroke by transplanting hiPSC-derived neural progenitor cells (NPCs) into the postischemic striatum. Grafts received host tyrosine hydroxylase-positive afferents and contained developing interneurons and homotopic GABAergic medium spiny neurons that, with time, sent axons to the host substantia nigra. Grafting reversed stroke-induced somatosensory and motor deficits. Grafting also protected the host substantia nigra from the atrophy that follows disruption of reciprocal striatonigral connections. Graft innervation by tyrosine hydoxylase fibers, substantia nigra protection, and somatosensory functional recovery were early events, temporally dissociated from the slow maturation of GABAergic neurons in the grafts and innervation of substantia nigra. This suggests that grafted hiPSC-NPCs initially exert trophic effects on host brain structures, which precede integration and potential pathway reconstruction. We believe that transplantation of NPCs derived from hiPSCs can provide useful interventions to limit the functional consequences of stroke through both neuroprotective effects and reconstruction of impaired pathways.


Cribier A.,French Institute of Health and Medical Research
Retrovirology | Year: 2011

Integration of human immunodeficiency virus type 1 (HIV-1) into a host cell chromosome is an essential step under the control of the viral integrase (IN). Although this enzyme is necessary and sufficient to catalyze the integration reaction in vitro, cellular cofactors are involved in the process in vivo. The chromatin-associated factor LEDGF/p75 interacts with IN and promotes integration to transcription units of the host genome. HIV-1 IN also binds the karyopherin TNPO3, however the significance of this interaction during viral replication remains to be explored. Here we present a functional analysis of IN mutants impaired for LEDGF/p75 and TNPO3 interaction. Among them, IN W131A and IN Q168L, that were previously identified to be deficient for LEDGF/p75 interaction, were also partially impaired for TNPO3 binding. We observed that mutations abolishing IN ability to form tetramers resulted in a severe reduction in LEDGF/p75 binding. In sharp contrast, no correlation could be found between the ability of IN to multimerize and TNPO3 interaction. Most of the mutant viruses were essentially impaired for the integration step whereas the amount of 2-LTR circles, reflecting the nuclear import of the viral DNA, was not significantly affected. Our functional analysis of HIV-1 IN mutants reveals distinct structural basis for TNPO3 interaction and suggests that the interaction between IN and TNPO3 is not a major determinant of nuclear import but could take place at a nuclear step prior to integration. © 2011 Cribier et al; licensee BioMed Central Ltd.


Benjamin F.,French Institute of Health and Medical Research
Frontiers in bioscience (Elite edition) | Year: 2011

The adenine nucleotide translocator (ANT) is a control point of several fundamental cell processes, as diverse as cell energy supply, mitochondrial DNA maintenance, and apoptosis. This paper describes six individual structures of the carrier, distinguished according to ANT1 oligomeric and conformational states, as well as associations with other proteins. Transitions between these structures depend on energy demand and thus contribute to a metabolic reserve of oxidative phosphorylation (OXPHOS) activity. Moreover, at low respiratory chain activity, we demonstrate that, unlike a mitochondrial Ca2+ upload, Bax, a pro-apoptotic Bcl-2-family protein, is able to trigger a massive release of cytochrome c from one of these ANT1 structures. These new insights emphasize the close relationship between structural rearrangements of ANT and molecular apoptotic events at distinct cell energy levels. OXPHOS functioning has to therefore be considered a crucial control point for the events leading to these contrasting pathways.


Vitale I.,French Institute of Health and Medical Research
Nature reviews. Molecular cell biology | Year: 2011

The improper distribution of chromosomes during mitosis compromises cellular functions and can reduce cellular fitness or contribute to malignant transformation. As a countermeasure, higher eukaryotes have developed strategies for eliminating mitosis-incompetent cells, one of which is mitotic catastrophe. Mitotic catastrophe is driven by a complex and poorly understood signalling cascade but, from a functional perspective, it can be defined as an oncosuppressive mechanism that precedes (and is distinct from) apoptosis, necrosis or senescence. Accordingly, the disruption of mitotic catastrophe precipitates tumorigenesis and cancer progression, and its induction constitutes a therapeutic endpoint.


Thibaut F.,French Institute of Health and Medical Research
Israel Journal of Psychiatry and Related Sciences | Year: 2012

Background: The psychiatrist's main role is to provide care to the paraphilic patient and to reduce personal distress. However, in cases of paraphilia associated with sexual offences, reducing paraphilic behavior is critical in an approach to preventing sexual violence and reducing victimization. This review will focus on this specific population. Method: We discuss the recently published recommendations for the treatment of paraphilias of the World Federation of Societies of Biological Psychiatry which were based on a review of the available literature about pharmacological treatment of paraphilias (1970-2010). Results and Conclusion: Antiandrogens, and mostly GnRH analogues, significantly reduce the intensity and frequency of deviant sexual arousal and behavior, although informed consent is necessary in all cases. GnRH analogue treatment constitutes the most promising treatment for sex offenders at high risk of sexual violence, such as pedophiles or serial rapists. SSRIs remain an interesting option in adolescents, in patients with depressive or OCD disorders, or in mild paraphilias such as exhibitionism. Pharmacological interventions should be part of a more comprehensive treatment plan including psychotherapy and, in most cases, behavior therapy.


Jacquelin S.,French Institute of Health and Medical Research
Blood | Year: 2013

The chemokine receptor CCR2 controls the release of Ly6C(high) monocytes from the bone marrow and their recruitment to sites of inflammation. A second chemokine receptor, CX3CR1, is differentially expressed on monocyte subsets. We examined the role of CX3CR1 in monocyte trafficking during the recovery phase after cyclophosphamide (CP)-induced myeloablation and observed that, in the absence of CCR2, Ly6C(high) monocytes accumulated in the bone marrow and peripheral reconstitution was severely impaired compared with wild-type (WT) mice. In contrast, in the absence of CX3CR1, Ly6C(high) monocytes accumulated less rapidly in the marrow but recovered faster in the blood and were more recruited into the spleen, suggesting an opposite action between CCR2 and CX3CR1 in myelorestoration. During the recovery phase, marrow medullar monocytes displayed lower CX3CR1 expression and reduced their adherence to coated CX3CL1. Intravital imaging of the bone marrow showed that CP treatment impacts monocyte trafficking between the parenchyma and the vasculature. Medullar monocytes in CX3CR1(-/-) mice and mice treated with a specific antagonist of CX3CR1 displayed increased mean velocity and displacement and a reduced arrest coefficient compared with WT mice. This study indicates that CX3CR1 reduces the motility of Ly6C(high) monocytes in the bone marrow and thereby controls their release.


Despite the use of immunosuppressive drugs, chronic allograft rejection remains a major hurdle in transplantation medicine. Induction of specific immunologic tolerance to antigens expressed by the graft would avoid its eventual functional loss and the severe side effects of paralyzing the immune system. We previously showed that donor-specific regulatory T-lymphocytes prevent rejection of fully allogeneic bone marrow (BM) grafts in mice. Thus generated hematopoietic chimeras then accepted skin and heart allografts of the same donor. We noticed that injected regulatory T-cells (Tregs) disappeared with time and investigated the mechanisms involved in the nevertheless long-term persistence of allograft tolerance. Using Tregs that can be depleted in vivo with diphtheria toxin, we show that injected cells are required for induction but not for maintenance of tolerance to BM allografts. We observed progressive deletion of donor-specific T-lymphocytes, accounting at least in part for maintenance of tolerance. Toxin-induced depletion of administered as well as host Tregs did not affect hematopoietic chimerism but it led to rapid loss of skin allografts. Therefore, our data show that newly generated host Tregs can prevent chronic allograft rejection. Long-lasting tolerance to allografts is thus achieved.


Cassereau J.,French Institute of Health and Medical Research
Orphanet journal of rare diseases | Year: 2011

The ganglioside-induced differentiation-associated protein 1 gene (GDAP1), which is involved in the Charcot-Marie-Tooth disease (CMT), the most commonly inherited peripheral neuropathy, encodes a protein anchored to the mitochondrial outer membrane. The phenotypic presentations of patients carrying GDAP1 mutations are heterogeneous, making it difficult to determine genotype-phenotype correlations, since the majority of the mutations have been found in only a few unrelated patients. Locus-specific databases (LSDB) established in the framework of the Human Variome Project provide powerful tools for the investigation of such rare diseases. We report the development of a publicly accessible LSDB for the GDAP1 gene. The GDAP1 LSDB has adopted the Leiden Open-source Variation Database (LOVD) software platform. This database, which now contains 57 unique variants reported in 179 cases of CMT, offers a detailed description of the molecular, clinical and electrophysiological data of the patients. The usefulness of the GDAP1 database is illustrated by the finding that GDAP1 mutations lead to primary axonal damage in CMT, with secondary demyelination in the more severe cases of the disease. Findings of this nature should lead to a better understanding of the pathophysiology of CMT. Finally, the GDAP1 LSDB, which is part of the mitodyn.org portal of databases of genes incriminated in disorders involving mitochondrial dynamics and bioenergetics, should yield new insights into mitochondrial diseases.


Duffau H.,Montpellier University | Duffau H.,French Institute of Health and Medical Research
Acta Neurochirurgica | Year: 2012

WHO grade II glioma, i.e. diffuse low-grade glioma, is a pre-malignant tumour, usually revealed by seizures in young patients with a normal life. This tumour has a constant growth, and will inescapably become anaplastic. Surgical resection significantly increases the overall survival by delaying the malignant transformation. Thus, the dilemma is to perform early surgery in order to optimise the extent of resection (and thus the median survival) by removing smaller tumours while preserving the quality of life. To this end, the new concept proposed in this review is to achieve surgical resection according to functional and not to oncological boundaries. In other words, the principle is to first understand the cerebral anatomo-functional organisation at the individual level (because of a major inter-individual variability), with the aim of resecting a part of the brain invaded by a diffuse chronic disease, on the condition nonetheless that this part of the brain can be functionally compensated- i.e. with no consequences on the quality of life. To this end, in addition to the preoperative functional neuroimaging and the intraoperative electrical cortical mapping in awake patients, it is also crucial to map both horizontal cortico-cortical connectivity (long-distance association fibres) as well as vertical cortico-subcortical connectivity (projection fibres), with the aim to preserve the networks underlying the minimal common core of the brain. Interestingly, this "hodotopical" workframe, based on the study of both cortical epicentres and subcortical pathways, opens the door to mechanisms of functional reshaping. These recent technical and conceptual advances in the hodotopical and plastic view of brain processing have allowed a dramatic improvement of the benefit-to-risk ratio of surgery, concerning both oncological and functional outcomes. In summary, it is time to move towards "functional neurooncology" and "preventive neurosurgery" in low-grade gliomas. Stronger interactions with fundamental neurosciences should be developed, in order (1) to build updated models of cognition and brain plasticity; (2) to elaborate biomathematical models of low-grade glioma growth and migration; (3) to study in silico the dynamic interactions between the natural course of this disease and the adaptative behaviour of its host (the brain), with the goal to adapt the best individualised therapeutic strategy. © Springer-Verlag 2012.


Lowy I.,French Institute of Health and Medical Research
Studies in History and Philosophy of Science Part C :Studies in History and Philosophy of Biological and Biomedical Sciences | Year: 2014

Prenatal diagnosis was developed in the 1970s, a result of a partly contingent coming together of three medical innovations-amniocentesis, the study of human chromosomes and obstetrical ultrasound-with a social innovation, the decriminalization of abortion. Initially this diagnostic approach was proposed only to women at high risk of fetal malformations. Later, however, the supervision of the fetus was extended to all pregnant women. The latter step was strongly favoured by professionals' aspiration to prevent the birth of children with Down syndrome, an inborn condition perceived as a source of suffering for families and a burden on public purse. Experts who promoted screening for 'Down risk' assumed that the majority of women who carry a Down fetus will decide to terminate the pregnancy, and will provide a private solution to a public health problem. The generalization of screening for Down risk increased in turn the frequency of diagnoses of other, confirmed or potential fetal pathologies, and of dilemmas linked with such diagnoses. Debates on such dilemmas are usually limited to professionals. The transformation of prenatal diagnosis into a routine medical technology was, to a great extent, an invisible revolution. © 2013 Elsevier Ltd.


Savagner P.,French Institute of Health and Medical Research
Current Topics in Developmental Biology | Year: 2015

Epithelial-mesenchymal transition (EMT) is a developmental cellular process occurring during early embryo development, including gastrulation and neural crest cell migration. It can be broken down in distinct functional steps: (1) loss of baso-apical polarization characterized by cytoskeleton, tight junctions, and hemidesmosomes remodeling; (2) individualization of cells, including a decrease in cell-cell adhesion forces, (3) emergence of motility, and (4) invasive properties, including passing through the subepithelial basement membrane. These phases occur in an uninterrupted process, without requiring mitosis, in an order and with a degree of completion dictated by the microenvironment. The whole process reflects the activation of specific transcription factor families, called EMT transcription factors. Several mechanisms can combine to induce EMT. Some are reversible, involving growth factors and cytokines and/or environmental signals including extracellular matrix and local physical conditions. Others are irreversible, such as genomic alterations during carcinoma progression, along a selective and irreversible clonal drift. In carcinomas, these signals can converge to initiate a metastable phenotype. In this state, similarly to activated keratinocytes during re-epithelialization, cells can initiate a cohort migration and engage into a transient and reversible EMT controlled by the local environment prior to efficient intravasation and metastasis. EMT transcription factors also participate in cancer progression by inducing apoptosis resistance and maintaining stem-like properties exposed in tumor recurrences. These properties, very important on a clinical point of view, are not intrinsically linked to EMT, but can share common pathways. © 2015 Elsevier Inc.


Tapper E.B.,Beth Israel Deaconess Medical Center | Castera L.,French Institute of Health and Medical Research | Afdhal N.H.,Beth Israel Deaconess Medical Center
Clinical Gastroenterology and Hepatology | Year: 2015

With widespread screening and increasingly effective treatments for patients with viral hepatitis as well as the increasing prevalence of nonalcoholic fatty liver disease, the population presenting to the care of gastroenterologists and hepatologists is certain to increase. Assessment of advanced liver disease is traditionally invasive and expensive. Vibration-controlled transient elastography, commonly delivered by the FibroScan device, is an option recently approved by the Food and Drug Administration for the noninvasive assessment of liver disease at the point of care. Herein, we review the promise and pitfalls of vibration-controlled transient elastography with the aim of providing clinicians with a framework to interpret its results and apply this technology to the changing needs of our patients. © 2015 AGA Institute.


Bernheim A.,French Institute of Health and Medical Research
Molecular Oncology | Year: 2010

The role of acquired chromosomal rearrangements in oncogenesis (cytogenomics) and tumor progression is now well established. These alterations are multiple and diverse and the products of these rearranged genes play an essential role in the transformation and growth of cancer cells. The validity of this assumption is demonstrated by the development of specific inhibitors or antibodies that eliminate tumoral cells by targeting some of these changes. Imatinib, an inhibitor of the tyrosine kinase ABL, the prototype of these targeting drugs, is yielding complete remissions in most CML patients. Knowledge of chromosomal abnormalities is becoming an essential contribution to the diagnosis and prognosis of cancers but also for monitoring minimal residual disease or relapse. The concept of the " cytogenetic uniqueness" of each cancer has resulted in personalized treatment. This investigation will expound upon, besides the recurrent genomic alterations, the numerous products of perverted Darwinian selection at the cellular level. © 2010 Federation of European Biochemical Societies.


Bankir L.,French Institute of Health and Medical Research | Yang B.,Peking University | Yang B.,Key Laboratory of Molecular Cardiovascular science
Kidney International | Year: 2012

The mechanism by which urine is concentrated in the mammalian kidney remains incompletely understood. Urea is the dominant urinary osmole in most mammals and may be concentrated a 100-fold above its plasma level in humans and even more in rodents. Several facilitated urea transporters have been cloned. The phenotypes of mice with deletion of the transporters expressed in the kidney have challenged two previously well-accepted paradigms regarding urea and sodium handling in the renal medulla but have provided no alternative explanation for the accumulation of solutes that occurs in the inner medulla. In this review, we present evidence supporting the existence of an active urea secretion in the pars recta of the proximal tubule and explain how it changes our views regarding intrarenal urea handling and UT-A2 function. The transporter responsible for this secretion could be SGLT1, a sodium-glucose cotransporter that also transports urea. Glucagon may have a role in the regulation of this secretion. Further, we describe a possible transfer of osmotic energy from the outer to the inner medulla via an intrarenal Cori cycle converting glucose to lactate and back. Finally, we propose that an active urea transporter, expressed in the urothelium, may continuously reclaim urea that diffuses out of the ureter and bladder. These hypotheses are all based on published findings. They may not all be confirmed later on, but we hope they will stimulate further research in new directions. © 2012 International Society of Nephrology.


LeMasson G.,French Institute of Health and Medical Research | LeMasson G.,Bordeaux University Hospital Center | Przedborski S.,Columbia University | Abbott L.F.,Columbia University
Neuron | Year: 2014

To explore the link between bioenergetics and motorneuron degeneration, we used a computational model in which detailed morphology and ion conductance are paired with intracellular ATP production and consumption. We found that reduced ATP availability increases the metabolic cost of a single action potential and disrupts K+/Na+ homeostasis, resulting ina chronic depolarization. The magnitude of the ATP shortage at which this ionic instability occurs depends on the morphology and intrinsic conductance characteristic of the neuron. If ATP shortageisconfined to the distal part of the axon, the ensuinglocal ionic instability eventually spreads tothe wholeneuron and involves fasciculatio