Showing papers by "French Institute of Health and Medical Research published in 2014"
TL;DR: Associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses.
Abstract: Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.
6,809 citations
TL;DR: The extracellular matrix is crucial for regulating the morphogenesis of the intestine and lungs, as well as of the mammary and submandibular glands, and its regulation contributes to several pathological conditions, such as fibrosis and invasive cancer.
Abstract: The extracellular matrix (ECM) is a highly dynamic structure that is present in all tissues and continuously undergoes controlled remodelling. This process involves quantitative and qualitative changes in the ECM, mediated by specific enzymes that are responsible for ECM degradation, such as metalloproteinases. The ECM interacts with cells to regulate diverse functions, including proliferation, migration and differentiation. ECM remodelling is crucial for regulating the morphogenesis of the intestine and lungs, as well as of the mammary and submandibular glands. Dysregulation of ECM composition, structure, stiffness and abundance contributes to several pathological conditions, such as fibrosis and invasive cancer. A better understanding of how the ECM regulates organ structure and function and of how ECM remodelling affects disease progression will contribute to the development of new therapeutics.
2,854 citations
French Institute of Health and Medical Research1, Pierre-and-Marie-Curie University2, University of British Columbia3, UBC Hospital4, Beta5, Sahlgrenska University Hospital6, University of Virginia7, McGill University8, Brigham and Women's Hospital9, Washington University in St. Louis10, Vita-Salute San Raffaele University11, University College London12, University of Antwerp13, University of Geneva14, University of California, San Diego15, University of Kentucky16, Karolinska University Hospital17, university of lille18, University of California, San Francisco19, University of Nice Sophia Antipolis20, Brown University21, University of Paris22, Universidade Federal de Minas Gerais23, Maastricht University Medical Centre24, University of Southern California25, NewYork–Presbyterian Hospital26, VU University Amsterdam27, Lou Ruvo Brain Institute28
TL;DR: It is proposed that downstream topographical biomarkers of the disease, such as volumetric MRI and fluorodeoxyglucose PET, might better serve in the measurement and monitoring of the course of disease.
Abstract: In the past 8 years, both the International Working Group (IWG) and the US National Institute on Aging-Alzheimer's Association have contributed criteria for the diagnosis of Alzheimer's disease (AD) that better define clinical phenotypes and integrate biomarkers into the diagnostic process, covering the full staging of the disease. This Position Paper considers the strengths and limitations of the IWG research diagnostic criteria and proposes advances to improve the diagnostic framework. On the basis of these refinements, the diagnosis of AD can be simplified, requiring the presence of an appropriate clinical AD phenotype (typical or atypical) and a pathophysiological biomarker consistent with the presence of Alzheimer's pathology. We propose that downstream topographical biomarkers of the disease, such as volumetric MRI and fluorodeoxyglucose PET, might better serve in the measurement and monitoring of the course of disease. This paper also elaborates on the specific diagnostic criteria for atypical forms of AD, for mixed AD, and for the preclinical states of AD.
2,581 citations
University of Gothenburg1, University of Melbourne2, University of California, San Diego3, Semmelweis University4, Cedars-Sinai Medical Center5, University of Oxford6, Pohang University of Science and Technology7, Agency for Science, Technology and Research8, La Trobe University9, Brown University10, Icahn School of Medicine at Mount Sinai11, Hiroshima University12, Utrecht University13, Johns Hopkins University14, French Institute of Health and Medical Research15
TL;DR: The International Society for Extracellular Vesicles (ISEV) provides researchers with a minimal set of biochemical, biophysical and functional standards that should be used to attribute any specific biological cargo or functions to EVs.
Abstract: Secreted membrane-enclosed vesicles, collectively called extracellular vesicles (EVs), which include exosomes, ectosomes, microvesicles, microparticles, apoptotic bodies and other EV subsets, encompass a very rapidly growing scientific field in biology and medicine. Importantly, it is currently technically challenging to obtain a totally pure EV fraction free from non-vesicular components for functional studies, and therefore there is a need to establish guidelines for analyses of these vesicles and reporting of scientific studies on EV biology. Here, the International Society for Extracellular Vesicles (ISEV) provides researchers with a minimal set of biochemical, biophysical and functional standards that should be used to attribute any specific biological cargo or functions to EVs.
2,028 citations
Broad Institute1, Harvard University2, Monash University3, Kyoto University4, Genentech5, Vanderbilt University6, New York University7, NewYork–Presbyterian Hospital8, Second Military Medical University9, University of Queensland10, University of Toronto11, University of Groningen12, University of Tartu13, Beijing Jiaotong University14, Icahn School of Medicine at Mount Sinai15, Radboud University Nijmegen16, Medisch Spectrum Twente17, Leiden University18, University of Paris19, French Institute of Health and Medical Research20, University of Alabama at Birmingham21, University of Amsterdam22, University of Cambridge23, GlaxoSmithKline24, Hanyang University25, Spanish National Research Council26, Complutense University of Madrid27, Umeå University28, Boston University29, Council on Education for Public Health30, McGill University31, National Health Service32, University of Manchester33, University of Pittsburgh34, University of California, San Francisco35, Karolinska Institutet36, North Shore-LIJ Health System37, University of Chicago38, University of Tokyo39
TL;DR: A genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries provides empirical evidence that the genetics of RA can provide important information for drug discovery, and sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis.
Abstract: A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)1. Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ~10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2, 3, 4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation5, cis-acting expression quantitative trait loci6 and pathway analyses7, 8, 9—as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes—to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.
1,910 citations
TL;DR: The dialogue between autophagy and cell death pathways influences the normal clearance of dying cells, as well as immune recognition of dead cell antigens, and the disruption of the relationship between autphagy and apoptosis has important pathophysiological consequences.
Abstract: Autophagy and apoptosis control the turnover of organelles and proteins within cells, and of cells within organisms, respectively, and many stress pathways sequentially elicit autophagy, and apoptosis within the same cell. Generally autophagy blocks the induction of apoptosis, and apoptosis-associated caspase activation shuts off the autophagic process. However, in special cases, autophagy or autophagy-relevant proteins may help to induce apoptosis or necrosis, and autophagy has been shown to degrade the cytoplasm excessively, leading to 'autophagic cell death'. The dialogue between autophagy and cell death pathways influences the normal clearance of dying cells, as well as immune recognition of dead cell antigens. Therefore, the disruption of the relationship between autophagy and apoptosis has important pathophysiological consequences.
1,721 citations
National Institutes of Health1, University of Minnesota2, Max Planck Society3, University College London4, University of Washington5, French Institute of Health and Medical Research6, Paul Sabatier University7, Boston University8, University of Tübingen9, deCODE genetics10, Columbia University Medical Center11, Erasmus University Rotterdam12, Stanford University13, University of Thessaly14, Washington University in St. Louis15, Michael J. Fox Foundation16, German Center for Neurodegenerative Diseases17, New York State Department of Health18, University of Paris19, Centre national de la recherche scientifique20, University of Miami21, Indiana University22
TL;DR: This article conducted a meta-analysis of Parkinson's disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls.
Abstract: We conducted a meta-analysis of Parkinson's disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls. Twenty-six loci were identified as having genome-wide significant association; these and 6 additional previously reported loci were then tested in an independent set of 5,353 cases and 5,551 controls. Of the 32 tested SNPs, 24 replicated, including 6 newly identified loci. Conditional analyses within loci showed that four loci, including GBA, GAK-DGKQ, SNCA and the HLA region, contain a secondary independent risk variant. In total, we identified and replicated 28 independent risk variants for Parkinson's disease across 24 loci. Although the effect of each individual locus was small, risk profile analysis showed substantial cumulative risk in a comparison of the highest and lowest quintiles of genetic risk (odds ratio (OR) = 3.31, 95% confidence interval (CI) = 2.55–4.30; P = 2 × 10−16). We also show six risk loci associated with proximal gene expression or DNA methylation.
1,636 citations
University of Bonn1, German Center for Neurodegenerative Diseases2, Harvard University3, Maastricht University4, Aix-Marseille University5, Pierre-and-Marie-Curie University6, French Institute of Health and Medical Research7, University of Melbourne8, VU University Amsterdam9, New York University10, Mayo Clinic11, City University of New York12, University of New South Wales13, Indiana University14, King's College London15, University of Toulouse16
TL;DR: Research criteria for SCD in pre‐mild cognitive impairment (MCI) are presented and a list of core features proposed for reporting in SCD studies is provided, which will enable comparability of research across different settings.
Abstract: There is increasing evidence that subjective cognitive decline (SCD) in individuals with unimpaired performance on cognitive tests may represent the first symptomatic manifestation of Alzheimer's disease (AD). The research on SCD in early AD, however, is limited by the absence of common standards. The working group of the Subjective Cognitive Decline Initiative (SCD-I) addressed this deficiency by reaching consensus on terminology and on a conceptual framework for research on SCD in AD. In this publication, research criteria for SCD in pre-mild cognitive impairment (MCI) are presented. In addition, a list of core features proposed for reporting in SCD studies is provided, which will enable comparability of research across different settings. Finally, a set of features is presented, which in accordance with current knowledge, increases the likelihood of the presence of preclinical AD in individuals with SCD. This list is referred to as SCD plus.
1,626 citations
Paris 12 Val de Marne University1, French Institute of Health and Medical Research2, University of Göttingen3, Ghent University4, University Hospital of Lausanne5, University of Lisbon6, university of lille7, Università Campus Bio-Medico8, University of Belgrade9, University of Hamburg10, Turku University Hospital11, Aristotle University of Thessaloniki12, University of Regensburg13, University of Bern14, Ludwig Maximilian University of Munich15, University of Siena16, The Catholic University of America17, University College London18, University of Ulm19, Copenhagen University Hospital20, University of Oxford21, University of Barcelona22, University of Tübingen23
TL;DR: There is a sufficient body of evidence to accept with level A (definite efficacy) the analgesic effect of high-frequency rTMS of the primary motor cortex (M1) contralateral to the pain and the antidepressant effect of HF-rT MS of the left dorsolateral prefrontal cortex (DLPFC).
1,554 citations
Valentina Escott-Price1, Céline Bellenguez2, Li-San Wang3, Seung Hoan Choi4 +191 more•Institutions (67)
TL;DR: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimers disease.
Abstract: Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This s ...
1,518 citations
TL;DR: Hypoxia selectively up-regulates PD-L1 on myeloid-derived suppressor cells via HIF-1a, thus affecting T cell activation.
Abstract: Tumor-infiltrating myeloid cells such as myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) form an important component of the hypoxic tumor microenvironment. Here, we investigated the influence of hypoxia on immune checkpoint receptors (programmed death [PD]-1 and CTLA-4) and their respective ligands (PD-1 ligand 1 [PD-L1], PD-L2, CD80, and CD86) on MDSCs. We demonstrate that MDSCs at the tumor site show a differential expression of PD-L1 as compared with MDSCs from peripheral lymphoid organ (spleen). Hypoxia caused a rapid, dramatic, and selective up-regulation of PD-L1 on splenic MDSCs in tumor-bearing mice. This was not limited to MDSCs, as hypoxia also significantly increased the expression of PD-L1 on macrophages, dendritic cells, and tumor cells. Furthermore, PD-L1 up-regulation under hypoxia was dependent on hypoxia-inducible factor-1α (HIF-1α) but not HIF-2α. Chromatin immunoprecipitation and luciferase reporter assay revealed direct binding of HIF-1α to a transcriptionally active hypoxia-response element (HRE) in the PD-L1 proximal promoter. Blockade of PD-L1 under hypoxia enhanced MDSC-mediated T cell activation and was accompanied by the down-regulation of MDSCs IL-6 and IL-10. Finally, neutralizing antibodies against IL-10 under hypoxia significantly abrogated the suppressive activity of MDSCs. Simultaneous blockade of PD-L1 along with inhibition of HIF-1α may thus represent a novel approach for cancer immunotherapy.
Catholic University of the Sacred Heart1, University of Nice Sophia Antipolis2, Autonomous University of Baja California3, Kyoto University4, Institut national de la recherche agronomique5, Taipei Veterans General Hospital6, Tufts University7, Guy's and St Thomas' NHS Foundation Trust8, University of Central Florida9, University of Pittsburgh10, French Institute of Health and Medical Research11, The Chinese University of Hong Kong12, University of Verona13, Uppsala University14
TL;DR: Prevalence of sarcopenia is substantial in most geriatric settings, and well-designed, standardised studies evaluating exercise or nutrition interventions are needed before treatment guidelines can be developed.
Abstract: OBJECTIVE: to examine the clinical evidence reporting the prevalence of sarcopenia and the effect of nutrition and exercise interventions from studies using the consensus definition of sarcopenia proposed by the European Working Group on Sarcopenia in Older People (EWGSOP).METHODS: PubMed and Dialog databases were searched (January 2000-October 2013) using pre-defined search terms. Prevalence studies and intervention studies investigating muscle mass plus strength or function outcome measures using the EWGSOP definition of sarcopenia, in well-defined populations of adults aged ≥50 years were selected.RESULTS: prevalence of sarcopenia was, with regional and age-related variations, 1-29% in community-dwelling populations, 14-33% in long-term care populations and 10% in the only acute hospital-care population examined. Moderate quality evidence suggests that exercise interventions improve muscle strength and physical performance. The results of nutrition interventions are equivocal due to the low number of studies and heterogeneous study design. Essential amino acid (EAA) supplements, including ∼2.5 g of leucine, and β-hydroxy β-methylbutyric acid (HMB) supplements, show some effects in improving muscle mass and function parameters. Protein supplements have not shown consistent benefits on muscle mass and function.CONCLUSION: prevalence of sarcopenia is substantial in most geriatric settings. Well-designed, standardised studies evaluating exercise or nutrition interventions are needed before treatment guidelines can be developed. Physicians should screen for sarcopenia in both community and geriatric settings, with diagnosis based on muscle mass and function. Supervised resistance exercise is recommended for individuals with sarcopenia. EAA (with leucine) and HMB may improve muscle outcomes.
TL;DR: Interest in the release of membrane-enclosed vesicles by cells into their surrounding environment has been the subject of increasing interest in the past few years, and different families of molecules have been shown to allow intracellular formation of exosomes and their subsequent secretion, which suggests that even among exosome different sub-types exist.
TL;DR: Intestinal permeability, which is a feature of intestinal barrier function, is increasingly recognized as being of relevance for health and disease, and therefore, this topic warrants more attention.
Abstract: Data are accumulating that emphasize the important role of the intestinal barrier and intestinal permeability for health and disease. However, these terms are poorly defined, their assessment is a matter of debate, and their clinical significance is not clearly established. In the present review, current knowledge on mucosal barrier and its role in disease prevention and therapy is summarized. First, the relevant terms ‘intestinal barrier’ and ‘intestinal permeability’ are defined. Secondly, the key element of the intestinal barrier affecting permeability are described. This barrier represents a huge mucosal surface, where billions of bacteria face the largest immune system of our body. On the one hand, an intact intestinal barrier protects the human organism against invasion of microorganisms and toxins, on the other hand, this barrier must be open to absorb essential fluids and nutrients. Such opposing goals are achieved by a complex anatomical and functional structure the intestinal barrier consists of, the functional status of which is described by ‘intestinal permeability’. Third, the regulation of intestinal permeability by diet and bacteria is depicted. In particular, potential barrier disruptors such as hypoperfusion of the gut, infections and toxins, but also selected over-dosed nutrients, drugs, and other lifestyle factors have to be considered. In the fourth part, the means to assess intestinal permeability are presented and critically discussed. The means vary enormously and probably assess different functional components of the barrier. The barrier assessments are further hindered by the natural variability of this functional entity depending on species and genes as well as on diet and other environmental factors. In the final part, we discuss selected diseases associated with increased intestinal permeability such as critically illness, inflammatory bowel diseases, celiac disease, food allergy, irritable bowel syndrome, and – more recently recognized – obesity and metabolic diseases. All these diseases are characterized by inflammation that might be triggered by the translocation of luminal components into the host. In summary, intestinal permeability, which is a feature of intestinal barrier function, is increasingly recognized as being of relevance for health and disease, and therefore, this topic warrants more attention.
TL;DR: Developing new therapies that can improve HBsAg clearance and virological cure is warranted because long-term antiviral treatment can reverse cirrhosis and reduce hepatocellular carcinoma.
Pierre-and-Marie-Curie University1, Paris Descartes University2, French Institute of Health and Medical Research3, University of Bern4, University of Erlangen-Nuremberg5, Providence Portland Medical Center6, Radboud University Nijmegen7, Umeå University8, Karolinska Institutet9, Humanitas University10, Medical University of Graz11, Dorset County Hospital NHS Foundation Trust12, Charles University in Prague13, Cornell University14, University Health Network15, University of Toronto16, Keio University17, Yamaguchi University18, Kindai University19, Harvard University20, Royal Melbourne Hospital21, University of Melbourne22, Sapporo Medical University23, Kurume University24, Xi'an Jiaotong University25, University of Texas MD Anderson Cancer Center26, Mayo Clinic27, Grigore T. Popa University of Medicine and Pharmacy28, Oregon Health & Science University29
TL;DR: In colorectal cancer, the Immunoscore may add to the significance of the current AJCC/UICC TNM classification, since it has been demonstrated to be a prognostic factor superior to the AJCC or UICCTNM classification.
Abstract: The American Joint Committee on Cancer/Union Internationale Contre le Cancer (AJCC/UICC) TNM staging system provides the most reliable guidelines for the routine prognostication and treatment of colorectal carcinoma. This traditional tumour staging summarizes data on tumour burden (T), the presence of cancer cells in draining and regional lymph nodes (N) and evidence for distant metastases (M). However, it is now recognized that the clinical outcome can vary significantly among patients within the same stage. The current classification provides limited prognostic information and does not predict response to therapy. Multiple ways to classify cancer and to distinguish different subtypes of colorectal cancer have been proposed, including morphology, cell origin, molecular pathways, mutation status and gene expression-based stratification. These parameters rely on tumour-cell characteristics. Extensive literature has investigated the host immune response against cancer and demonstrated the prognostic impact of the in situ immune cell infiltrate in tumours. A methodology named 'Immunoscore' has been defined to quantify the in situ immune infiltrate. In colorectal cancer, the Immunoscore may add to the significance of the current AJCC/UICC TNM classification, since it has been demonstrated to be a prognostic factor superior to the AJCC/UICC TNM classification. An international consortium has been initiated to validate and promote the Immunoscore in routine clinical settings. The results of this international consortium may result in the implementation of the Immunoscore as a new component for the classification of cancer, designated TNM-I (TNM-Immune).
Utrecht University1, University of Copenhagen2, University of Ulm3, University of Düsseldorf4, National and Kapodistrian University of Athens5, Imperial College London6, University College London7, Umeå University8, National Institutes of Health9, Norwegian Institute of Public Health10, University of Oslo11, Karolinska Institutet12, Aarhus University13, University Medical Center Utrecht14, Cancer Epidemiology Unit15, Swiss Tropical and Public Health Institute16, University of Basel17, French Institute of Health and Medical Research18, Institut Gustave Roussy19, University of Washington20, University of Turin21, Basque Government22
TL;DR: In this article, the authors investigated the association between natural-cause mortality and long-term exposure to several air pollutants, such as PM2.5, nitrogen oxides, and NOx.
TL;DR: In this paper, the authors aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry.
Abstract: To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry.
TL;DR: Convincing data place energy metabolism at the center of metformin's mechanism of action in diabetes and may also be of importance in cardiovascular diseases and cancer.
University of Bonn1, German Center for Neurodegenerative Diseases2, Harvard University3, Maastricht University4, Aix-Marseille University5, Pierre-and-Marie-Curie University6, French Institute of Health and Medical Research7, University of Melbourne8, VU University Amsterdam9, New York University10, Mayo Clinic11, City University of New York12, University of New South Wales13, Indiana University14, King's College London15, University of Toulouse16
TL;DR: In this paper, research criteria for subjective cognitive decline in individuals with unimpaired performance on cognitive tests may represent the first symptomatic manifestation of Alzheimer's disease (AD) are presented.
Abstract: There is increasing evidence that subjective cognitive decline (SCD) in individuals with unimpaired performance on cognitive tests may represent the first symptomatic manifestation of Alzheimer's disease (AD). The research on SCD in early AD, however, is limited by the absence of common standards. The working group of the Subjective Cognitive Decline Initiative (SCD-I) addressed this deficiency by reaching consensus on terminology and on a conceptual framework for research on SCD in AD. In this publication, research criteria for SCD in pre-mild cognitive impairment (MCI) are presented. In addition, a list of core features proposed for reporting in SCD studies is provided, which will enable comparability of research across different settings. Finally, a set of features is presented, which in accordance with current knowledge, increases the likelihood of the presence of preclinical AD in individuals with SCD. This list is referred to as SCD plus.
TL;DR: In this paper, the authors point out that unless research is adequately reported, the time and resources invested in the conduct of research is wasted, and the high amount of waste also warrants future investment in the monitoring of and research into reporting of research, and active implementation of the findings to ensure that research reports better address the needs of the range of research users.
University of Manchester1, University of Oxford2, Brown University3, French Institute of Health and Medical Research4, Brigham and Women's Hospital5, Rensselaer Polytechnic Institute6, University of Alabama at Birmingham7, Public Health England8, University of Virginia9, University of Surrey10, Thomas Jefferson University11
TL;DR: A new light-measurement strategy taking account of the complex photoreceptive inputs to these non-visual responses is proposed for use by researchers, and simple suggestions for artificial/architectural lighting are provided for regulatory authorities, lighting manufacturers, designers, and engineers.
TL;DR: In this phase 3 trial of an oral, interferon-free regimen evaluated exclusively in patients with HCV genotype 1 infection and cirrhosis, multitargeted therapy with the use of three new antiviral agents and ribavirin resulted in high rates of sustained virology response.
Abstract: Background Interferon-containing regimens for the treatment of hepatitis C virus (HCV) infection are associated with increased toxic effects in patients who also have cirrhosis. We evaluated the interferon-free combination of the protease inhibitor ABT-450 with ritonavir (ABT-450/r), the NS5A inhibitor ombitasvir (ABT-267), the nonnucleoside polymerase inhibitor dasabuvir (ABT-333), and ribavirin in an open-label phase 3 trial involving previously untreated and previously treated adults with HCV genotype 1 infection and compensated cirrhosis. Methods We randomly assigned 380 patients with Child–Pugh class A cirrhosis to receive either 12 or 24 weeks of treatment with ABT-450/r–ombitasvir (at a once-daily dose of 150 mg of ABT-450, 100 mg of ritonavir, and 25 mg of ombitasvir), dasabuvir (250 mg twice daily), and ribavirin administered according to body weight. The primary efficacy end point was a sustained virologic response 12 weeks after the end of treatment. The rate of sustained virologic response in ...
TL;DR: It is proposed that the plasticity of BCSCs that allows them to transition between EMT- and MET-like states endows these cells with the capacity for tissue invasion, dissemination, and growth at metastatic sites.
Abstract: Previous studies have suggested that breast cancer stem cells (BCSCs) mediate metastasis, are resistant to radiation and chemotherapy, and contribute to relapse. Although several BCSC markers have been described, it is unclear whether these markers identify the same or independent BCSCs. Here, we show that BCSCs exist in distinct mesenchymal-like (epithelial-mesenchymal transition [EMT]) and epithelial-like (mesenchymal-epithelial transition [MET]) states. Mesenchymal-like BCSCs characterized as CD24−CD44+ are primarily quiescent and localized at the tumor invasive front, whereas epithelial-like BCSCs express aldehyde dehydrogenase (ALDH), are proliferative, and are located more centrally. The gene-expression profiles of mesenchymal-like and epithelial-like BCSCs are remarkably similar across different molecular subtypes of breast cancer, and resemble those of distinct basal and luminal stem cells found in the normal breast. We propose that the plasticity of BCSCs that allows them to transition between EMT- and MET-like states endows these cells with the capacity for tissue invasion, dissemination, and growth at metastatic sites.
Icahn School of Medicine at Mount Sinai1, Pierre-and-Marie-Curie University2, French Institute of Health and Medical Research3, Centre national de la recherche scientifique4, University of Toronto5, Trinity College, Dublin6, University of Pittsburgh7, Utrecht University8, McMaster University9, University College Dublin10, Our Lady's Children's Hospital11, University of Oxford12, University of Lisbon13, Instituto Nacional de Saúde Dr. Ricardo Jorge14, University of California, Los Angeles15, University of Miami16, Goethe University Frankfurt17, University of Pennsylvania18, Vanderbilt University19, Temple University20, University of Bologna21, Cancer Care Ontario22, University of Southern California23, University of Alberta24, University of Birmingham25, Université de Montréal26, Rush University Medical Center27, University of Coimbra28, Kaiser Permanente29, Cornell University30, Newcastle University31, University of Illinois at Chicago32, University of Minnesota33, University of Gothenburg34, Memorial University of Newfoundland35, Duke University36, University of Paris37, Centre for Mental Health38, King's College London39, University of Washington40, Nationwide Children's Hospital41, Indiana University42, Tufts University43, German Cancer Research Center44, University of Utah45, Stanford University46
TL;DR: For example, the authors analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability.
Abstract: Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.
Paris Descartes University1, Necker-Enfants Malades Hospital2, French Institute of Health and Medical Research3, Semmelweis University4, University of Helsinki5, University of Toronto6, Wolfson Medical Center7, Erasmus University Rotterdam8, Boston Children's Hospital9, Karolinska Institutet10, Paris Diderot University11, University of Zagreb12, University of Naples Federico II13, Iuliu Hațieganu University of Medicine and Pharmacy14, Rappaport Faculty of Medicine15, University Medical Center Groningen16, Sheba Medical Center17, Royal Hospital for Sick Children18, Harvard University19, Hebrew University of Jerusalem20
TL;DR: These guidelines are intended to give practical (whenever possible evidence-based) answers to (pediatric) gastroenterologists who take care of children and adolescents with CD, since many different clinical scenario exist requiring treatment strategies not covered by or different from these guidelines.
TL;DR: It is found that embryonic precursor cells seeded the intestinal mucosa and demonstrated extensive in situ proliferation during the neonatal period, but these cells did not persist in the intestine of adult mice and were replaced around the time of weaning by the chemokine receptor CCR2–dependent influx of Ly6Chi monocytes that differentiated locally into mature, anti-inflammatory macrophages.
Abstract: The paradigm that macrophages that reside in steady-state tissues are derived from embryonic precursors has never been investigated in the intestine, which contains the largest pool of macrophages. Using fate-mapping models and monocytopenic mice, together with bone marrow chimera and parabiotic models, we found that embryonic precursor cells seeded the intestinal mucosa and demonstrated extensive in situ proliferation during the neonatal period. However, these cells did not persist in the intestine of adult mice. Instead, they were replaced around the time of weaning by the chemokine receptor CCR2-dependent influx of Ly6C(hi) monocytes that differentiated locally into mature, anti-inflammatory macrophages. This process was driven largely by the microbiota and had to be continued throughout adult life to maintain a normal intestinal macrophage pool.
University of Lyon1, French Institute of Health and Medical Research2, Yale University3, University of Notre Dame4, Babeș-Bolyai University5, Max Planck Society6, Valparaiso University7, Netherlands Institute for Neuroscience8, University of Oxford9, McGill University10, Washington University in St. Louis11
TL;DR: The directed and weighted G29 × 91 connectivity matrix for the macaque will be valuable for comparison with connectivity analyses in other species, including humans, and inform future modeling studies that explore the regularities of cortical networks.
Abstract: Retrograde tracer injections in 29 of the 91 areas of the macaque cerebral cortex revealed 1,615 interareal pathways, a third of which have not previously been reported. A weight index (extrinsic fraction of labeled neurons [FLNe]) was determined for each area-to-area pathway. Newly found projections were weaker on average compared with the known projections; nevertheless, the 2 sets of pathways had extensively overlapping weight distributions. Repeat injections across individuals revealed modest FLNe variability given the range of FLNe values (standard deviation <1 log unit, range 5 log units). The connectivity profile for each area conformed to a lognormal distribution, where a majority of projections are moderate or weak in strength. In the G29 × 29 interareal subgraph, two-thirds of the connections that can exist do exist. Analysis of the smallest set of areas that collects links from all 91 nodes of the G29 × 91 subgraph (dominating set analysis) confirms the dense (66%) structure of the cortical matrix. The G29 × 29 subgraph suggests an unexpectedly high incidence of unidirectional links. The directed and weighted G29 × 91 connectivity matrix for the macaque will be valuable for comparison with connectivity analyses in other species, including humans. It will also inform future modeling studies that explore the regularities of cortical networks.
TL;DR: The myeloma genome is heterogeneous across the cohort, and exhibits diversity in clonal admixture and in dynamics of evolution, which may impact prognostic stratification, therapeutic approaches and assessment of disease response to treatment.
Abstract: Multiple myeloma is an incurable plasma cell malignancy with a complex and incompletely understood molecular pathogenesis. Here we use whole-exome sequencing, copy-number profiling and cytogenetics to analyse 84 myeloma samples. Most cases have a complex subclonal structure and show clusters of subclonal variants, including subclonal driver mutations. Serial sampling reveals diverse patterns of clonal evolution, including linear evolution, differential clonal response and branching evolution. Diverse processes contribute to the mutational repertoire, including kataegis and somatic hypermutation, and their relative contribution changes over time. We find heterogeneity of mutational spectrum across samples, with few recurrent genes. We identify new candidate genes, including truncations of SP140, LTB, ROBO1 and clustered missense mutations in EGR1. The myeloma genome is heterogeneous across the cohort, and exhibits diversity in clonal admixture and in dynamics of evolution, which may impact prognostic stratification, therapeutic approaches and assessment of disease response to treatment.
University of Paris-Sud1, Tel Aviv University2, University of California, Irvine3, French Institute of Health and Medical Research4, National Institutes of Health5, University of Glasgow6, University of California, Davis7, University of Copenhagen8, University of Milan9, Harvard University10, University of Tokyo11, Kumamoto University12, Merck KGaA13, University of Birmingham14, University of Brescia15, Kindai University16
TL;DR: This work reviews this extended family of chemokine receptors and Chemokine-binding proteins at the basic, translational, and clinical levels, including an update on drug development and introduces a new nomenclature for atypical chemokin receptors with the stem ACKR (atypicalChemokine receptor).
Abstract: Sixteen years ago, the Nomenclature Committee of the International Union of Pharmacology approved a system for naming human seven-transmembrane (7TM) G protein-coupled chemokine receptors, the large family of leukocyte chemoattractant receptors that regulates immune system development and function, in large part by mediating leukocyte trafficking. This was announced in Pharmacological Reviews in a major overview of the first decade of research in this field [Murphy PM, Baggiolini M, Charo IF, Hebert CA, Horuk R, Matsushima K, Miller LH, Oppenheim JJ, and Power CA (2000) Pharmacol Rev 52:145–176]. Since then, several new receptors have been discovered, and major advances have been made for the others in many areas, including structural biology, signal transduction mechanisms, biology, and pharmacology. New and diverse roles have been identified in infection, immunity, inflammation, development, cancer, and other areas. The first two drugs acting at chemokine receptors have been approved by the U.S. Food and Drug Administration (FDA), maraviroc targeting CCR5 in human immunodeficiency virus (HIV)/AIDS, and plerixafor targeting CXCR4 for stem cell mobilization for transplantation in cancer, and other candidates are now undergoing pivotal clinical trials for diverse disease indications. In addition, a subfamily of atypical chemokine receptors has emerged that may signal through arrestins instead of G proteins to act as chemokine scavengers, and many microbial and invertebrate G protein-coupled chemokine receptors and soluble chemokine-binding proteins have been described. Here, we review this extended family of chemokine receptors and chemokine-binding proteins at the basic, translational, and clinical levels, including an update on drug development. We also introduce a new nomenclature for atypical chemokine receptors with the stem ACKR (atypical chemokine receptor) approved by the Nomenclature Committee of the International Union of Pharmacology and the Human Genome Nomenclature Committee.