Showing papers by "Pierre-and-Marie-Curie University published in 2016"
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TL;DR: In this paper, the authors present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macro-autophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes.
Abstract: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes.
For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy.
Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagy-related protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.
5,187 citations
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TL;DR: In this article, the authors present the background and rationale for the new structure of CMIP, provides a detailed description of the DECK and CMIP6 historical simulations, and includes a brief introduction to the 21-CMIP6-Endorsed MIPs.
Abstract: . By coordinating the design and distribution of global climate model simulations of the past, current, and future climate, the Coupled Model Intercomparison Project (CMIP) has become one of the foundational elements of climate science. However, the need to address an ever-expanding range of scientific questions arising from more and more research communities has made it necessary to revise the organization of CMIP. After a long and wide community consultation, a new and more federated structure has been put in place. It consists of three major elements: (1) a handful of common experiments, the DECK (Diagnostic, Evaluation and Characterization of Klima) and CMIP historical simulations (1850–near present) that will maintain continuity and help document basic characteristics of models across different phases of CMIP; (2) common standards, coordination, infrastructure, and documentation that will facilitate the distribution of model outputs and the characterization of the model ensemble; and (3) an ensemble of CMIP-Endorsed Model Intercomparison Projects (MIPs) that will be specific to a particular phase of CMIP (now CMIP6) and that will build on the DECK and CMIP historical simulations to address a large range of specific questions and fill the scientific gaps of the previous CMIP phases. The DECK and CMIP historical simulations, together with the use of CMIP data standards, will be the entry cards for models participating in CMIP. Participation in CMIP6-Endorsed MIPs by individual modelling groups will be at their own discretion and will depend on their scientific interests and priorities. With the Grand Science Challenges of the World Climate Research Programme (WCRP) as its scientific backdrop, CMIP6 will address three broad questions: – How does the Earth system respond to forcing? – What are the origins and consequences of systematic model biases? – How can we assess future climate changes given internal climate variability, predictability, and uncertainties in scenarios? This CMIP6 overview paper presents the background and rationale for the new structure of CMIP, provides a detailed description of the DECK and CMIP6 historical simulations, and includes a brief introduction to the 21 CMIP6-Endorsed MIPs.
4,192 citations
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TL;DR: Galaxy seeks to make data-intensive research more accessible, transparent and reproducible by providing a Web-based environment in which users can perform computational analyses and have all of the details automatically tracked for later inspection, publication, or reuse.
Abstract: High-throughput data production technologies, particularly 'next-generation' DNA sequencing, have ushered in widespread and disruptive changes to biomedical research. Making sense of the large datasets produced by these technologies requires sophisticated statistical and computational methods , as well as substantial computational power. This has led to an acute crisis in life sciences, as researchers without informatics training attempt to perform computation-dependent analyses. Since 2005, the Galaxy project has worked to address this problem by providing a framework that makes advanced computational tools usable by non experts. Galaxy seeks to make data-intensive research more accessible , transparent and reproducible by providing a Web-based environment in which users can perform computational analyses and have all of the details automatically tracked for later inspection, publication , or reuse. In this report we highlight recently added features enabling biomedical analyses on a large scale.
1,774 citations
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TL;DR: The Microenvironment Cell Populations-counter method is introduced, which allows the robust quantification of the absolute abundance of eight immune and two stromal cell populations in heterogeneous tissues from transcriptomic data and demonstrates that MCP-counter overcomes several limitations or weaknesses of previously proposed computational approaches.
Abstract: We introduce the Microenvironment Cell Populations-counter (MCP-counter) method, which allows the robust quantification of the absolute abundance of eight immune and two stromal cell populations in heterogeneous tissues from transcriptomic data. We present in vitro mRNA mixture and ex vivo immunohistochemical data that quantitatively support the validity of our method's estimates. Additionally, we demonstrate that MCP-counter overcomes several limitations or weaknesses of previously proposed computational approaches. MCP-counter is applied to draw a global picture of immune infiltrates across human healthy tissues and non-hematopoietic human tumors and recapitulates microenvironment-based patient stratifications associated with overall survival in lung adenocarcinoma and colorectal and breast cancer.
1,663 citations
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Pierre-and-Marie-Curie University1, AXA2, University of British Columbia3, VU University Medical Center4, University of Southern California5, University of Toulouse6, ICM Partners7, French Institute of Health and Medical Research8, Imperial College London9, University of Lübeck10, Sahlgrenska University Hospital11, Federal Institute for Drugs and Medical Devices12, UCL Institute of Neurology13, University of Bordeaux14, University of Geneva15, McGill University16, University of Paris17, University of Washington18, University of Eastern Finland19, Karolinska University Hospital20, University of North Texas Health Science Center21, University of California, San Francisco22, University of Melbourne23, Brown University24, Harvard University25, Brigham and Women's Hospital26, Alzheimer's Association27, Lou Ruvo Brain Institute28, Mayo Clinic29
TL;DR: An updated review of the literature and evidence on the definitions and lexicon, the limits, the natural history, the markers of progression, and the ethical consequence of detecting the disease at this asymptomatic stage of Alzheimer's disease are provided.
Abstract: During the past decade, a conceptual shift occurred in the field of Alzheimer's disease (AD) considering the disease as a continuum. Thanks to evolving biomarker research and substantial discoveries, it is now possible to identify the disease even at the preclinical stage before the occurrence of the first clinical symptoms. This preclinical stage of AD has become a major research focus as the field postulates that early intervention may offer the best chance of therapeutic success. To date, very little evidence is established on this "silent" stage of the disease. A clarification is needed about the definitions and lexicon, the limits, the natural history, the markers of progression, and the ethical consequence of detecting the disease at this asymptomatic stage. This article is aimed at addressing all the different issues by providing for each of them an updated review of the literature and evidence, with practical recommendations.
1,235 citations
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Karolinska Institutet1, Karolinska University Hospital2, Pasteur Institute3, University of Toulouse4, Wolfson Centre for Age-Related Diseases5, University of Cambridge6, University of New South Wales7, Pierre-and-Marie-Curie University8, La Trobe University9, Umeå University10, University of British Columbia11, University of Geneva12, Douglas Mental Health University Institute13, Alzheimer Europe14, University of Cologne15, German Center for Neurodegenerative Diseases16, London School of Economics and Political Science17, Radboud University Nijmegen18, Rockefeller University19, VU University Medical Center20, University of Southern California21, Brigham and Women's Hospital22, University of Copenhagen23, UCL Institute of Neurology24, University of Gothenburg25
TL;DR: This poster aims to demonstrate the efforts towards in-situ applicability of EMMARM, which aims to provide real-time information about the physical and cognitive properties of Alzheimer's disease and other dementias.
Abstract: Defeating Alzheimer's disease and other dementias : a priority for European science and society
1,215 citations
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Lars G. Fritsche1, Wilmar Igl2, Jessica N. Cooke Bailey3, Felix Grassmann2 +182 more•Institutions (58)
TL;DR: The results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.
Abstract: Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.
1,088 citations
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TL;DR: In this article, a relationship between the host and the gut microbiota govern intestinal homeostasis is revealed, and the authors reveal that host genes affect the composition and function of the Gut microbiota, altering the production of microbial metabolites and intestinal inflammation.
Abstract: Complex interactions between the host and the gut microbiota govern intestinal homeostasis but remain poorly understood. Here we reveal a relationship between gut microbiota and caspase recruitment domain family member 9 (CARD9), a susceptibility gene for inflammatory bowel disease (IBD) that functions in the immune response against microorganisms. CARD9 promotes recovery from colitis by promoting interleukin (IL)-22 production, and Card9-/- mice are more susceptible to colitis. The microbiota is altered in Card9-/- mice, and transfer of the microbiota from Card9-/- to wild-type, germ-free recipients increases their susceptibility to colitis. The microbiota from Card9-/- mice fails to metabolize tryptophan into metabolites that act as aryl hydrocarbon receptor (AHR) ligands. Intestinal inflammation is attenuated after inoculation of mice with three Lactobacillus strains capable of metabolizing tryptophan or by treatment with an AHR agonist. Reduced production of AHR ligands is also observed in the microbiota from individuals with IBD, particularly in those with CARD9 risk alleles associated with IBD. Our findings reveal that host genes affect the composition and function of the gut microbiota, altering the production of microbial metabolites and intestinal inflammation.
887 citations
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Université Paris-Saclay1, University of Toronto2, Karolinska University Hospital3, Pierre-and-Marie-Curie University4, Cincinnati Children's Hospital Medical Center5, Memorial Sloan Kettering Cancer Center6, Paris Descartes University7, Necker-Enfants Malades Hospital8, University of Texas MD Anderson Cancer Center9, Icahn School of Medicine at Mount Sinai10, University of Pittsburgh11, Harvard University12, Brigham and Women's Hospital13, Mayo Clinic14
TL;DR: This revised classification system consists of 5 groups of diseases: (1) Langerhans-related, (2) cutaneous and mucocutaneous, and (3) malignant histiocytoses as well as (4) Rosai-Dorfman disease and (5) hemophagocytic lymphohistiocyts and macrophage activation syndrome.
848 citations
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French Institute of Health and Medical Research1, Pierre-and-Marie-Curie University2, San Antonio Military Medical Center3, University of Antwerp4, Paris Diderot University5, University of Melbourne6, Catholic University of Leuven7, University of Angers8, Duke University9, University of Virginia10, Radboud University Nijmegen11, Newcastle University12, university of lille13, Virginia Commonwealth University14, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico15, Semmelweis University16
TL;DR: A post-hoc analysis of data from trial of patients with NASH showed that elafibranor (120 mg/d for 1 year) resolved NASH without fibrosis worsening, based on a modified definition, in the intention-to-treat analysis and in patients with moderate or severe NASH.
813 citations
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TL;DR: Assessment of the immune status via Immunoscore provides a potent indicator of tumor recurrence beyond microsatellite-instability staging that could be an important guide for immunotherapy strategies.
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TL;DR: How a range of cancer-cell-autonomous cues, tumor-microenvironmental factors, and host-related influences might account for the heterogeneous responses and failures often encountered during therapies using immune-checkpoint blockade is reviewed.
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TL;DR: Practical guidelines are proposed for the oncologist to help in the clinical care of patients under ICB immunotherapy, which can become life-threatening if not anticipated and managed appropriately.
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TL;DR: Nuclear envelope opening in migrating leukocytes could have potentially important consequences for normal and pathological immune responses and survival of cells migrating through confining environments depended on efficient nuclear envelope and DNA repair machineries.
Abstract: In eukaryotic cells, the nuclear envelope separates the genomic DNA from the cytoplasmic space and regulates protein trafficking between the two compartments. This barrier is only transiently dissolved during mitosis. Here, we found that it also opened at high frequency in migrating mammalian cells during interphase, which allowed nuclear proteins to leak out and cytoplasmic proteins to leak in. This transient opening was caused by nuclear deformation and was rapidly repaired in an ESCRT (endosomal sorting complexes required for transport)-dependent manner. DNA double-strand breaks coincided with nuclear envelope opening events. As a consequence, survival of cells migrating through confining environments depended on efficient nuclear envelope and DNA repair machineries. Nuclear envelope opening in migrating leukocytes could have potentially important consequences for normal and pathological immune responses.
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TL;DR: The Extended Baryon Oscillation Spectroscopic Survey (eBOSS) as mentioned in this paper uses four different tracers of the underlying matter density field to expand the volume covered by BOSS and map the large-scale structures over the relatively unconstrained redshift range 0.6 0.87.
Abstract: In a six-year program started in 2014 July, the Extended Baryon Oscillation Spectroscopic Survey (eBOSS) will conduct novel cosmological observations using the BOSS spectrograph at Apache Point Observatory. These observations will be conducted simultaneously with the Time Domain Spectroscopic Survey (TDSS) designed for variability studies and the Spectroscopic Identification of eROSITA Sources (SPIDERS) program designed for studies of X-ray sources. In particular, eBOSS will measure with percent-level precision the distance-redshift relation with baryon acoustic oscillations (BAO) in the clustering of matter. eBOSS will use four different tracers of the underlying matter density field to vastly expand the volume covered by BOSS and map the large-scale-structures over the relatively unconstrained redshift range 0.6 0.6 sample of BOSS galaxies. With ~195,000 new emission line galaxy redshifts, we expect BAO measurements of d_A(z) to an accuracy of 3.1% and H(z) to 4.7% at an effective redshift of z = 0.87. A sample of more than 500,000 spectroscopically confirmed quasars will provide the first BAO distance measurements over the redshift range 0.9 2.1; these new data will enhance the precision of dA(z) and H(z) at z > 2.1 by a factor of 1.44 relative to BOSS. Furthermore, eBOSS will provide improved tests of General Relativity on cosmological scales through redshift-space distortion measurements, improved tests for non-Gaussianity in the primordial density field, and new constraints on the summed mass of all neutrino species. Here, we provide an overview of the cosmological goals, spectroscopic target sample, demonstration of spectral quality from early data, and projected cosmological constraints from eBOSS.
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Institut Gustave Roussy1, University of Paris2, French Institute of Health and Medical Research3, Pasteur Institute4, University of Caen Lower Normandy5, Université Paris-Saclay6, University of Burgundy7, Pierre-and-Marie-Curie University8, Paris Descartes University9, PSL Research University10, Centre national de la recherche scientifique11, Cornell University12, Monash University13, University of Kiel14, Aix-Marseille University15
TL;DR: Enterococcus hirae and B. intestinihominis represent valuable "oncomicrobiotics" ameliorating the efficacy of the most common alkylating immunomodulatory compound CTX, and selectively predicted longer progression-free survival in advanced lung and ovarian cancer patients treated with chemo-immunotherapy.
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TL;DR: In this paper, the effects of lower LDL cholesterol levels that were mediated by variants in PCSK9, HMGCR, or both on the risk of cardiovascular events and risk of diabetes were compared.
Abstract: BackgroundPharmacologic inhibitors of proprotein convertase subtilisin–kexin type 9 (PCSK9) are being evaluated in clinical trials for the treatment of cardiovascular disease. The effect of lowering low-density lipoprotein (LDL) cholesterol levels by inhibiting PCSK9 on the risk of cardiovascular events or diabetes is unknown. MethodsWe used genetic scores consisting of independently inherited variants in the genes encoding PCSK9 and 3-hydroxy-3-methylglutaryl–coenzyme A reductase (HMGCR; the target of statins) as instruments to randomly assign 112,772 participants from 14 studies, with 14,120 cardiovascular events and 10,635 cases of diabetes, to groups according to the number of LDL cholesterol–lowering alleles that they had inherited. We compared the effects of lower LDL cholesterol levels that were mediated by variants in PCSK9, HMGCR, or both on the risk of cardiovascular events and the risk of diabetes. ResultsVariants in PCSK9 and HMGCR were associated with nearly identical protective effects on th...
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TL;DR: A comprehensive database of economic costs of invasive insects is compiled, finding that invasive insects cost a minimum of US$70.0 billion per year globally, while associated health costs exceed US$6.9bn per year.
Abstract: Insects have presented human society with some of its greatest development challenges by spreading diseases, consuming crops and damaging infrastructure. Despite the massive human and financial toll of invasive insects, cost estimates of their impacts remain sporadic, spatially incomplete and of questionable quality. Here we compile a comprehensive database of economic costs of invasive insects. Taking all reported goods and service estimates, invasive insects cost a minimum of US$70.0 billion per year globally, while associated health costs exceed US$6.9 billion per year. Total costs rise as the number of estimate increases, although many of the worst costs have already been estimated (especially those related to human health). A lack of dedicated studies, especially for reproducible goods and service estimates, implies gross underestimation of global costs. Global warming as a consequence of climate change, rising human population densities and intensifying international trade will allow these costly insects to spread into new areas, but substantial savings could be achieved by increasing surveillance, containment and public awareness.
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TL;DR: A comprehensive overview of the main findings in AD and normal aging over the past twenty years, focusing on the patterns of gray and white matter changes assessed in vivo using MRI.
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University of Cagliari1, University of Sydney2, Katholieke Universiteit Leuven3, Lund University4, University of Milan5, University of Rome Tor Vergata6, University of São Paulo7, Pierre-and-Marie-Curie University8, University of Navarra9, University of Bologna10, Leeds Teaching Hospitals NHS Trust11, Wollongong Hospital12, Imperial College London13, University of Genoa14, University College Hospital15, Brigham and Women's Hospital16, University of Tokyo17
TL;DR: The IDEA (International Deep Endometriosis Analysis group) statement is a consensus opinion on terms, definitions and measurements that may be used to describe the sonographic features of the different phenotypes of endometiosis.
Abstract: The IDEA (International Deep Endometriosis Analysis group) statement is a consensus opinion on terms, definitions and measurements that may be used to describe the sonographic features of the different phenotypes of endometriosis. Currently, it is difficult to compare results between published studies because authors use different terms when describing the same structures and anatomical locations. We hope that the terms and definitions suggested herein will be adopted in centers around the world. This would result in consistent use of nomenclature when describing the ultrasound location and extent of endometriosis. We believe that the standardization of terminology will allow meaningful comparisons between future studies in women with an ultrasound diagnosis of endometriosis and should facilitate multicenter research. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.
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University of Oxford1, Chongqing Medical University2, University of Modena and Reggio Emilia3, University of Melbourne4, University of Dundee5, University of Sydney6, Technische Universität München7, VU University Amsterdam8, Pierre-and-Marie-Curie University9, University of Toronto10, Centre for Addiction and Mental Health11, Appalachian State University12
TL;DR: Comparisons of antidepressants and placebo for major depressive disorder in young people aimed at finding fluoxetine is probably the best option to consider when a pharmacological treatment is indicated and the quality of evidence was rated as very low in most comparisons.
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University of Pennsylvania1, Pierre-and-Marie-Curie University2, University of Cambridge3, Leiden University Medical Center4, Wellcome Trust Sanger Institute5, British Heart Foundation6, University of Glasgow7, Glasgow Clinical Research Facility8, International Centre for Diarrhoeal Disease Research, Bangladesh9, University of Michigan10, University of Lübeck11, Copenhagen University Hospital12, University of Copenhagen13, National Institutes of Health14, Pennsylvania State University15, University of Hamburg16, Pasteur Institute17, University of Strasbourg18, University of Toulouse19, Ludwig Maximilian University of Munich20, University of Insubria21, Queen's University Belfast22, National Institute for Health Research23, Technische Universität München24, Harvard University25, Washington University in St. Louis26
TL;DR: In this paper, the authors identified a homozygote for a loss-of-function variant, in which leucine replaces proline 376 (P376L), in SCARB1, the gene encoding SR-BI.
Abstract: Scavenger receptor BI (SR-BI) is the major receptor for high-density lipoprotein (HDL) cholesterol (HDL-C). In humans, high amounts of HDL-C in plasma are associated with a lower risk of coronary heart disease (CHD). Mice that have depleted Scarb1 (SR-BI knockout mice) have markedly elevated HDL-C levels but, paradoxically, increased atherosclerosis. The impact of SR-BI on HDL metabolism and CHD risk in humans remains unclear. Through targeted sequencing of coding regions of lipid-modifying genes in 328 individuals with extremely high plasma HDL-C levels, we identified a homozygote for a loss-of-function variant, in which leucine replaces proline 376 (P376L), in SCARB1, the gene encoding SR-BI. The P376L variant impairs posttranslational processing of SR-BI and abrogates selective HDL cholesterol uptake in transfected cells, in hepatocyte-like cells derived from induced pluripotent stem cells from the homozygous subject, and in mice. Large population-based studies revealed that subjects who are heterozygous carriers of the P376L variant have significantly increased levels of plasma HDL-C. P376L carriers have a profound HDL-related phenotype and an increased risk of CHD (odds ratio = 1.79, which is statistically significant).
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TL;DR: The distinct immune orientations of the colorectal cancer molecular subtypes pave the way for tailored immunotherapies.
Abstract: Purpose: The tumor microenvironment is formed by many distinct and interacting cell populations, and its composition may predict patient9s prognosis and response to therapies. Colorectal cancer (CRC) is a heterogeneous disease in which immune classifications and four consensus molecular subgroups (CMS) have been described. Our aim was to integrate the composition of the tumor microenvironment with the consensus molecular classification of CRC.
Experimental design: We retrospectively analyzed the composition and the functional orientation of the immune, fibroblastic and angiogenic microenvironment of 1388 CRC tumors from three independent cohorts using transcriptomics. We validated our findings using immunohistochemistry.
Results: We report that CRC molecular subgroups and microenvironmental signatures are highly correlated. Out of the four molecular subgroups, two highly express immune-specific genes. The good-prognosis microsatellite-instable-enriched subgroup (CMS1) is characterized by overexpression of genes specific to cytotoxic lymphocytes. In contrast, the poor-prognosis Mesenchymal subgroup (CMS4) expresses markers of lymphocytes and of cells of monocytic origin. The Mesenchymal subgroup also displays an angiogenic, inflammatory and immunosuppressive signature, a coordinated pattern that we also found in breast (n=254), ovarian (n=97), lung (n=80) and kidney (n=143) cancers. Pathological examination revealed that the Mesenchymal subtype is characterized by a high density of fibroblasts that likely produce the chemokines and cytokines which favor tumor-associated inflammation and support angiogenesis, resulting in a poor prognosis. In contrast, the Canonical (CMS2) and Metabolic (CMS3) subtypes with intermediate prognosis exhibit low immune and inflammatory signatures.
Conclusions: The distinct immune orientations of the CRC molecular subtypes pave the way for tailored immunotherapies.
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Wesley C. Van Voorhis1, John H. Adams2, Roberto Adelfio3, Roberto Adelfio4 +197 more•Institutions (62)
TL;DR: The results reveal the immense potential for translating the dispersed expertise in biological assays involving human pathogens into drug discovery starting points, by providing open access to new families of molecules, and emphasize how a small additional investment made to help acquire and distribute compounds, and sharing the data, can catalyze drug discovery for dozens of different indications.
Abstract: A major cause of the paucity of new starting points for drug discovery is the lack of interaction between academia and industry. Much of the global resource in biology is present in universities, whereas the focus of medicinal chemistry is still largely within industry. Open source drug discovery, with sharing of information, is clearly a first step towards overcoming this gap. But the interface could especially be bridged through a scale-up of open sharing of physical compounds, which would accelerate the finding of new starting points for drug discovery. The Medicines for Malaria Venture Malaria Box is a collection of over 400 compounds representing families of structures identified in phenotypic screens of pharmaceutical and academic libraries against the Plasmodium falciparum malaria parasite. The set has now been distributed to almost 200 research groups globally in the last two years, with the only stipulation that information from the screens is deposited in the public domain. This paper reports for the first time on 236 screens that have been carried out against the Malaria Box and compares these results with 55 assays that were previously published, in a format that allows a meta-analysis of the combined dataset. The combined biochemical and cellular assays presented here suggest mechanisms of action for 135 (34%) of the compounds active in killing multiple life-cycle stages of the malaria parasite, including asexual blood, liver, gametocyte, gametes and insect ookinete stages. In addition, many compounds demonstrated activity against other pathogens, showing hits in assays with 16 protozoa, 7 helminths, 9 bacterial and mycobacterial species, the dengue fever mosquito vector, and the NCI60 human cancer cell line panel of 60 human tumor cell lines. Toxicological, pharmacokinetic and metabolic properties were collected on all the compounds, assisting in the selection of the most promising candidates for murine proof-of-concept experiments and medicinal chemistry programs. The data for all of these assays are presented and analyzed to show how outstanding leads for many indications can be selected. These results reveal the immense potential for translating the dispersed expertise in biological assays involving human pathogens into drug discovery starting points, by providing open access to new families of molecules, and emphasize how a small additional investment made to help acquire and distribute compounds, and sharing the data, can catalyze drug discovery for dozens of different indications. Another lesson is that when multiple screens from different groups are run on the same library, results can be integrated quickly to select the most valuable starting points for subsequent medicinal chemistry efforts.
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TL;DR: An angular analysis of the B0 → K*0(→ K+π−)μ+μ− decay is presented in this paper, where the angular observables and their correlations are reported in bins of q2, the invariant mass squared of the dimuon system.
Abstract: An angular analysis of the B0 → K*0(→ K+π−)μ+μ− decay is presented. The dataset corresponds to an integrated luminosity of 3.0 fb−1 of pp collision data collected at the LHCb experiment. The complete angular information from the decay is used to determine CP-averaged observables and CP asymmetries, taking account of possible contamination from decays with the K+π− system in an S-wave configuration. The angular observables and their correlations are reported in bins of q2, the invariant mass squared of the dimuon system. The observables are determined both from an unbinned maximum likelihood fit and by using the principal moments of the angular distribution. In addition, by fitting for q2-dependent decay amplitudes in the region 1.1 < q2 < 6.0 GeV2/c4, the zero-crossing points of several angular observables are computed. A global fit is performed to the complete set of CP-averaged observables obtained from the maximum likelihood fit. This fit indicates differences with predictions based on the Standard Model at the level of 3.4 standard deviations. These differences could be explained by contributions from physics beyond the Standard Model, or by an unexpectedly large hadronic effect that is not accounted for in the Standard Model predictions.[Figure not available: see fulltext.]
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TL;DR: The transcriptional response of primary monocytes from Africans and Europeans to bacterial and viral stimuli is characterized and regulatory variants are enriched in population-specific signals of natural selection and admixture with Neandertals introduced regulatory variants into European genomes, affecting preferentially responses to viral challenges.
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University of Paris1, Université Paris-Saclay2, Pierre-and-Marie-Curie University3, University of Reims Champagne-Ardenne4, College of William & Mary5, Centre national de la recherche scientifique6, California Institute of Technology7, University of Grenoble8, University of Paris-Sud9, University College London10, Université catholique de Louvain11, university of lille12, University of Massachusetts Lowell13, University of Leicester14, University of Science and Technology of China15, University of Castilla–La Mancha16, Russian Academy of Sciences17, University of Colorado Boulder18, Tomsk Polytechnic University19, University of Cologne20, University of Oslo21, Karlsruhe Institute of Technology22, University of Lethbridge23, University College Cork24, Université libre de Bruxelles25
TL;DR: The GEISA database (Gestion et Etude des Informations Spectroscopiques Atmospheriques: Management and Study of Atmospheric Spectroscopic Information) has been developed and maintained by the ARA/ABC(t) group at LMD since 1974.
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University of Washington1, University of Cambridge2, University of Leicester3, University of Lübeck4, University of Copenhagen5, University of Wisconsin–Milwaukee6, University of Michigan7, Montreal Heart Institute8, University of Oxford9, Broad Institute10, Samsung Medical Center11, University of Amsterdam12, Queen Mary University of London13, University of Göttingen14, University of Dundee15, University of Verona16, Vanderbilt University17, University of Kiel18, University of Bonn19, University of Basel20, Norwegian University of Science and Technology21, Umeå University22, University of Duisburg-Essen23, Technische Universität München24, University of Tartu25, Lund University26, University of Ottawa27, King Abdulaziz University28, Merck & Co.29, Ohio State University30, National Institutes of Health31, Johns Hopkins University32, Harvard University33, University of Insubria34, University of Glasgow35, Leiden University36, Queen's University Belfast37, Pierre-and-Marie-Curie University38, Wellcome Trust Sanger Institute39, University of Leeds40, Duke University41, University of Pennsylvania42
TL;DR: It was found that carriers of loss-of-function mutations in ANGPTL4 had triglyceride levels that were lower than those among noncarriers; these mutations were also associated with protection from coronary artery disease.
Abstract: BACKGROUND The discovery of low-frequency coding variants affecting the risk of coronary artery disease has facilitated the identification of therapeutic targets. METHODS Through DNA genotyping, we ...
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TL;DR: In this article, the authors identified 66 blood pressure-associated loci, of which 17 were new; 15 harbored multiple distinct association signals, and 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues.
Abstract: To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure-associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. Our findings expand current knowledge of blood pressure-related pathways and highlight tissues beyond the classical renal system in blood pressure regulation.
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TL;DR: Patients with rare defects in the gene encoding proopiomelanocortin have extreme early-onset obesity, hyperphagia, hypopigmentation, and hypocortisolism and are treated with setmelanotide, a new melanocortIn-4 receptor agonist, which had a sustainable reduction in hunger and substantial weight loss.
Abstract: Patients with rare defects in the gene encoding proopiomelanocortin (POMC) have extreme early-onset obesity, hyperphagia, hypopigmentation, and hypocortisolism, resulting from the lack of the proopiomelanocortin-derived peptides melanocyte-stimulating hormone and corticotropin. In such patients, adrenal insufficiency must be treated with hydrocortisone early in life. No effective pharmacologic treatments have been available for the hyperphagia and obesity that characterize the condition. In this investigator-initiated, open-label study, two patients with proopiomelanocortin deficiency were treated with setmelanotide, a new melanocortin-4 receptor agonist. The patients had a sustainable reduction in hunger and substantial weight loss (51.0 kg after 42 weeks in Patient 1 and 20.5 kg after 12 weeks in Patient 2).