Showing papers by "Université Paris-Saclay published in 2015"
TL;DR: The anti-PD-1 antibody pembrolizumab prolonged progression-free survival and overall survival and had less high-grade toxicity than did ipilimumab in patients with advanced melanoma.
Abstract: Background The immune checkpoint inhibitor ipilimumab is the standard-of-care treatment for patients with advanced melanoma. Pembrolizumab inhibits the programmed cell death 1 (PD-1) immune checkpoint and has antitumor activity in patients with advanced melanoma. Methods In this randomized, controlled, phase 3 study, we assigned 834 patients with advanced melanoma in a 1:1:1 ratio to receive pembrolizumab (at a dose of 10 mg per kilogram of body weight) every 2 weeks or every 3 weeks or four doses of ipilimumab (at 3 mg per kilogram) every 3 weeks. Primary end points were progressionfree and overall survival. Results The estimated 6-month progression-free-survival rates were 47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for ipilimumab (hazard ratio for disease progression, 0.58; P<0.001 for both pembrolizumab regimens versus ipilimumab; 95% confidence intervals [CIs], 0.46 to 0.72 and 0.47 to 0.72, respectively). Estimated 12-month survival rates were 74.1%, 68.4%, and 58.2%, respectively (hazard ratio for death for pembrolizumab every 2 weeks, 0.63; 95% CI, 0.47 to 0.83; P = 0.0005; hazard ratio for pembrolizumab every 3 weeks, 0.69; 95% CI, 0.52 to 0.90; P = 0.0036). The response rate was improved with pembrolizumab administered every 2 weeks (33.7%) and every 3 weeks (32.9%), as compared with ipilimumab (11.9%) (P<0.001 for both comparisons). Responses were ongoing in 89.4%, 96.7%, and 87.9% of patients, respectively, after a median follow-up of 7.9 months. Efficacy was similar in the two pembrolizumab groups. Rates of treatment-related adverse events of grade 3 to 5 severity were lower in the pembrolizumab groups (13.3% and 10.1%) than in the ipilimumab group (19.9%). Conclusions The anti–PD-1 antibody pembrolizumab prolonged progression-free survival and overall survival and had less high-grade toxicity than did ipilimumab in patients with advanced melanoma. (Funded by Merck Sharp & Dohme; KEYNOTE-006 ClinicalTrials .gov number, NCT01866319.)
4,612 citations
Paris Descartes University1, Institut Gustave Roussy2, Mount Sinai Hospital3, University of Texas Southwestern Medical Center4, University of Kiel5, Thomas Jefferson University6, Seconda Università degli Studi di Napoli7, University of Toronto8, University of Massachusetts Medical School9, Louisiana State University10, Ghent University11, Flanders Institute for Biotechnology12, Cancer Research UK13, Queen Mary University of London14, Roswell Park Cancer Institute15, Karolinska Institutet16, University of Freiburg17, University of California, San Francisco18, Buck Institute for Research on Aging19, Université Paris-Saclay20, French Institute of Health and Medical Research21, University College London22, University of Rome Tor Vergata23, Northwestern University24, Memorial Sloan Kettering Cancer Center25, National Institutes of Health26, Technion – Israel Institute of Technology27, Johns Hopkins University28, University of Chieti-Pescara29, University of Ulm30, Genentech31, New York University32, Pennsylvania State University33, University of Salento34, Yale University35, Goethe University Frankfurt36, University of Burgundy37, Pasteur Institute38, University of Strasbourg39, University of Zurich40, University of Tokyo41, Technische Universität München42, University of Bern43, University of Michigan44, Medical Research Council45, University of South Australia46, University of Adelaide47, Medical University of South Carolina48, Howard Hughes Medical Institute49, University of Texas at Dallas50, St. John's University51, University of Oviedo52, University of Graz53, Istituto Superiore di Sanità54, Katholieke Universiteit Leuven55, Trinity College, Dublin56, University of Geneva57, University of Amsterdam58, Stony Brook University59, University of Washington60, University of Ferrara61, Royal College of Surgeons in Ireland62, La Trobe University63, University of Buenos Aires64, University of Virginia65, University of Padua66, University of Lisbon67, University of Cambridge68, University of Würzburg69, Soochow University (Suzhou)70, Columbia University71, University of Glasgow72, University of Crete73, Foundation for Research & Technology – Hellas74, Innsbruck Medical University75, Carlos III Health Institute76, Rutgers University77, University of Minnesota78, Harvard University79, City University of New York80, Moscow State University81
TL;DR: The Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death.
Abstract: Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as ‘accidental cell death’ (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. ‘Regulated cell death’ (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death.
809 citations
TL;DR: Rociletinib was active in patients with EGFR-mutated NSCLC associated with the T790M resistance mutation and the only common dose-limiting adverse event was hyperglycemia.
Abstract: BackgroundNon–small-cell lung cancer (NSCLC) with a mutation in the gene encoding epidermal growth factor receptor (EGFR) is sensitive to approved EGFR inhibitors, but resistance develops, mediated by the T790M EGFR mutation in most cases. Rociletinib (CO-1686) is an EGFR inhibitor active in preclinical models of EGFR-mutated NSCLC with or without T790M. MethodsIn this phase 1–2 study, we administered rociletinib to patients with EGFR-mutated NSCLC who had disease progression during previous treatment with an existing EGFR inhibitor. In the expansion (phase 2) part of the study, patients with T790M-positive disease received rociletinib at a dose of 500 mg twice daily, 625 mg twice daily, or 750 mg twice daily. Key objectives were assessment of safety, side-effect profile, pharmacokinetics, and preliminary antitumor activity of rociletinib. Tumor biopsies to identify T790M were performed during screening. Treatment was administered in continuous 21-day cycles. ResultsA total of 130 patients were enrolled. ...
618 citations
Kyriaki Michailidou1, Jonathan Beesley2, Sara Lindström3, Sander Canisius +280 more•Institutions (76)
TL;DR: 15 new loci associated with breast cancer at P < 5 × 10−8 are identified, and one association appears to be driven by an amino acid substitution encoded in EXO1, which is found in women of European ancestry.
Abstract: Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1.
523 citations
Nasim Mavaddat1, Paul D.P. Pharoah1, Kyriaki Michailidou1, Jonathan Tyrer1 +239 more•Institutions (68)
TL;DR: The PRS stratifies breast cancer risk in women both with and without a family history of breast cancer, and the observed level of risk discrimination could inform targeted screening and prevention strategies.
Abstract: Background: Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking. Methods: We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates. Results: There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1% of the PRS had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 2.95 to 3.83). The ORs for ER-positive and ER-negative disease were 3.73 (95% CI = 3.24 to 4.30) and 2.80 (95% CI = 2.26 to 3.46), respectively. Lifetime risk of breast cancer for women in the lowest and highest quintiles of the PRS were 5.2% and 16.6% for a woman without family history, and 8.6% and 24.4% for a woman with a first-degree family history of breast cancer. Conclusions: The PRS stratifies breast cancer risk in women both with and without a family history of breast cancer. The observed level of risk discrimination could inform targeted screening and prevention strategies. Further discrimination may be achievable through combining the PRS with lifestyle/environmental factors, although these were not considered in this report.
471 citations
TL;DR: H3K27 alterations appear as the founding event in DIPG and the mutations in the two main histone H3 variants drive two distinct oncogenic programmes with potential specific therapeutic targets.
Abstract: Diffuse intrinsic pontine glioma (DIPG) is the most severe paediatric solid tumour, with no significant therapeutic progress made in the past 50 years. Recent studies suggest that diffuse midline glioma, H3-K27M mutant, may comprise more than one biological entity. The aim of the study was to determine the clinical and biological variables that most impact their prognosis. Ninety-one patients with classically defined DIPG underwent a systematic stereotactic biopsy and were included in this observational retrospective study. Histone H3 genes mutations were assessed by immunochemistry and direct sequencing, whilst global gene expression profiling and chromosomal imbalances were determined by microarrays. A full description of the MRI findings at diagnosis and at relapse was integrated with the molecular profiling data and clinical outcome. All DIPG but one were found to harbour either a somatic H3-K27M mutation and/or loss of H3K27 trimethylation. We also discovered a novel K27M mutation in HIST2H3C, and a lysine-to-isoleucine substitution (K27I) in H3F3A, also creating a loss of trimethylation. Patients with tumours harbouring a K27M mutation in H3.3 (H3F3A) did not respond clinically to radiotherapy as well, relapsed significantly earlier and exhibited more metastatic recurrences than those in H3.1 (HIST1H3B/C). H3.3-K27M-mutated DIPG have a proneural/oligodendroglial phenotype and a pro-metastatic gene expression signature with PDGFRA activation, while H3.1-K27M-mutated tumours exhibit a mesenchymal/astrocytic phenotype and a pro-angiogenic/hypoxic signature supported by expression profiling and radiological findings. H3K27 alterations appear as the founding event in DIPG and the mutations in the two main histone H3 variants drive two distinct oncogenic programmes with potential specific therapeutic targets.
444 citations
French Institute of Health and Medical Research1, Institut Gustave Roussy2, Istituto Superiore di Sanità3, National Research Council4, University of Bonn5, Paris-Sorbonne University6, University of Burgundy7, University of Siena8, Université Paris-Saclay9, University of Franche-Comté10, University of Rome Tor Vergata11
TL;DR: A loss-of-function allele of the gene coding for formyl peptide receptor 1 (FPR1) was identified that was associated with poor metastasis-free and overall survival in breast and colorectal cancer patients receiving adjuvant chemotherapy.
Abstract: Antitumor immunity driven by intratumoral dendritic cells contributes to the efficacy of anthracycline-based chemotherapy in cancer. We identified a loss-of-function allele of the gene coding for formyl peptide receptor 1 (FPR1) that was associated with poor metastasis-free and overall survival in breast and colorectal cancer patients receiving adjuvant chemotherapy. The therapeutic effects of anthracyclines were abrogated in tumor-bearing Fpr1(-/-) mice due to impaired antitumor immunity. Fpr1-deficient dendritic cells failed to approach dying cancer cells and, as a result, could not elicit antitumor T cell immunity. Experiments performed in a microfluidic device confirmed that FPR1 and its ligand, annexin-1, promoted stable interactions between dying cancer cells and human or murine leukocytes. Altogether, these results highlight the importance of FPR1 in chemotherapy-induced anticancer immune responses.
342 citations
TL;DR: A taxonomy of five distinct cerebral mechanisms for sequence coding: transitions and timing knowledge, chunking, ordinal knowledge, algebraic patterns, and nested tree structures is proposed.
317 citations
Oregon State University1, United States Geological Survey2, Seoul National University3, Dartmouth College4, Pennsylvania State University5, University of California, San Diego6, University of California, Berkeley7, University of Wisconsin-Madison8, Desert Research Institute9, South Dakota State University10, University of Washington11, New Mexico Institute of Mining and Technology12, University of Colorado Boulder13, University of Copenhagen14, Columbia University15, University of Maine16, Victoria University of Wellington17, Université Paris-Saclay18, University of Alaska Fairbanks19, Montana State University20, University of New Hampshire21, Lake Superior State University22, Purdue University23
TL;DR: A north-to-south directionality of the abrupt climatic signal is demonstrated, which is propagated to the Southern Hemisphere high latitudes by oceanic rather than atmospheric processes, which confirms a central role for ocean circulation in the bipolar seesaw.
Abstract: A new ice core from West Antarctica shows that, during the last ice age, abrupt Northern Hemisphere climate variations were followed two centuries later by a response in Antarctica, suggesting an oceanic propagation of the climate signal to the Southern Hemisphere high latitudes.
298 citations
TL;DR: It is shown that Snf7, the main component of ESCRT-III, polymerizes into spirals at the surface of lipid bilayers, and it is observed that the elastic expansion of compressed Snf 7 spirals generated an area difference between the two sides of the membrane and thus curvature.
275 citations
Université Paris-Saclay1, University of Savoy2, CERN3, Czech Technical University in Prague4, Technische Universität München5, University of Belgrade6, University of Santiago de Compostela7, University of Tokyo8, École des mines de Nantes9, Nanjing University of Science and Technology10, University of Cape Town11, Saint Petersburg State University12, Federico Santa María Technical University13, Utrecht University14, Duke University15, University of Bergen16, University of Auvergne17, Texas A&M University18, Iowa State University19, Bielefeld University20, Heidelberg University21, University of Grenoble22, Tata Institute of Fundamental Research23, Kent State University24, University of Lyon25, Goethe University Frankfurt26, Los Alamos National Laboratory27, University of California, Davis28, Lawrence Livermore National Laboratory29, Central China Normal University30, Tsinghua University31
TL;DR: This report reviews the study of open heavy-flavour and quarkonium production in high-energy hadronic collisions, as tools to investigate fundamental aspects of Quantum Chromodynamics, from the proton and nucleus structure at high energy to deconfinement and the properties of the Quark–Gluon Plasma.
Abstract: This report reviews the study of open heavy-flavour and quarkonium production in high-energy hadronic collisions, as tools to investigate fundamental aspects of Quantum Chromodynamics, from the proton and nucleus structure at high energy to deconfinement and the properties of the Quark-Gluon Plasma. Emphasis is given to the lessons learnt from LHC Run 1 results, which are reviewed in a global picture with the results from SPS and RHIC at lower energies, as well as to the questions to be addressed in the future. The report covers heavy flavour and quarkonium production in proton-proton, proton-nucleus and nucleus-nucleus collisions. This includes discussion of the effects of hot and cold strongly interacting matter, quarkonium photo-production in nucleus-nucleus collisions and perspectives on the study of heavy flavour and quarkonium with upgrades of existing experiments and new experiments. The report results from the activity of the SaporeGravis network of the I3 Hadron Physics programme of the European Union 7th Framework Programme.
TL;DR: This work explores how a definition of confidence as Bayesian probability can unify these viewpoints, and entails that there are distinct forms in which confidence is represented and used in the brain, including distributional confidence, pertaining to neural representations of probability distributions, and summary confidence, referring to scalar summaries of those distributions.
TL;DR: In this paper, the authors provide a pedagogical review of the current state-of-the-art algorithms for the planted spin glass problem, with a focus on the Ising model.
Abstract: Many questions of fundamental interest in todays science can be formulated as inference problems: Some partial, or noisy, observations are performed over a set of variables and the goal is to recover, or infer, the values of the variables based on the indirect information contained in the measurements. For such problems, the central scientific questions are: Under what conditions is the information contained in the measurements sufficient for a satisfactory inference to be possible? What are the most efficient algorithms for this task? A growing body of work has shown that often we can understand and locate these fundamental barriers by thinking of them as phase transitions in the sense of statistical physics. Moreover, it turned out that we can use the gained physical insight to develop new promising algorithms. Connection between inference and statistical physics is currently witnessing an impressive renaissance and we review here the current state-of-the-art, with a pedagogical focus on the Ising model which formulated as an inference problem we call the planted spin glass. In terms of applications we review two classes of problems: (i) inference of clusters on graphs and networks, with community detection as a special case and (ii) estimating a signal from its noisy linear measurements, with compressed sensing as a case of sparse estimation. Our goal is to provide a pedagogical review for researchers in physics and other fields interested in this fascinating topic.
TL;DR: The giant negative electrocaloric effect may open up a new paradigm for light, compact, reliable, and high-efficiency refrigeration devices.
Abstract: Antiferroelectric thin films are demonstrated as a new class of giant electrocaloric materials that exhibit a negative electrocaloric response of about -5 K near room temperature. The giant negative electrocaloric effect may open up a new paradigm for light, compact, reliable, and high-efficiency refrigeration devices.
Steward Health Care System1, European Space Agency2, Max Planck Society3, Space Telescope Science Institute4, Ghent University5, Ames Research Center6, University of Vienna7, ETH Zurich8, Chalmers University of Technology9, Université Paris-Saclay10, Johns Hopkins University11, Technical University of Denmark12, Dublin Institute for Advanced Studies13, California Institute of Technology14, Leiden University15, Katholieke Universiteit Leuven16
TL;DR: MIRI as discussed by the authors is the mid-infrared instrument for the James Webb Space Telescope [JWST] and combines unprecedented sensitivity levels; subarcsecond angular resolution; freedom from atmospheric interference; inherent stability of observing in space; and a suite of versatile capabilities including imaging, low and medium-resolution spectroscopy with an integral field unit, and coronagraphy.
Abstract: MIRI (the Mid-Infrared Instrument for the James Webb Space Telescope [JWST]) operates from 5 to 28: 5 mu m and combines over this range: (1) unprecedented sensitivity levels; (2) subarcsecond angular resolution; (3) freedom from atmospheric interference; (4) the inherent stability of observing in space; and (5) a suite of versatile capabilities including imaging, low- and medium-resolution spectroscopy (with an integral field unit), and coronagraphy. We illustrate the potential uses of this unique combination of capabilities with various science examples: (1) imaging exoplanets; (2) transit and eclipse spectroscopy of exoplanets; (3) probing the first stages of star and planet formation, including identifying bioactive molecules; (4) determining star formation rates and mass growth as galaxies are assembled; and (5) characterizing the youngest massive galaxies.
TL;DR: In this paper, the secondary astrophysical antiproton to proton ratio and its uncertainties are compared with the ratio preliminarly reported by AMS-02, finding no unambiguous evidence for a significant excess with respect to expectations.
Abstract: Using the updated proton and helium fluxes just released by the AMS-02 experiment we reevaluate the secondary astrophysical antiproton to proton ratio and its uncertainties, and compare it with the ratio preliminarly reported by AMS-02. We find no unambiguous evidence for a significant excess with respect to expectations. Yet, some preference for a flatter energy dependence of the diffusion coefficient (with respect to the MED benchmark often used in the literature) starts to emerge. Also, we provide a first assessment of the room left for exotic components such as Galactic Dark Matter annihilation or decay, deriving new stringent constraints.
TL;DR: This analysis of the largest cohort of ALPPS patients so far identifies those patients in whom stage-2 ALPPS surgery should be delayed or even denied, and may help to make ALPPS safer.
Abstract: OBJECTIVES: The aim of this study was to identify predictors of 90-day mortality after Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS), available after stage-1, either to omit or delay stage-2.
BACKGROUND DATA: ALPPS is a two-stage hepatectomy for patients with extensive liver tumors with predicted small liver remnants, which has been criticized for its high mortality rate. Risk factors for mortality are unknown.
METHODS: Patients in the International Registry undergoing ALPPS from April 2011 to July 2014 were analyzed. Primary outcome was 90-day mortality. Liver function after stage-1 was assessed using the criteria of the International Study Group for Liver Surgery (ISGLS) after stage-1 among others. A multivariable model was used to identify independent predictors of 90-day mortality.
RESULTS: Three hundred twenty patients registered by 55 centers worldwide were evaluated. Overall 90-day mortality was 8.8% (28/320). The predominant cause for 90-day mortality was postoperative liver failure in 75% of patients. Fourteen percent of patients developed liver failure according to ISGLS criteria already after stage-1 ALPPS. Those and patients with a model of end-stage liver disease (MELD) score more than 10 before stage-2 were at significantly higher risk for 90-day mortality after stage-2 with an odds ratio (OR) 3.9 [confidence interval (CI) 1.4-10.9, P = 0.01] and OR 4.9 (CI 1.9-12.7, P = 0.006), respectively. Other factors, such as size of future liver remnant (FLR) before stage-2 and time between stages, were not predictive.
CONCLUSIONS: This analysis of the largest cohort of ALPPS patients so far identifies those patients in whom stage-2 ALPPS surgery should be delayed or even denied. These findings may help to make ALPPS safer.
University of Maryland, College Park1, University of Toledo2, Ohio State University3, University of Cambridge4, University of Massachusetts Amherst5, California Institute of Technology6, Max Planck Society7, National Radio Astronomy Observatory8, Leiden University9, University of Arizona10, University of Wyoming11, Université Paris-Saclay12, European Southern Observatory13, University of Paris14, Raytheon15
TL;DR: In this article, the authors investigated the relation of surface brightness and luminosity with SFR using the Herschel KINGFISH sample of 46 nearby galaxies, and showed that surface brightness relations are better behaved than the luminosity relations because the former is more closely related to the local far-UV field strength, most likely the main parameter controlling the efficiency of the conversion of farUV radiation into gas heating.
Abstract: The [C II] 157.74 μm transition is the dominant coolant of the neutral interstellar gas, and has great potential as a star formation rate (SFR) tracer. Using the Herschel KINGFISH sample of 46 nearby galaxies, we investigate the relation of [C II] surface brightness and luminosity with SFR. We conclude that [C II] can be used for measurements of SFR on both global and kiloparsec scales in normal star-forming galaxies in the absence of strong active galactic nuclei (AGNs). The uncertainty of the Σ_([C II]) – Σ_(SFR) calibration is ±0.21 dex. The main source of scatter in the correlation is associated with regions that exhibit warm IR colors, and we provide an adjustment based on IR color that reduces the scatter. We show that the color-adjusted Σ_([C II]) – Σ_(SFR) correlation is valid over almost five orders of magnitude in Σ_(SFR), holding for both normal star-forming galaxies and non-AGN luminous infrared galaxies. Using [C II] luminosity instead of surface brightness to estimate SFR suffers from worse systematics, frequently underpredicting SFR in luminous infrared galaxies even after IR color adjustment (although this depends on the SFR measure employed). We suspect that surface brightness relations are better behaved than the luminosity relations because the former are more closely related to the local far-UV field strength, most likely the main parameter controlling the efficiency of the conversion of far-UV radiation into gas heating. A simple model based on Starburst99 population-synthesis code to connect SFR to [C II] finds that heating efficiencies are 1%-3% in normal galaxies.
TL;DR: In this article, the results of a search for events containing at least one long-lived particle that decays at a significant distance from its production point into two leptons or into five or more charged particles are presented.
Abstract: Many extensions of the Standard Model posit the existence of heavy particles with long lifetimes. This article presents the results of a search for events containing at least one long-lived particle that decays at a significant distance from its production point into two leptons or into five or more charged particles. This analysis uses a data sample of proton-proton collisions at root s = 8 TeV corresponding to an integrated luminosity of 20.3 fb(-1) collected in 2012 by the ATLAS detector operating at the Large Hadron Collider. No events are observed in any of the signal regions, and limits are set on model parameters within supersymmetric scenarios involving R-parity violation, split supersymmetry, and gauge mediation. In some of the search channels, the trigger and search strategy are based only on the decay products of individual long-lived particles, irrespective of the rest of the event. In these cases, the provided limits can easily be reinterpreted in different scenarios.
TL;DR: Study of the strengths and limitations of early learning, and of brain dynamics in relation to regional maturational stages, promise to yield a better understanding of the sources of human cognitive achievements.
TL;DR: In this article, the role of coding variation on intermediate traits for type 2 diabetes was explored by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls.
Abstract: Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=-0.09±0.01 mmol l(-1), P=3.4 × 10(-12)), T2D risk (OR[95%CI]=0.86[0.76-0.96], P=0.010), early insulin secretion (β=-0.07±0.035 pmolinsulin mmolglucose(-1), P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l(-1), P=4.3 × 10(-4)). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l(-1), P=1.3 × 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
TL;DR: In this paper, a single-flavor limit to the diffuse flux of ultrahigh energy neutrinos with an E-2 spectrum in the energy range 1.0×1017eV-2.
Abstract: Neutrinos in the cosmic ray flux with energies near 1 EeV and above are detectable with the Surface Detector array (SD) of the Pierre Auger Observatory. We report here on searches through Auger data from 1 January 2004 until 20 June 2013. No neutrino candidates were found, yielding a limit to the diffuse flux of ultrahigh energy neutrinos that challenges the Waxman-Bahcall bound predictions. Neutrino identification is attempted using the broad time structure of the signals expected in the SD stations, and is efficiently done for neutrinos of all flavors interacting in the atmosphere at large zenith angles, as well as for "Earth-skimming" neutrino interactions in the case of tau neutrinos. In this paper the searches for downward-going neutrinos in the zenith angle bins 60°-75°and 75°-90°as well as for upward-going neutrinos, are combined to give a single limit. The 90% C.L. single-flavor limit to the diffuse flux of ultrahigh energy neutrinos with an E-2 spectrum in the energy range 1.0×1017eV-2.5×1019eV is Eν2dNν/dEν<6.4×10-9GeVcm-2s-1sr-1.
TL;DR: In this paper, the secondary astrophysical antiproton to proton ratio and its uncertainties are compared with the ratio preliminarly reported by AMS-02, and the room left for exotic components such as Galactic Dark Matter annihilation or decay is assessed.
Abstract: Using the updated proton and helium fluxes just released by the AMS-02 experiment we reevaluate the secondary astrophysical antiproton to proton ratio and its uncertainties, and compare it with the ratio preliminarly reported by AMS-02. We find no unambiguous evidence for a significant excess with respect to expectations. Yet, some preference for a flatter energy dependence of the diffusion coefficient starts to emerge. Also, we provide a first assessment of the room left for exotic components such as Galactic Dark Matter annihilation or decay, deriving new stringent constraints.
TL;DR: In this paper, a search for the b (b) over bar decay of the Standard Model Higgs boson is performed with the ATLAS experiment using the full dataset recorded at the LHC in Run 1.
Abstract: A search for the b (b) over bar decay of the Standard Model Higgs boson is performed with the ATLAS experiment using the full dataset recorded at the LHC in Run 1. The integrated luminosities used are 4.7 and 20.3 fb(-1) from pp collisions at root s = 7 and 8 TeV, respectively. The processes considered are associated (WIZ)H production, where W -> e nu/mu nu, Z -> ee/mu mu, and Z -> nu nu. The observed (expected) deviation from the backgroundonly hypothesis corresponds to a significance of 1.4 (2.6) standard deviations and the ratio of the measured signal yield to the Standard Model expectation is found to be mu = 0.52 +/- 0.32 (stat.) +/- 0.24 (syst.) for a Higgs boson mass of 125.36 GeV. The analysis procedure is validated by a measurement of the yield of (W/Z)Z production with Z -> b (b) over bar in the same final states as for the Higgs boson search, from which the ratio of the observed signal yield to the Standard Model expectation is found to be 0.74 +/- 0.09 (stat.) +/- 0.14 (syst.).
Joshua N. Sampson1, William Wheeler, Meredith Yeager1, Orestis A. Panagiotou1 +445 more•Institutions (113)
TL;DR: Correlation analysis indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the Genetic etiology for the same disease can vary by population and environmental exposures.
Abstract: Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the add ...
TL;DR: In this paper, the authors search for high-mass diphoton resonances in pp collisions at pffisffi root s=8 TeV with the ATLAS detector.
Abstract: Search for high-mass diphoton resonances in pp collisions at pffisffi root s=8 TeV with the ATLAS detector
TL;DR: The first measurement of elliptic and triangular flow in high-multiplicity (3)He+Au collisions at √(s(NN))=200 GeV is presented, indicating the formation of low-viscosity quark-gluon plasma even in these small collision systems.
Abstract: We present the first measurement of elliptic ($v_2$) and triangular ($v_3$) flow in high-multiplicity $^{3}$He$+$Au collisions at $\sqrt{s_{_{NN}}}=200$ GeV. Two-particle correlations, where the particles have a large separation in pseudorapidity, are compared in $^{3}$He$+$Au and in $p$$+$$p$ collisions and indicate that collective effects dominate the second and third Fourier components for the correlations observed in the $^{3}$He$+$Au system. The collective behavior is quantified in terms of elliptic $v_2$ and triangular $v_3$ anisotropy coefficients measured with respect to their corresponding event planes. The $v_2$ values are comparable to those previously measured in $d$$+$Au collisions at the same nucleon-nucleon center-of-mass energy. Comparison with various theoretical predictions are made, including to models where the hot spots created by the impact of the three $^{3}$He nucleons on the Au nucleus expand hydrodynamically to generate the triangular flow. The agreement of these models with data may indicate the formation of low-viscosity quark-gluon plasma even in these small collision systems.
Idaho National Laboratory1, University College London2, University of Manchester3, Joint Institute for Nuclear Research4, National Research Nuclear University MEPhI5, University of Texas at Austin6, Czech Technical University in Prague7, Université Paris-Saclay8, University of Warwick9, Osaka University10, Saga University11, Comenius University in Bratislava12, Imperial College London13, Institut Universitaire de France14, University of Jyväskylä15, Charles University in Prague16
TL;DR: The NEMO-3 detector was designed to search for neutrinoless double neutrino decay as mentioned in this paper, and no evidence of neutrinos decaying in the data was found.
Abstract: The NEMO-3 detector, which had been operating in the Modane Underground Laboratory from 2003 to 2010, was designed to search for neutrinoless double $\beta$ ($0
u\beta\beta$) decay. We report final results of a search for $0
u\beta\beta$ decays with $6.914$ kg of $^{100}$Mo using the entire NEMO-3 data set with a detector live time of $4.96$ yr, which corresponds to an exposure of 34.3 kg$\cdot$yr. We perform a detailed study of the expected background in the $0
u\beta\beta$ signal region and find no evidence of $0
u\beta\beta$ decays in the data. The level of observed background in the $0
u\beta\beta$ signal region $[2.8-3.2]$ MeV is $0.44 \pm 0.13$ counts/yr/kg, and no events are observed in the interval $[3.2-10]$ MeV. We therefore derive a lower limit on the half-life of $0
u\beta\beta$ decays in $^{100}$Mo of $T_{1/2}(0
u\beta\beta)> 1.1 \times 10^{24}$ yr at the $90\%$ Confidence Level, under the hypothesis of light Majorana neutrino exchange. Depending on the model used for calculating nuclear matrix elements, the limit for the effective Majorana neutrino mass lies in the range $\langle m_{
u} \rangle < 0.33$--$0.62$ eV. We also report constraints on other lepton-number violating mechanisms for $0
u\beta\beta$ decays.
TL;DR: It is reported here that CD74 and MIF are markedly increased and activated in patients with iPAH, contributing to the abnormal proinflammatory phenotype of pulmonary ECs in iPAh.
Abstract: Rationale: Inflammation and endothelial dysfunction are considered two primary instigators of pulmonary arterial hypertension (PAH). CD74 is a receptor for the proinflammatory cytokine macrophage migration inhibitory factor (MIF). This ligand/receptor complex initiates survival pathways and cell proliferation, and it triggers the synthesis and secretion of major proinflammatory factors and cell adhesion molecules.Objectives: We hypothesized that the MIF/CD74 signaling pathway is overexpressed in idiopathic PAH (iPAH) and contributes to a proinflammatory endothelial cell (EC) phenotype.Methods: Primary early passage cultures of human ECs isolated from lung tissues obtained from patients with iPAH and controls were examined for their ability to secrete proinflammatory mediators and bind inflammatory cells with or without modulation of the functional activities of the MIF/CD74 complex. In addition, we tested the efficacies of curative treatments with either the MIF antagonist ISO-1 or anti-CD74 neutralizing ...
TL;DR: In this article, the authors investigate the gains of proactive caching in terms of backhaul of-floadings and request satisfactions, while tackling the large-amount of available data for content popularity estimation.
Abstract: Mobile cellular networks are becoming increasingly complex to manage while classical deployment/optimization techniques and current solutions (i.e., cell densification, acquiring more spectrum, etc.) are cost-ineffective and thus seen as stopgaps. This calls for development of novel approaches that leverage recent advances in storage/memory, context-awareness, edge/cloud computing, and falls into framework of big data. However, the big data by itself is yet another complex phenomena to handle and comes with its notorious 4V: Velocity, voracity, volume, and variety. In this work, we address these issues in optimization of 5G wireless networks via the notion of proactive caching at the base stations. In particular, we investigate the gains of proactive caching in terms of backhaul of-floadings and request satisfactions, while tackling the large-amount of available data for content popularity estimation. In order to estimate the content popularity, we first collect users' mobile traffic data from a Turkish telecom operator from several base stations in hours of time interval. Then, an analysis is carried out locally on a big data platform and the gains of proactive caching at the base stations are investigated via numerical simulations. It turns out that several gains are possible depending on the level of available information and storage size. For instance, with 10% of content ratings and 15.4 Gbyte of storage size (87% of total catalog size), proactive caching achieves 100% of request satisfaction and offloads 98% of the backhaul when considering 16 base stations.