Showing papers by "University of Barcelona published in 2012"
TL;DR: Prevalence and severity of health loss were weakly correlated and age-specific prevalence of YLDs increased with age in all regions and has decreased slightly from 1990 to 2010, but population growth and ageing have increased YLD numbers and crude rates over the past two decades.
7,021 citations
TL;DR: The results for 1990 and 2010 supersede all previously published Global Burden of Disease results and highlight the importance of understanding local burden of disease and setting goals and targets for the post-2015 agenda taking such patterns into account.
6,861 citations
Daniel J. Klionsky1, Fábio Camargo Abdalla2, Hagai Abeliovich3, Robert T. Abraham4 +1284 more•Institutions (463)
TL;DR: These guidelines are presented 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.
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. 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 vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased 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. 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. 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 autophagy assays, we hope to encourage technical innovation in the field.
4,316 citations
Johns Hopkins University1, University of Barcelona2, St George's, University of London3, Taipei Veterans General Hospital4, Maastricht University5, Washington University in St. Louis6, Imperial College London7, University of Virginia8, Virginia Commonwealth University9, Thomas Jefferson University10, Beaumont Hospital11, University of Bordeaux12, Leipzig University13, University of Oklahoma14, University of Michigan15, Royal Melbourne Hospital16, University College Dublin17, Korea University18, University of Birmingham19, University of Münster20, University of Western Ontario21, Cleveland Clinic22, Harvard University23, University of Pennsylvania24, Northwestern University25, Université de Montréal26, Mayo Clinic27, Icahn School of Medicine at Mount Sinai28, University of California, Los Angeles29, National Yang-Ming University30, Loyola University Chicago31
TL;DR: This 2012 Consensus Statement is to provide a state-of-the-art review of the field of catheter and surgical ablation of AF and to report the findings of a Task Force, convened by the Heart Rhythm Society, the European Heart Rhythm Association, and the European Cardiac Arrhythmia Society and charged with defining the indications, techniques, and outcomes of this procedure.
Abstract: During the past decade, catheter ablation of atrial fibrillation (AF) has evolved rapidly from an investigational procedure to its current status as a commonly performed ablation procedure in many major hospitals throughout the world. Surgical ablation of AF, using either standard or minimally invasive techniques, is also performed in many major hospitals throughout the world.
In 2007, an initial Consensus Statement on Catheter and Surgical AF Ablation was developed as a joint effort of the Heart Rhythm Society, the European Heart Rhythm Association, and the European Cardiac Arrhythmia Society.1 The 2007 document was also developed in collaboration with the Society of Thoracic Surgeons and the American College of Cardiology. Since the publication of the 2007 document, there has been much learned about AF ablation, and the indications for these procedures have changed. Therefore the purpose of this 2012 Consensus Statement is to provide a state-of-the-art review of the field of catheter and surgical ablation of AF and to report the findings of a Task Force, convened by the Heart Rhythm Society, the European Heart Rhythm Association, and the European Cardiac Arrhythmia Society and charged with defining the indications, techniques, and outcomes of this procedure. Included within this document are recommendations pertinent to the design of clinical trials in the field of AF ablation, including definitions relevant to this topic.
This statement summarizes the opinion of the Task Force members based on an extensive literature review as well as their own experience. It is directed to all health care professionals who are involved in the care of patients with AF, particularly those who are undergoing, or are being considered for, catheter or surgical ablation procedures for AF. This statement is not intended to recommend or promote catheter ablation of AF. Rather the ultimate judgment regarding care of a particular patient …
2,754 citations
University of Washington1, Paris Diderot University2, Lawrence Berkeley National Laboratory3, New York University4, University of Utah5, Apache Corporation6, Autonomous University of Madrid7, Yale University8, University of Barcelona9, Harvard University10, Aix-Marseille University11, Princeton University12, Carnegie Mellon University13, Ohio State University14, University of Portsmouth15, University of California, Irvine16, University College London17, University of Valencia18, Max Planck Society19, Leibniz Institute for Astrophysics Potsdam20, Institut d'Astrophysique de Paris21, Spanish National Research Council22, Columbia University23, University of California, Berkeley24, Drexel University25, Korea Institute for Advanced Study26, Institute for the Physics and Mathematics of the Universe27, Abastumani Astrophysical Observatory28, Pennsylvania State University29, University of California, San Diego30, University of Wisconsin-Madison31, Open University32, Case Western Reserve University33
TL;DR: In this paper, the authors present a measurement of the cosmic distance scale from detections of the baryon acoustic oscillations in the clustering of galaxies from the Baryon Oscillation Spectroscopic Survey (BOSS), which is part of the Sloan Digital Sky Survey III (SDSS-III).
Abstract: We present a one per cent measurement of the cosmic distance scale from the detections of the baryon acoustic oscillations in the clustering of galaxies from the Baryon Oscillation Spectroscopic Survey (BOSS), which is part of the Sloan Digital Sky Survey III (SDSS-III). Our results come from the Data Release 11 (DR11) sample, containing nearly one million galaxies and covering approximately $8\,500$ square degrees and the redshift range $0.2
2,040 citations
TL;DR: This Review discusses both genetic and non-genetic causes of phenotypic heterogeneity of tumour cells, with an emphasis on heritable phenotypes that serve as a substrate for clonal selection and the implications of intra-tumour heterogeneity in diagnostics and the development of therapeutic resistance.
Abstract: Populations of tumour cells display remarkable variability in almost every discernable phenotypic trait, including clinically important phenotypes such as ability to seed metastases and to survive therapy. This phenotypic diversity results from the integration of both genetic and non-genetic influences. Recent technological advances have improved the molecular understanding of cancers and the identification of targets for therapeutic interventions. However, it has become exceedingly apparent that the utility of profiles based on the analysis of tumours en masse is limited by intra-tumour genetic and epigenetic heterogeneity, as characteristics of the most abundant cell type might not necessarily predict the properties of mixed populations. In this Review, we discuss both genetic and non-genetic causes of phenotypic heterogeneity of tumour cells, with an emphasis on heritable phenotypes that serve as a substrate for clonal selection. We discuss the implications of intra-tumour heterogeneity in diagnostics and the development of therapeutic resistance.
1,717 citations
Christopher P. Ahn1, Rachael Alexandroff2, Carlos Allende Prieto3, Scott F. Anderson4 +256 more•Institutions (65)
TL;DR: In this paper, the authors presented the first spectroscopic data from the Baryon Oscillation Spectroscopic Survey (BOSS) for the Sloan Digital Sky Survey III (SDSS-III) dataset.
Abstract: The Sloan Digital Sky Survey III (SDSS-III) presents the first spectroscopic data from the Baryon Oscillation Spectroscopic Survey (BOSS). This ninth data release (DR9) of the SDSS project includes 535,995 new galaxy spectra (median z ~ 0.52), 102,100 new quasar spectra (median z ~ 2.32), and 90,897 new stellar spectra, along with the data presented in previous data releases. These spectra were obtained with the new BOSS spectrograph and were taken between 2009 December and 2011 July. In addition, the stellar parameters pipeline, which determines radial velocities, surface temperatures, surface gravities, and metallicities of stars, has been updated and refined with improvements in temperature estimates for stars with T eff -0.5. DR9 includes new stellar parameters for all stars presented in DR8, including stars from SDSS-I and II, as well as those observed as part of the SEGUE-2. The astrometry error introduced in the DR8 imaging catalogs has been corrected in the DR9 data products. The next data release for SDSS-III will be in Summer 2013, which will present the first data from the APOGEE along with another year of data from BOSS, followed by the final SDSS-III data release in 2014 December.
1,623 citations
TL;DR: The Drosophila melanogaster Genetic Reference Panel is described, a community resource for analysis of population genomics and quantitative traits, which reveals reduced polymorphism in centromeric autosomal regions and the X chromosomes, evidence for positive and negative selection, and rapid evolution of the X chromosome.
Abstract: A major challenge of biology is understanding the relationship between molecular genetic variation and variation in quantitative traits, including fitness. This relationship determines our ability to predict phenotypes from genotypes and to understand how evolutionary forces shape variation within and between species. Previous efforts to dissect the genotype-phenotype map were based on incomplete genotypic information. Here, we describe the Drosophila melanogaster Genetic Reference Panel (DGRP), a community resource for analysis of population genomics and quantitative traits. The DGRP consists of fully sequenced inbred lines derived from a natural population. Population genomic analyses reveal reduced polymorphism in centromeric autosomal regions and the X chromosome, evidence for positive and negative selection, and rapid evolution of the X chromosome. Many variants in novel genes, most at low frequency, are associated with quantitative traits and explain a large fraction of the phenotypic variance. The DGRP facilitates genotype-phenotype mapping using the power of Drosophila genetics.
1,568 citations
TL;DR: Continuous ruxolitinib therapy, as compared with the best available therapy, was associated with marked and durable reductions in splenomegaly and disease-related symptoms, improvements in role functioning and quality of life, and modest toxic effects.
Abstract: Background Treatment options for myelofibrosis are limited. We evaluated the efficacy and safety of ruxolitinib, a potent and selective Janus kinase (JAK) 1 and 2 inhibitor, as compared with the best available therapy, in patients with myelofibrosis. Methods We assigned 219 patients with intermediate-2 or high-risk primary myelofibrosis, post–polycythemia vera myelofibrosis, or post–essential thrombocythemia myelofi brosis to receive oral ruxolitinib or the best available therapy. The primary end point and key secondary end point of the study were the percentage of patients with at least a 35% reduction in spleen volume at week 48 and at week 24, respectively, as assessed with the use of magnetic resonance imaging or computed tomography. Results A total of 28% of the patients in the ruxolitinib group had at least a 35% reduction in spleen volume at week 48, as compared with 0% in the group receiving the best available therapy (P<0.001); the corresponding percentages at week 24 were 32% and 0% (P<0.001). At 48 weeks, the mean palpable spleen length had decreased by 56% with ruxolitinib but had increased by 4% with the best available therapy. The median duration of response with ruxolitinib was not reached, with 80% of patients still having a response at a median follow-up of 12 months. Patients in the ruxolitinib group had an improvement in overall quality-of-life measures and a reduction in symptoms associated with myelofibrosis. The most common hematologic abnormalities of grade 3 or higher in either group were thrombocytopenia and anemia, which were managed with a dose reduction, interruption of treatment, or transfusion. One patient in each group discontinued treatment owing to thrombocytopenia, and none discontinued owing to anemia. Nonhematologic adverse events were rare and mostly grade 1 or 2. Two cases of acute myeloid leukemia were reported with the best available therapy. Conclusions Continuous ruxolitinib therapy, as compared with the best available therapy, was associated with marked and durable reductions in splenomegaly and disease-related symptoms, improvements in role functioning and quality of life, and modest toxic effects. An influence on overall survival has not yet been shown. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT00934544.)
1,483 citations
University of Pennsylvania1, Johns Hopkins University2, Mayo Clinic3, University of Barcelona4, St George's, University of London5, Maastricht University6, Cleveland Clinic7, University of Virginia8, Baylor University9, Virginia Commonwealth University10, Thomas Jefferson University11, Beaumont Hospital12, University of Bordeaux13, Leipzig University14, University of Oklahoma15, University of Michigan16, Royal Melbourne Hospital17, University College Dublin18, Korea University19, University of Münster20, University of Birmingham21, University of Western Ontario22, Imperial College London23, Harvard University24, Northwestern University25, National Yang-Ming University26, Washington University in St. Louis27, Université de Montréal28, Icahn School of Medicine at Mount Sinai29, University of California, Los Angeles30, Loyola University Chicago31
TL;DR: A report of the Heart Rhythm Society (HRS) Task Force on Catheter and Surgical Ablation of Atrial Fibrillation, developed in partnership with the European Heart Rhythm Association (EHRA), a registered branch of the European Society of Cardiology and the European Cardiac Arrhythmia Society (ECAS), was published in this paper.
1,271 citations
Karol Estrada1, Unnur Styrkarsdottir, Evangelos Evangelou2, Yi-Hsiang Hsu3 +187 more•Institutions (69)
TL;DR: Light is shed on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility and within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways.
Abstract: Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.
TL;DR: Gut sterilization restricted to late stages of hepatocarcinogenesis reduced HCC, suggesting that the intestinal microbiota and TLR4 represent therapeutic targets for HCC prevention in advanced liver disease.
Stockholm University1, University of New Hampshire2, University of Alaska Fairbanks3, Scott Polar Research Institute4, Canadian Hydrographic Service5, Norwegian Mapping Authority6, University Centre in Svalbard7, Alfred Wegener Institute for Polar and Marine Research8, Science Applications International Corporation9, Johns Hopkins University Applied Physics Laboratory10, University of Barcelona11, University of New Brunswick12, University of Hawaii at Manoa13, University of Bergen14, Geological Survey of Denmark and Greenland15, Geological Survey of Canada16, California Institute of Technology17, British Oceanographic Data Centre18
TL;DR: The International Bathymetric Chart of the Arctic Ocean (IBCAO) released its first gridded bathymetric compilation in 1999 as discussed by the authors, which has since supported a wide range of Arc...
Abstract: The International Bathymetric Chart of the Arctic Ocean (IBCAO) released its first gridded bathymetric compilation in 1999. The IBCAO bathymetric portrayals have since supported a wide range of Arc ...
TL;DR: This work provides the first comprehensive catalog of somatic mutations in CLL with relevant clinical correlates and defines a large set of new genes that may drive the development of this common form of leukemia.
Abstract: Here we perform whole-exome sequencing of samples from 105 individuals with chronic lymphocytic leukemia (CLL), the most frequent leukemia in adults in Western countries. We found 1,246 somatic mutations potentially affecting gene function and identified 78 genes with predicted functional alterations in more than one tumor sample. Among these genes, SF3B1, encoding a subunit of the spliceosomal U2 small nuclear ribonucleoprotein (snRNP), is somatically mutated in 9.7% of affected individuals. Further analysis in 279 individuals with CLL showed that SF3B1 mutations were associated with faster disease progression and poor overall survival. This work provides the first comprehensive catalog of somatic mutations in CLL with relevant clinical correlates and defines a large set of new genes that may drive the development of this common form of leukemia. The results reinforce the idea that targeting several well-known genetic pathways, including mRNA splicing, could be useful in the treatment of CLL and other malignancies.
William F. Laurance1, William F. Laurance2, D. Carolina Useche2, Julio Rendeiro2 +213 more•Institutions (101)
TL;DR: These findings suggest that tropical protected areas are often intimately linked ecologically to their surrounding habitats, and that a failure to stem broad-scale loss and degradation of such habitats could sharply increase the likelihood of serious biodiversity declines.
Abstract: The rapid disruption of tropical forests probably imperils global biodiversity more than any other contemporary phenomenon(1-3). With deforestation advancing quickly, protected areas are increasingly becoming final refuges for threatened species and natural ecosystem processes. However, many protected areas in the tropics are themselves vulnerable to human encroachment and other environmental stresses(4-9). As pressures mount, it is vital to know whether existing reserves can sustain their biodiversity. A critical constraint in addressing this question has been that data describing a broad array of biodiversity groups have been unavailable for a sufficiently large and representative sample of reserves. Here we present a uniquely comprehensive data set on changes over the past 20 to 30 years in 31 functional groups of species and 21 potential drivers of environmental change, for 60 protected areas stratified across the world's major tropical regions. Our analysis reveals great variation in reserve 'health': about half of all reserves have been effective or performed passably, but the rest are experiencing an erosion of biodiversity that is often alarmingly widespread taxonomically and functionally. Habitat disruption, hunting and forest-product exploitation were the strongest predictors of declining reserve health. Crucially, environmental changes immediately outside reserves seemed nearly as important as those inside in determining their ecological fate, with changes inside reserves strongly mirroring those occurring around them. These findings suggest that tropical protected areas are often intimately linked ecologically to their surrounding habitats, and that a failure to stem broad-scale loss and degradation of such habitats could sharply increase the likelihood of serious biodiversity declines.
TL;DR: This review of the psychometric properties and validity of CT measures as well as individual, environmental and genetic factors that influence the circadian typology provides a state of the art discussion to allow professionals to integrate chronobiological aspects of human behavior into their daily practice.
Abstract: The interest in the systematic study of the circadian typology (CT) is relatively recent and has developed rapidly in the two last decades. All the existing data suggest that this individual difference affects our biological and psychological functioning, not only in health, but also in disease. In the present study, we review the current literature concerning the psychometric properties and validity of CT measures as well as individual, environmental and genetic factors that influence the CT. We present a brief overview of the biological markers that are used to define differences between CT groups (sleep-wake cycle, body temperature, cortisol and melatonin), and we assess the implications for CT and adjustment to shiftwork and jet lag. We also review the differences between CT in terms of cognitive abilities, personality traits and the incidence of psychiatric disorders. When necessary, we have emphasized the methodological limitations that exist today and suggested some future avenues of work in order to overcome these. This is a new field of interest to professionals in many different areas (research, labor, academic and clinical), and this review provides a state of the art discussion to allow professionals to integrate chronobiological aspects of human behavior into their daily practice.
University of Kiel1, University of British Columbia2, University of Messina3, National Institutes of Health4, University of Freiburg5, University of Bern6, Kyoto University7, University of Siena8, University of Western Australia9, The Catholic University of America10, Goethe University Frankfurt11, University of Barcelona12, Copenhagen University Hospital13
TL;DR: These guidelines cover practical aspects of TMS in a clinical setting and lay out the general principles that apply to a standardized clinical examination of the fast-conducting corticomotor pathways with single-pulse TMS.
TL;DR: The Di@bet.es Study shows, for the first time, the prevalence rates of diabetes and impaired glucose regulation in a representative sample of the Spanish population, and was higher in men than in women.
Abstract: Aims/hypothesis
The Di@bet.es Study is the first national study in Spain to examine the prevalence of diabetes and impaired glucose regulation.
TL;DR: A working definition of the Sense of Embodiment is provided which states that SoE consists of three subcomponents: the sense of self-location, thesense of agency, and the senseof body ownership.
Abstract: What does it feel like to own, to control, and to be inside a body? The multidimensional nature of this experience together with the continuous presence of one's biological body, render both theoretical and experimental approaches problematic. Nevertheless, exploitation of immersive virtual reality has allowed a reframing of this question to whether it is possible to experience the same sensations towards a virtual body inside an immersive virtual environment as toward the biological body, and if so, to what extent. The current paper addresses these issues by referring to the Sense of Embodiment (SoE). Due to the conceptual confusion around this sense, we provide a working definition which states that SoE consists of three subcomponents: the sense of self-location, the sense of agency, and the sense of body ownership. Under this proposed structure, measures and experimental manipulations reported in the literature are reviewed and related challenges are outlined. Finally, future experimental studies are proposed to overcome those challenges, toward deepening the concept of SoE and enhancing it in virtual applications.
TL;DR: A prometastatic program induced by TGF-β in the microenvironment that associates with a high risk of CRC relapse upon treatment is unveiled and could be exploited to improve the diagnosis and treatment of CRC.
University of Crete1, National and Kapodistrian University of Athens2, University of Paris3, Leiden University Medical Center4, Radboud University Nijmegen5, University of Barcelona6, Charité7, University of Padua8, RWTH Aachen University9, Cliniques Universitaires Saint-Luc10, Stanford University11, University College London12, University Medical Center Groningen13, Imperial College London14, Great Ormond Street Hospital15, University of Genoa16, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico17, Complutense University of Madrid18, University of Düsseldorf19, Charles University in Prague20, University of Porto21, Karolinska University Hospital22, Hannover Medical School23, University of Birmingham24
TL;DR: Recommendations for the management of lupus nephritis were developed using an evidence-based approach followed by expert consensus and there is no evidence to suggest that management of LN should differ in children versus adults.
Abstract: Objectives To develop recommendations for the management of adult and paediatric lupus nephritis (LN).
University of New South Wales1, National Health Service2, MedStar Washington Hospital Center3, Wake Forest University4, Claude Bernard University Lyon 15, Institut Gustave Roussy6, Mercy Medical Center (Baltimore, Maryland)7, St George's Hospital8, University of Barcelona9, Ghent University10, University of Würzburg11, University of Regensburg12, University of Texas MD Anderson Cancer Center13
TL;DR: The combined modality strategy for PMP may be performed safely with acceptable morbidity and mortality in a specialized unit setting with 63% of patients surviving beyond 10 years with Optimal cytoreduction achieves the best outcomes.
Abstract: Purpose Pseudomyxoma peritonei (PMP) originating from an appendiceal mucinous neoplasm remains a biologically heterogeneous disease. The purpose of our study was to evaluate outcome and long-term survival after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) consolidated through an international registry study. Patients and Methods A retrospective multi-institutional registry was established through collaborative efforts of participating units affiliated with the Peritoneal Surface Oncology Group International. Results Two thousand two hundred ninety-eight patients from 16 specialized units underwent CRS for PMP. Treatment-related mortality was 2% and major operative complications occurred in 24% of patients. The median survival rate was 196 months (16.3 years) and the median progression-free survival rate was 98 months (8.2 years), with 10- and 15-year survival rates of 63% and 59%, respectively. Multivariate analysis identified prior chemotherapy treatment (P < .001), p...
TL;DR: An overview on the electrochemical methods devised for the treatment of pharmaceutical residues from both, synthetic solutions and real pharmaceutical wastewaters is presented and progress on the promising solar photoelectro-Fenton process devised and further developed in the laboratory is highlighted and documented.
TL;DR: Assessment of MYC and BCL2 expression by IHC represents a robust, rapid, and inexpensive approach to risk-stratify patients with DLBCL at diagnosis.
Abstract: Purpose Diffuse large B-cell lymphoma (DLBCL) is curable in 60% of patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). MYC translocations, with or without BCL2 translocations, have been associated with inferior survival in DLBCL. We investigated whether expression of MYC protein, with or without BCL2 protein expression, could risk-stratify patients at diagnosis. Patients and Methods We determined the correlation between presence of MYC and BCL2 proteins by immunohistochemistry (IHC) with survival in two independent cohorts of patients with DLBCL treated with R-CHOP. We further determined if MYC protein expression correlated with high MYC mRNA and/or presence of MYC translocation. Results In the training cohort (n = 167), MYC and BCL2 proteins were detected in 29% and 44% of patients, respectively. Concurrent expression (MYC positive/BCL2 positive) was present in 21% of patients. MYC protein correlated with presence of high MYC mRNA and MYC translocatio...
National Institutes of Health1, University of Würzburg2, University of Groningen3, Bosch4, University of British Columbia5, University of Arizona6, University of Barcelona7, University of Oslo8, St Mary's Hospital9, University of Rochester10, Oregon Health & Science University11, Cleveland Clinic12, University of Nebraska Medical Center13, University of Birmingham14, United States Department of Health and Human Services15
TL;DR: High-throughput RNA sequencing and RNA interference screening is used to discover essential regulatory pathways in Burkitt's lymphoma that cooperate with MYC, the defining oncogene of this cancer.
Abstract: Burkitt's lymphoma (BL) can often be cured by intensive chemotherapy, but the toxicity of such therapy precludes its use in the elderly and in patients with endemic BL in developing countries, necessitating new strategies. The normal germinal centre B cell is the presumed cell of origin for both BL and diffuse large B-cell lymphoma (DLBCL), yet gene expression analysis suggests that these malignancies may use different oncogenic pathways. BL is subdivided into a sporadic subtype that is diagnosed in developed countries, the Epstein-Barr-virus-associated endemic subtype, and an HIV-associated subtype, but it is unclear whether these subtypes use similar or divergent oncogenic mechanisms. Here we used high-throughput RNA sequencing and RNA interference screening to discover essential regulatory pathways in BL that cooperate with MYC, the defining oncogene of this cancer. In 70% of sporadic BL cases, mutations affecting the transcription factor TCF3 (E2A) or its negative regulator ID3 fostered TCF3 dependency. TCF3 activated the pro-survival phosphatidylinositol-3-OH kinase pathway in BL, in part by augmenting tonic B-cell receptor signalling. In 38% of sporadic BL cases, oncogenic CCND3 mutations produced highly stable cyclin D3 isoforms that drive cell cycle progression. These findings suggest opportunities to improve therapy for patients with BL.
University of Bologna1, University of Barcelona2, INAF3, University of Edinburgh4, University of Toulouse5, Centre national de la recherche scientifique6, European Southern Observatory7, California Institute of Technology8, ETH Zurich9, Max Planck Society10, Paris Diderot University11, University of Vienna12, Spanish National Research Council13, University of Insubria14, Institute for the Physics and Mathematics of the Universe15, University of Nottingham16, National Taiwan Normal University17, Johns Hopkins University18, Space Telescope Science Institute19, Institut d'Astrophysique de Paris20, University of California, Santa Cruz21, University of California, Davis22, Lawrence Livermore National Laboratory23
TL;DR: In this paper, the authors presented new improved constraints on the Hubble parameter H(z) in the redshift range 0.15 -1.1, obtained from the differential spectroscopic evolution of early-type galaxies as a function of redshift.
Abstract: We present new improved constraints on the Hubble parameter H(z) in the redshift range 0.15 \textless z \textless 1.1, obtained from the differential spectroscopic evolution of early-type galaxies as a function of redshift. We extract a large sample of early-type galaxies ( 11000) from several spectroscopic surveys, spanning almost 8 billion years of cosmic lookback time (0.15 \textless z \textless 1.42). We select the most massive, red elliptical galaxies, passively evolving and without signature of ongoing star formation. Those galaxies can be used as standard cosmic chronometers, as firstly proposed by Jimenez & Loeb (2002), whose (life! Nit age evolution as a function of cosmic time directly probes H (z). We analyze the 4000 angstrom break (D4000) as a function of redshift, use stellar population synthesis models to theoretically calibrate the dependence of the differential age evolution on the differential D4000, and estimate the Hubble parameter taking into account both statistical and systematical errors. We provide 8 new measurements of H(z) (see table 4), and determine its change in H(z) to a precision of 5-12% mapping homogeneously the redshift range up to z 1.1; for the first time, we place a constraint on 11(z) at z not equal 0 with a precision comparable with the one achieved for the Hubble constant (about 5-6% at z similar to 0.2), and covered a redshift range (0.5 \textless z \textless 0.8) which is crucial to distinguish many different quintessence cosmologies. These measurements have been tested to best match a ACDM model, clearly providing a statistically robust indication that the Universe is undergoing an accelerated expansion. This method shows the potentiality to open a new avenue in constrain a variety of alternative cosmologies, especially when future surveys (e.g. Euclid) will open the possibility to extend it up to z similar to 2.
TL;DR: This study constitutes a unique DNA methylation analysis of the extreme points of human life at a single-nucleotide resolution level and demonstrated DNA methylomes in the crossroad between the newborn and the nonagenarian/centenarian groups.
Abstract: Human aging cannot be fully understood in terms of the constrained genetic setting. Epigenetic drift is an alternative means of explaining age-associated alterations. To address this issue, we performed whole-genome bisulfite sequencing (WGBS) of newborn and centenarian genomes. The centenarian DNA had a lower DNA methylation content and a reduced correlation in the methylation status of neighboring cytosine—phosphate—guanine (CpGs) throughout the genome in comparison with the more homogeneously methylated newborn DNA. The more hypomethylated CpGs observed in the centenarian DNA compared with the neonate covered all genomic compartments, such as promoters, exonic, intronic, and intergenic regions. For regulatory regions, the most hypomethylated sequences in the centenarian DNA were present mainly at CpG-poor promoters and in tissue-specific genes, whereas a greater level of DNA methylation was observed in CpG island promoters. We extended the study to a larger cohort of newborn and nonagenarian samples using a 450,000 CpG-site DNA methylation microarray that reinforced the observation of more hypomethylated DNA sequences in the advanced age group. WGBS and 450,000 analyses of middle-age individuals demonstrated DNA methylomes in the crossroad between the newborn and the nonagenarian/centenarian groups. Our study constitutes a unique DNA methylation analysis of the extreme points of human life at a single-nucleotide resolution level.
TL;DR: This Review focuses on epigenetic profiling, which has started to be of clinical value in cancer and may in the future be extended to other diseases, such as neurological and autoimmune disorders.
Abstract: Knowledge of epigenetic alterations in disease is rapidly increasing owing to the development of genome-wide techniques for their identification. The ever-growing number of genes that show epigenetic alterations in disease emphasizes the crucial role of these epigenetic alterations - particularly DNA methylation - for future diagnosis, prognosis and prediction of response to therapies. This Review focuses on epigenetic profiling, which has started to be of clinical value in cancer and may in the future be extended to other diseases, such as neurological and autoimmune disorders.
University of Barcelona1, Research Triangle Park2, University of Nebraska Medical Center3, University of Edinburgh4, GlaxoSmithKline5, University of Manchester6, University of Copenhagen7, University of Cambridge8, University of Liverpool9, Maastricht University10, Brigham and Women's Hospital11, University of British Columbia12, University of Bergen13
TL;DR: Overall, the results identify a novel systemic inflammatory COPD phenotype that may be the target of specific research and treatment and show associations but do not prove causality.
Abstract: Background: Because chronic obstructive pulmonary disease (COPD) is a heterogeneous condition, the identification of specific clinical phenotypes is key to developing more effective therapies. To explore if the persistence of systemic inflammation is associated with poor clinical outcomes in COPD we assessed patients recruited to the well-characterized ECLIPSE cohort (NCT00292552). Methods and Findings: Six inflammatory biomarkers in peripheral blood (white blood cells (WBC) count and CRP, IL-6, IL-8, fibrinogen and TNF-a levels) were quantified in 1,755 COPD patients, 297 smokers with normal spirometry and 202 nonsmoker controls that were followed-up for three years. We found that, at baseline, 30% of COPD patients did not show evidence of systemic inflammation whereas 16% had persistent systemic inflammation. Even though pulmonary abnormalities were similar in these two groups, persistently inflamed patients during follow-up had significantly increased all-cause mortality (13% vs. 2%, p,0.001) and exacerbation frequency (1.5 (1.5) vs. 0.9 (1.1) per year, p,0.001) compared to non-inflamed ones. As a descriptive study our results show associations but do not prove causality. Besides this, the inflammatory response is complex and we studied only a limited panel of biomarkers, albeit they are those investigated by the majority of previous studies and are often and easily measured in clinical practice. Conclusions: Overall, these results identify a novel systemic inflammatory COPD phenotype that may be the target of specific research and treatment.
Selidji T Agnandji1, Selidji T Agnandji2, Bertrand Lell2, Bertrand Lell1 +165 more•Institutions (14)
TL;DR: The RTS,S/AS01 vaccine coadministered with EPI vaccines provided modest protection against both clinical and severe malaria in young infants.
Abstract: BACKGROUND: The candidate malaria vaccine RTS,S/AS01 reduced episodes of both clinical and severe malaria in children 5 to 17 months of age by approximately 50% in an ongoing phase 3 trial. We studied infants 6 to 12 weeks of age recruited for the same trial. METHODS: We administered RTS,S/AS01 or a comparator vaccine to 6537 infants who were 6 to 12 weeks of age at the time of the first vaccination in conjunction with Expanded Program on Immunization (EPI) vaccines in a three-dose monthly schedule. Vaccine efficacy against the first or only episode of clinical malaria during the 12 months after vaccination, a coprimary end point, was analyzed with the use of Cox regression. Vaccine efficacy against all malaria episodes, vaccine efficacy against severe malaria, safety, and immunogenicity were also assessed. RESULTS: The incidence of the first or only episode of clinical malaria in the intention-to-treat population during the 14 months after the first dose of vaccine was 0.31 per person-year in the RTS,S/AS01 group and 0.40 per person-year in the control group, for a vaccine efficacy of 30.1% (95% confidence interval [CI], 23.6 to 36.1). Vaccine efficacy in the per-protocol population was 31.3% (97.5% CI, 23.6 to 38.3). Vaccine efficacy against severe malaria was 26.0% (95% CI, -7.4 to 48.6) in the intention-to-treat population and 36.6% (95% CI, 4.6 to 57.7) in the per-protocol population. Serious adverse events occurred with a similar frequency in the two study groups. One month after administration of the third dose of RTS,S/AS01, 99.7% of children were positive for anti-circumsporozoite antibodies, with a geometric mean titer of 209 EU per milliliter (95% CI, 197 to 222). CONCLUSIONS: The RTS,S/AS01 vaccine coadministered with EPI vaccines provided modest protection against both clinical and severe malaria in young infants. (Funded by GlaxoSmithKline Biologicals and the PATH Malaria Vaccine Initiative; RTS,S ClinicalTrials.gov number, NCT00866619.).