Showing papers by "Katholieke Universiteit Leuven published in 2012"
Katholieke Universiteit Leuven1, Ghent University2, Karolinska Institutet3, Cairo University4, University of São Paulo5, Cincinnati Children's Hospital Medical Center6, Innsbruck Medical University7, University of Duisburg-Essen8, Tufts University9, University of Aberdeen10, University of California, San Diego11, University College Dublin12, University of the Witwatersrand13, Brown University14, Heidelberg University15, Jikei University School of Medicine16
4,482 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
Wellcome Trust Sanger Institute1, Broad Institute2, University of Groningen3, University of Pittsburgh4, Cedars-Sinai Medical Center5, Yale University6, University of Cambridge7, University of Chicago8, Harvard University9, Katholieke Universiteit Leuven10, University of Liège11, King's College London12, Université de Montréal13, New Jersey Institute of Technology14, Cleveland Clinic15, Peninsula College of Medicine and Dentistry16, Université libre de Bruxelles17, Aarhus University18, University of Adelaide19, University of Kiel20, Flinders University21, McGill University22, Ludwig Maximilian University of Munich23, Charité24, Icahn School of Medicine at Mount Sinai25, University of Bonn26, Karolinska Institutet27, Torbay Hospital28, University of Auckland29, Christchurch Hospital30, Imperial College London31, Queen's University32, University of Oslo33, Lithuanian University of Health Sciences34, Emory University35, Casa Sollievo della Sofferenza36, Ghent University37, University of Western Australia38, University of Edinburgh39, Queensland Health40, Newcastle University41, University of Dundee42, University of Manchester43, University of Amsterdam44, University of Maribor45, Royal Hospital for Sick Children46, Guy's and St Thomas' NHS Foundation Trust47, QIMR Berghofer Medical Research Institute48, Norfolk and Norwich University Hospital49, Leiden University50, Technische Universität München51, University of Toronto52, University of Pennsylvania53, Johns Hopkins University54, University of Queensland55
TL;DR: A meta-analysis of Crohn’s disease and ulcerative colitis genome-wide association scans is undertaken, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls.
Abstract: Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations. Genome-wide association studies and subsequent meta-analyses of these two diseases as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases. Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.
4,094 citations
University of Pennsylvania1, Broad Institute2, Harvard University3, Boston University4, National Institutes of Health5, Lund University6, University of Copenhagen7, University of Texas Health Science Center at Houston8, deCODE genetics9, Queen Mary University of London10, University of Lübeck11, Glenfield Hospital12, University of Leicester13, University of Oxford14, University of Cambridge15, University of Ottawa16, University of Iceland17, Population Health Research Institute18, McGill University19, Vanderbilt University20, University of Missouri–Kansas City21, University of Münster22, University of Verona23, Queen's University Belfast24, MedStar Washington Hospital Center25, GlaxoSmithKline26, University of Helsinki27, Karolinska Institutet28, University of Mainz29, Utrecht University30, University of Groningen31, University of Michigan32, Centro Nacional de Investigaciones Cardiovasculares33, United States Department of Agriculture34, University of North Carolina at Chapel Hill35, University of Regensburg36, Katholieke Universiteit Leuven37, University of Edinburgh38, University of Kiel39, University of Leeds40, Aarhus University41, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico42, University of Washington43, Wellcome Trust Sanger Institute44
TL;DR: In this paper, a Mendelian randomisation analysis was performed to compare the effect of HDL cholesterol, LDL cholesterol, and genetic score on risk of myocardial infarction.
Abstract: Methods We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20 913 myocardial infarction cases, 95 407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12 482 cases of myocardial infarction and 41 331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol. – ¹³) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with noncarriers. This diff erence in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0·87, 95% CI 0·84–0·91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0·99, 95% CI 0·88–1·11, p=0·85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0·62, 95% CI 0·58–0·66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0·93, 95% CI 0·68–1·26, p=0·63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol associated with OR 1·54, 95% CI 1·45–1·63) was concordant with that from genetic score (OR 2·13, 95% CI 1·69–2·69, p=2×10
1,878 citations
TL;DR: This critical review covers the advances made using the 4-bora-3a,4a-diaza-s-indacene (BODIPY) scaffold as a fluorophore in the design, synthesis and application of fluorescent indicators for pH, metal ions, anions, biomolecules, reactive oxygen species, reactive nitrogen species, redox potential, chemical reactions and various physical phenomena.
Abstract: This critical review covers the advances made using the 4-bora-3a,4a-diaza-s-indacene (BODIPY) scaffold as a fluorophore in the design, synthesis and application of fluorescent indicators for pH, metal ions, anions, biomolecules, reactive oxygen species, reactive nitrogen species, redox potential, chemical reactions and various physical phenomena. The sections of the review describing the criteria for rational design of fluorescent indicators and the mathematical expressions for analyzing spectrophotometric and fluorometric titrations are applicable to all fluorescent probes (206 references).
1,846 citations
TL;DR: The role of endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) in regulating the immunogenicity of dying cancer cells and the effect of therapy-resistant cancer microevolution on ICD are discussed.
Abstract: Although it was thought that apoptotic cells, when rapidly phagocytosed, underwent a silent death that did not trigger an immune response, in recent years a new concept of immunogenic cell death (ICD) has emerged. The immunogenic characteristics of ICD are mainly mediated by damage-associated molecular patterns (DAMPs), which include surface-exposed calreticulin (CRT), secreted ATP and released high mobility group protein B1 (HMGB1). Most DAMPs can be recognized by pattern recognition receptors (PRRs). In this Review, we discuss the role of endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) in regulating the immunogenicity of dying cancer cells and the effect of therapy-resistant cancer microevolution on ICD.
1,736 citations
TL;DR: The evidence supporting toxic Aβ oligomers as drivers of neurodegeneration is reviewed and some suggestions that might facilitate progress are made to facilitate progress in this complex field.
Abstract: The 'toxic Aβ oligomer' hypothesis has attracted considerable attention among Alzheimer's disease researchers as a way of resolving the lack of correlation between deposited amyloid-β (Aβ) in amyloid plaques-in terms of both amount and location-and cognitive impairment or neurodegeneration. However, the lack of a common, agreed-upon experimental description of the toxic Aβ oligomer makes interpretation and direct comparison of data between different research groups impossible. Here we critically review the evidence supporting toxic Aβ oligomers as drivers of neurodegeneration and make some suggestions that might facilitate progress in this complex field.
1,722 citations
Wellcome Trust Sanger Institute1, Katholieke Universiteit Leuven2, Flanders Institute for Biotechnology3, Norwich Research Park4, University of East Anglia5, Lund University6, Harvard University7, Oslo University Hospital8, King's College London9, Erasmus University Rotterdam10, University of British Columbia11, Curie Institute12, The Breast Cancer Research Foundation13, Medical Research Council14, Cambridge University Hospitals NHS Foundation Trust15, University of Cambridge16
TL;DR: This work generated catalogs of somatic mutation from 21 breast cancers and applied mathematical methods to extract mutational signatures of the underlying processes, finding a remarkable phenomenon of localized hypermutation, termed “kataegis,” was observed.
1,699 citations
Radboud University Nijmegen1, Seoul National University Hospital2, Katholieke Universiteit Leuven3, University of Turin4, University of Pennsylvania5, Institut Gustave Roussy6, Leiden University Medical Center7, The Royal Marsden NHS Foundation Trust8, European Organisation for Research and Treatment of Cancer9, GlaxoSmithKline10, Harvard University11, Brigham and Women's Hospital12
TL;DR: This phase 3 study investigated the effect of pazopanib on progression-free survival in patients with metastatic non-adipocytic soft-tissue sarcoma after failure of standard chemotherapy.
1,671 citations
University of Amsterdam1, Ghent University2, University of Chicago3, University of Pennsylvania4, Auckland City Hospital5, University of Antwerp6, University of New South Wales7, Katholieke Universiteit Leuven8, St Thomas' Hospital9, University of Nottingham10, University of Zagreb11, Northwestern University12, Medical University of Łódź13, University of Aberdeen14, Innsbruck Medical University15, Medical University of South Carolina16, University of Southampton17, Children's Hospital of Philadelphia18, University of São Paulo19, National University of Singapore20, University of Adelaide21, Flinders University22
TL;DR: The European Position Paper on Rhinosinusitis and Nasal Polyps 2012 as discussed by the authors is the update of similar evidence-based position papers published in 2005 and 2007, it contains chapters on definitions and classification, we now also proposed definitions for difficult to treat rhinositis, control of disease, and better definitions for rhinosinitis in children.
Abstract: The European Position Paper on Rhinosinusitis and Nasal Polyps 2012 is the update of similar evidence based position papers published in 2005 and 2007. The document contains chapters on definitions and classification, we now also proposed definitions for difficult to treat rhinosinusitis, control of disease and better definitions for rhinosinusitis in children. More emphasis is placed on the diagnosis and treatment of acute rhinosinusitis. Throughout the document the terms chronic rhinosinusitis without nasal polyps (CRSsNP) and chronic rhinosinusitis with nasal polyps (CRSwNP) are used to further point out differences in pathophysiology and treatment of these two entities. There are extensive chapters on epidemiology and predisposing factors, inflammatory mechanisms, (differential) diagnosis of facial pain, genetics, cystic fibrosis, aspirin exacerbated respiratory disease, immunodeficiencies, allergic fungal rhinosinusitis and the relationship between upper and lower airways. The chapters on paediatric acute and chronic rhinosinusitis are totally rewritten. Last but not least all available evidence for management of acute rhinosinusitis and chronic rhinosinusitis with or without nasal polyps in adults and children is analyzed and presented and management schemes based on the evidence are proposed. This executive summary for otorhinolaryngologists focuses on the most important changes and issues for otorhinolaryngologists. The full document can be downloaded for free on the website of this journal: http://www.rhinologyjournal.com.
1,608 citations
Wellcome Trust Sanger Institute1, Wellcome Trust2, Katholieke Universiteit Leuven3, University of East Anglia4, Guy's and St Thomas' NHS Foundation Trust5, Academia Sinica6, Singapore General Hospital7, Netherlands Cancer Institute8, University of Queensland9, University of British Columbia10, Erasmus University Rotterdam11, Harvard University12, University of Cambridge13, Claude Bernard University Lyon 114, Curie Institute15, Royal Brisbane and Women's Hospital16, University of Amsterdam17, Université libre de Bruxelles18, The Breast Cancer Research Foundation19, Cambridge University Hospitals NHS Foundation Trust20, Oslo University Hospital21
TL;DR: Strong correlations between mutation number, age at which cancer was diagnosed and cancer histological grade are found, and multiple mutational signatures are observed, including one present in about ten per cent of tumours characterized by numerous mutations of cytosine at TpC dinucleotides.
Abstract: All cancers carry somatic mutations in their genomes. A subset, known as driver mutations, confer clonal selective advantage on cancer cells and are causally implicated in oncogenesis, and the remainder are passenger mutations. The driver mutations and mutational processes operative in breast cancer have not yet been comprehensively explored. Here we examine the genomes of 100 tumours for somatic copy number changes and mutations in the coding exons of protein-coding genes. The number of somatic mutations varied markedly between individual tumours. We found strong correlations between mutation number, age at which cancer was diagnosed and cancer histological grade, and observed multiple mutational signatures, including one present in about ten per cent of tumours characterized by numerous mutations of cytosine at TpC dinucleotides. Driver mutations were identified in several new cancer genes including AKT2, ARID1B, CASP8, CDKN1B, MAP3K1, MAP3K13, NCOR1, SMARCD1 and TBX3. Among the 100 tumours, we found driver mutations in at least 40 cancer genes and 73 different combinations of mutated cancer genes. The results highlight the substantial genetic diversity underlying this common disease.
University College London1, University of Duisburg-Essen2, University of Edinburgh3, Katholieke Universiteit Leuven4, Hillingdon Hospitals NHS Foundation Trust5, Royal Melbourne Hospital6, Sheba Medical Center7, Tel Aviv Sourasky Medical Center8, Indiana University – Purdue University Indianapolis9, AstraZeneca10, Harvard University11
TL;DR: Olaparib as maintenance treatment significantly improved progression-free survival among patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer and the toxicity profile of olaparIB in this population was consistent with that in previous studies.
Abstract: randomization on completion of chemotherapy; hazard ratio for progression or death, 0.35; 95% confidence interval [CI], 0.25 to 0.49; P<0.001). Subgroup analyses of progression-free survival showed that, regardless of subgroup, patients in the olaparib group had a lower risk of progression. Adverse events more commonly reported in the olaparib group than in the placebo group (by more than 10% of patients) were nausea (68% vs. 35%), fatigue (49% vs. 38%), vomiting (32% vs. 14%), and anemia (17% vs. 5%); the majority of adverse events were grade 1 or 2. An interim analysis of overall survival (38% maturity, meaning that 38% of the patients had died) showed no significant difference between groups (hazard ratio with olaparib, 0.94; 95% CI, 0.63 to 1.39; P = 0.75). CONCLUSIONS Olaparib as maintenance treatment significantly improved progression-free survival among patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer. Interim analysis showed no overall survival benefit. The toxicity profile of olaparib in this population was consistent with that in previous studies. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT00753545.)
St. Jude Children's Research Hospital1, Washington University in St. Louis2, Memorial Sloan Kettering Cancer Center3, Katholieke Universiteit Leuven4, University of California, San Francisco5, University of Toronto6, University of Padua7, University of Colorado Denver8, University of Florida9, Boston Children's Hospital10, University of New Mexico11, University of Virginia12
TL;DR: The mutational spectrum is similar to myeloid tumours, and moreover, the global transcriptional profile of ETP ALL was similar to that of normal andMyeloid leukaemia haematopoietic stem cells, suggesting that addition of myeloids-directed therapies might improve the poor outcome of E TP ALL.
Abstract: Early T-cell precursor acute lymphoblastic leukaemia (ETP ALL) is an aggressive malignancy of unknown genetic basis. We performed whole-genome sequencing of 12 ETP ALL cases and assessed the frequency of the identified somatic mutations in 94 T-cell acute lymphoblastic leukaemia cases. ETP ALL was characterized by activating mutations in genes regulating cytokine receptor and RAS signalling (67% of cases; NRAS, KRAS, FLT3, IL7R, JAK3, JAK1, SH2B3 and BRAF), inactivating lesions disrupting haematopoietic development (58%; GATA3, ETV6, RUNX1, IKZF1 and EP300) and histone-modifying genes (48%; EZH2, EED, SUZ12, SETD2 and EP300). We also identified new targets of recurrent mutation including DNM2, ECT2L and RELN. The mutational spectrum is similar to myeloid tumours, and moreover, the global transcriptional profile of ETP ALL was similar to that of normal and myeloid leukaemia haematopoietic stem cells. These findings suggest that addition of myeloid-directed therapies might improve the poor outcome of ETP ALL.
TL;DR: Evidence is reported that the syndecan heparan sulphate proteoglycans and their cytoplasmic adaptor syntenin control the formation of exosomes, indicating a key role for syndecans–syntenin–ALIX in membrane transport and signalling processes.
Abstract: The biogenesis of exosomes, small secreted vesicles involved in signalling processes, remains incompletely understood. Here, we report evidence that the syndecan heparan sulphate proteoglycans and their cytoplasmic adaptor syntenin control the formation of exosomes. Syntenin interacts directly with ALIX through LYPX(n)L motifs, similarly to retroviral proteins, and supports the intraluminal budding of endosomal membranes. Syntenin exosomes depend on the availability of heparan sulphate, syndecans, ALIX and ESCRTs, and impact on the trafficking and confinement of FGF signals. This study identifies a key role for syndecan-syntenin-ALIX in membrane transport and signalling processes.
TL;DR: In response to the proliferation of ambiguous or unquantifiable terms in the literature on medication adherence, this research has resulted in a new conceptual foundation for a transparent taxonomy, focused on promoting consistency and quantification in terminology and methods.
Abstract: Interest in patient adherence has increased in recent years, with a growing literature that shows the pervasiveness of poor adherence to appropriately prescribed medications. However, four decades of adherence research has not resulted in uniformity in the terminology used to describe deviations from prescribed therapies. The aim of this review was to propose a new taxonomy, in which adherence to medications is conceptualized, based on behavioural and pharmacological science, and which will support quantifiable parameters. A systematic literature review was performed using MEDLINE, EMBASE, CINAHL, the Cochrane Library and PsycINFO from database inception to 1 April 2009. The objective was to identify the different conceptual approaches to adherence research. Definitions were analyzed according to time and methodological perspectives. A taxonomic approach was subsequently derived, evaluated and discussed with international experts. More than 10 different terms describing medication-taking behaviour were identified through the literature review, often with differing meanings. The conceptual foundation for a new, transparent taxonomy relies on three elements, which make a clear distinction between processes that describe actions through established routines (‘Adherence to medications’, ‘Management of adherence’) and the discipline that studies those processes (‘Adherence-related sciences’). ‘Adherence to medications’ is the process by which patients take their medication as prescribed, further divided into three quantifiable phases: ‘Initiation’, ‘Implementation’ and ‘Discontinuation’. In response to the proliferation of ambiguous or unquantifiable terms in the literature on medication adherence, this research has resulted in a new conceptual foundation for a transparent taxonomy. The terms and definitions are focused on promoting consistency and quantification in terminology and methods to aid in the conduct, analysis and interpretation of scientific studies of medication adherence.
TL;DR: In this paper, the effect of several heat treatments on the microstructure and mechanical properties of Ti6Al4V processed by Selective Laser Melting (SLM) is studied.
Martin Luther University of Halle-Wittenberg1, Katholieke Universiteit Leuven2, Eppendorf (Germany)3, The Catholic University of America4, Karolinska Institutet5, Uppsala University6, Leiden University Medical Center7, Hebron University8, Radboud University Nijmegen9, Seconda Università degli Studi di Napoli10, University of São Paulo11, University of Oxford12, Medical University of Vienna13, Autonomous University of Barcelona14, Sheba Medical Center15, Ain Shams University16, Clínica Alemana17, Mount Vernon Hospital18, Bank of Cyprus19, Odense University Hospital20, University of Crete21, Marmara University22, University of Valencia23
TL;DR: This ESMO guideline is recommended to be used as the basis for treatment and management decisions, delivering a clear proposal for diagnostic and treatment measures in each stage of rectal and colon cancer and the individual clinical situations.
Wellcome Trust Sanger Institute1, Flanders Institute for Biotechnology2, Katholieke Universiteit Leuven3, University of East Anglia4, King's College London5, Curie Institute6, Claude Bernard University Lyon 17, Harvard University8, Oslo University Hospital9, University of British Columbia10, Erasmus University Rotterdam11, Lund University12, The Breast Cancer Research Foundation13, Cambridge University Hospitals NHS Foundation Trust14, University of Cambridge15
TL;DR: Algorithms were developed to decipher this narrative and applied them to 21 breast cancers, finding that expansion of the dominant subclone to an appreciable mass may represent the final rate-limiting step in a breast cancer's development, triggering diagnosis.
TL;DR: Adverse effects reported with aflibercept combined with FOLFIRI included the characteristic anti-vascular endothelial growth factor effects and also reflected an increased incidence of some chemotherapy-related toxicities.
Abstract: Purpose Treatment for metastatic colorectal cancer (mCRC) commonly involves a fluoropyrimidine-based chemotherapy regimen such as infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) or fluorouracil, leucovorin, and oxaliplatin, often combined with bevacizumab or an epidermal growth factor receptor monoclonal antibody. We studied the effect of adding the novel antiangiogenic agent aflibercept (also known as ziv-aflibercept in the United States) to FOLFIRI in patients with mCRC previously treated with oxaliplatin, including patients who received prior bevacizumab. Patients and Methods Patients were randomly assigned to receive aflibercept (4 mg/kg intravenously; 612 patients) or placebo (614 patients) every 2 weeks in combination with FOLFIRI. Treatment was administered until disease progression or unacceptable toxicity. The primary end point was overall survival. Results Adding aflibercept to FOLFIRI significantly improved overall survival relative to placebo plus FOLFIRI (hazard ratio [HR], 0.817; 95.34% CI, 0.713 to 0.937; P .0032) with median survival times of 13.50 versus 12.06 months, respectively. Aflibercept also significantly improved progression-free survival (PFS; HR, 0.758; 95% CI, 0.661 to 0.869; P .0001), with median PFS times of 6.90 versus 4.67 months, respectively. The effects on overall survival and PFS exhibited a consistent trend across prespecified subgroup analyses, including bevacizumab pretreated patients. Response rate was 19.8% (95% CI, 16.4% to 23.2%) with aflibercept plus FOLFIRI compared with 11.1% (95% CI, 8.5% to 13.8%) with placebo plus FOLFIRI (P .0001). Adverse effects reported with aflibercept combined with FOLFIRI included the characteristic anti–vascular endothelial growth factor effects and also reflected an increased incidence of some chemotherapy-related toxicities.
TL;DR: The authors presented the first comprehensive set of firm-level total factor productivity (TFP) estimates for China's manufacturing sector that spans China's entry into the WTO and found that net entry accounts for over two thirds of total TFP growth.
Eindhoven University of Technology1, Queensland University of Technology2, Capgemini3, University of Rome Tor Vergata4, Humboldt University of Berlin5, Software AG6, University of Padua7, Polytechnic University of Catalonia8, Hewlett-Packard9, Ghent University10, New Mexico State University11, IBM12, University of Milan13, University of Tartu14, University of Vienna15, Technical University of Lisbon16, Telecom SudParis17, Rabobank18, Infosys19, University of Calabria20, Fujitsu21, Pennsylvania State University22, University of Bari23, University of Bologna24, Vienna University of Economics and Business25, Free University of Bozen-Bolzano26, Stevens Institute of Technology27, Indian Council of Agricultural Research28, Pontifical Catholic University of Chile29, University of Haifa30, Ulsan National Institute of Science and Technology31, Cranfield University32, Katholieke Universiteit Leuven33, Deloitte34, Tsinghua University35, University of Innsbruck36, Hasso Plattner Institute37
TL;DR: This manifesto hopes to serve as a guide for software developers, scientists, consultants, business managers, and end-users to increase the maturity of process mining as a new tool to improve the design, control, and support of operational business processes.
Abstract: Process mining techniques are able to extract knowledge from event logs commonly available in today’s information systems. These techniques provide new means to discover, monitor, and improve processes in a variety of application domains. There are two main drivers for the growing interest in process mining. On the one hand, more and more events are being recorded, thus, providing detailed information about the history of processes. On the other hand, there is a need to improve and support business processes in competitive and rapidly changing environments. This manifesto is created by the IEEE Task Force on Process Mining and aims to promote the topic of process mining. Moreover, by defining a set of guiding principles and listing important challenges, this manifesto hopes to serve as a guide for software developers, scientists, consultants, business managers, and end-users. The goal is to increase the maturity of process mining as a new tool to improve the (re)design, control, and support of operational business processes.
TL;DR: The authors have reviewed the molecular mechanisms of the pathogenesis of acute and chronic doxorubicin-induced cardiotoxicity and propose potential pharmacological interventions and treatment options to prevent or reverse this specific type of heart failure.
TL;DR: An integrated review of the neural mechanisms involved in contour grouping, border ownership, and figure-ground perception is concluded by evaluating what modern vision science has offered compared to traditional Gestalt psychology, whether the authors can speak of a Gestalt revival, and where the remaining limitations and challenges lie.
Abstract: In 1912, Max Wertheimer published his paper on phi motion, widely recognized as the start of Gestalt psychology. Because of its continued relevance in modern psychology, this centennial anniversary is an excellent opportunity to take stock of what Gestalt psychology has offered and how it has changed since its inception. We first introduce the key findings and ideas in the Berlin school of Gestalt psychology, and then briefly sketch its development, rise, and fall. Next, we discuss its empirical and conceptual problems, and indicate how they are addressed in contemporary research on perceptual grouping and figure–ground organization. In particular, we review the principles of grouping, both classical (e.g., proximity, similarity, common fate, good continuation, closure, symmetry, parallelism) and new (e.g., synchrony, common region, element and uniform connectedness), and their role in contour integration and completion. We then review classic and new image-based principles of figure–ground organization, how it is influenced by past experience and attention, and how it relates to shape and depth perception. After an integrated review of the neural mechanisms involved in contour grouping, border ownership, and figure–ground perception, we conclude by evaluating what modern vision science has offered compared to traditional Gestalt psychology, whether we can speak of a Gestalt revival, and where the remaining limitations and challenges lie. A better integration of this research tradition with the rest of vision science requires further progress regarding the conceptual and theoretical foundations of the Gestalt approach, which is the focus of a second review article.
University of Cologne1, Misericordia University2, University Hospital of Lausanne3, Radboud University Nijmegen Medical Centre4, Necker-Enfants Malades Hospital5, Pasteur Institute6, Katholieke Universiteit Leuven7, Hacettepe University8, Statens Serum Institut9, Boston Children's Hospital10, Carlos III Health Institute11, University of Strasbourg12, University of Liverpool13, University of Copenhagen14, Innsbruck Medical University15, National and Kapodistrian University of Athens16, Manchester Academic Health Science Centre17, University of Genoa18, University of Würzburg19
TL;DR: This part of the EFISG guidelines focuses on non-neutropenic adult patients, and liposomal amphotericin B and voriconazole are supported with moderate, and fluconazole with marginal strength for the targeted initial treatment of candidaemia.
TL;DR: Adalimumab was safe and more effective than placebo in inducing and maintaining clinical remission in patients with moderate-to-severe ulcerative colitis who did not have an adequate response to conventional therapy with steroids or immunosuppressants.
TL;DR: It is shown that PS and SS sampling substantially outperform these estimators and adjust the conclusions made concerning previous analyses for the three real-world data sets that were reanalyzed.
Abstract: Recent developments in marginal likelihood estimation for model selection in the field of Bayesian phylogenetics and molecular evolution have emphasized the poor performance of the harmonic mean estimator (HME). Although these studies have shown the merits of new approaches applied to standard normally distributed examples and small real-world data sets, not much is currently known concerning the performance and computational issues of these methods when fitting complex evolutionary and population genetic models to empirical real-world data sets. Further, these approaches have not yet seen widespread application in the field due to the lack of implementations of these computationally demanding techniques in commonly used phylogenetic packages. We here investigate the performance of some of these new marginal likelihood estimators, specifically, path sampling (PS) and stepping-stone (SS) sampling for comparing models of demographic change and relaxed molecular clocks, using synthetic data and real-world examples for which unexpected inferences were made using the HME. Given the drastically increased computational demands of PS and SS sampling, we also investigate a posterior simulation-based analogue of Akaike’s information criterion (AIC) through Markov chain Monte Carlo (MCMC), a model comparison approach that shares with the HME the appealing feature of having a low computational overhead over the original MCMC analysis. We confirm that the HME systematically overestimates the marginal likelihood and fails to yield reliable model classification and show that the AICM performs better and may be a useful initial evaluation of model choice but that it is also, to a lesser degree, unreliable. We show that PS and SS sampling substantially outperform these estimators and adjust the conclusions made concerning previous analyses for the three real-world data sets that we reanalyzed. The methods used in this article are now available in BEAST, a powerful user-friendly software package to perform Bayesian evolutionary analyses.
University of California, San Diego1, Janssen Pharmaceutica2, Icahn School of Medicine at Mount Sinai3, University of Chicago4, Cedars-Sinai Medical Center5, Katholieke Universiteit Leuven6, University of Calgary7, University of Kentucky8, University of Toronto9, University of Kiel10, University of Western Ontario11
TL;DR: Patients with moderate-to-severe Crohn's disease that was resistant to TNF antagonists had an increased rate of response to induction with ustekinumab, as compared with placebo.
Abstract: Background In patients with Crohn's disease, the efficacy of ustekinumab, a human monoclonal antibody against interleukin-12 and interleukin-23, is unknown. Methods We evaluated ustekinumab in adul...
Umeå University1, University of Edinburgh2, University Hospital of Lausanne3, University of Turin4, Katholieke Universiteit Leuven5, Beaumont Hospital6, Hochschule Hannover7, Queen Elizabeth Hospital Birmingham8, University of Milan9, Jagiellonian University Medical College10, Ludwig Maximilian University of Munich11, University Hospital of Basel12
TL;DR: The evidence base for the diagnosis and management of amyotrophic lateral sclerosis (ALS) is weak and needs to be strengthened, according to the authors.
Abstract: Background: The evidence base for the diagnosis and management of amyotrophic lateral sclerosis (ALS) is weak. Objectives: To provide evidence-based or expert recommendations for the diagnosis and ...
TL;DR: The main cause is smoking tobacco, but other factors have been identified as mentioned in this paper, such as genetic determinants, lung growth, and environmental stimuli, which is further aggravated by exacerbations, particularly in patients with severe disease.