Showing papers by "University of Kiel published in 2017"
University of Sydney1, Alfred Hospital2, German Cancer Research Center3, University of Queensland4, Freeman Hospital5, University of Oslo6, University of Bordeaux7, French Institute of Health and Medical Research8, Sheba Medical Center9, University of Kiel10, University of Zurich11, Novartis12, Macquarie University13, University of Pittsburgh14
TL;DR: Adjuvant use of combination therapy with dabrafenib plus trametinib resulted in a significantly lower risk of recurrence in patients with stage III melanoma with BRAF V600E or V600K mutations than the adjuvantUse of placebo and was not associated with new toxic effects.
Abstract: BackgroundCombination therapy with the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib improved survival in patients with advanced melanoma with BRAF V600 mutations. We sought to determine whether adjuvant dabrafenib plus trametinib would improve outcomes in patients with resected, stage III melanoma with BRAF V600 mutations. MethodsIn this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 870 patients with completely resected, stage III melanoma with BRAF V600E or V600K mutations to receive oral dabrafenib at a dose of 150 mg twice daily plus trametinib at a dose of 2 mg once daily (combination therapy, 438 patients) or two matched placebo tablets (432 patients) for 12 months. The primary end point was relapse-free survival. Secondary end points included overall survival, distant metastasis–free survival, freedom from relapse, and safety. ResultsAt a median follow-up of 2.8 years, the estimated 3-year rate of relapse-free survival was 58% in the combination-therapy group a...
1,017 citations
TL;DR: In patients with moderately to severely active ulcerative colitis, tofacitinib was more effective as induction and maintenance therapy than placebo and was associated with increased lipid levels.
Abstract: BackgroundTofacitinib, an oral, small-molecule Janus kinase inhibitor, was shown to have potential efficacy as induction therapy for ulcerative colitis in a phase 2 trial. We further evaluated the efficacy of tofacitinib as induction and maintenance therapy. MethodsWe conducted three phase 3, randomized, double-blind, placebo-controlled trials of tofacitinib therapy in adults with ulcerative colitis. In the OCTAVE Induction 1 and 2 trials, 598 and 541 patients, respectively, who had moderately to severely active ulcerative colitis despite previous conventional therapy or therapy with a tumor necrosis factor antagonist were randomly assigned to receive induction therapy with tofacitinib (10 mg twice daily) or placebo for 8 weeks. The primary end point was remission at 8 weeks. In the OCTAVE Sustain trial, 593 patients who had a clinical response to induction therapy were randomly assigned to receive maintenance therapy with tofacitinib (either 5 mg or 10 mg twice daily) or placebo for 52 weeks. The primary...
1,000 citations
University of Cambridge1, University of the Basque Country2, National Autonomous University of Mexico3, University of Córdoba (Spain)4, Corvinus University of Budapest5, University of Southern Denmark6, University of Gothenburg7, University of East Anglia8, Lund University9, University of Kiel10, United Nations11, Helmholtz Centre for Environmental Research - UFZ12, University of Khartoum13, King Abdulaziz City for Science and Technology14, University of Washington15, University of Oxford16, Ministry of Forestry17, University College Dublin18, National University of Cordoba19, Carthage University20, University of Chile21, Harvard University22, Norwegian University of Life Sciences23, University of Pretoria24, University of Antwerp25, Wetlands International26, Universidade Federal Rural do Rio de Janeiro27, International Union for Conservation of Nature and Natural Resources28, Council for Scientific and Industrial Research29, University of Western Australia30, National University of General Sarmiento31, Calcutta Institute of Engineering and Management32, European Commission33, Government of Canada34, Finnish Environment Institute35, Federal University of Rio de Janeiro36, Pontifical Catholic University of Rio de Janeiro37, International Institute of Minnesota38, Victoria University of Wellington39, Indian Institute of Forest Management40, University of Tokyo41
TL;DR: In this paper, the authors present the rationale for the inclusive valuation of nature's contributions to people (NCP) in decision making, as well as broad methodological steps for doing so, and argue that transformative practices aiming at sustainable futures would benefit from embracing such diversity, which require recognizing and addressing power relationships across stakeholder groups that hold different values on human nature-relations and NCP.
985 citations
University of California, Los Angeles1, University of Utah2, University of South Florida3, University of Helsinki4, Primary Children's Hospital5, University of Groningen6, Norfolk and Norwich University Hospital7, Lund University8, Netherlands Cancer Institute9, University of Michigan10, Wake Forest University11, Ohio State University12, Peter MacCallum Cancer Centre13, University of Zurich14, University of Padua15, Pennsylvania State University16, Saint Louis University17, Tom Baker Cancer Centre18, University of Washington19, University of Lausanne20, Guy's and St Thomas' NHS Foundation Trust21, University of Kiel22, Thomas Jefferson University23, Sunnybrook Research Institute24, Vanderbilt University25, University of Queensland26, Fox Chase Cancer Center27, Greenville Health System28, Stony Brook University29, University Health Network30, Memorial Sloan Kettering Cancer Center31, Roswell Park Cancer Institute32, Northwestern University33, University of Wisconsin-Madison34, Rush University Medical Center35, Tel Aviv Sourasky Medical Center36, Dartmouth College37, Johns Hopkins University38, University of Louisville39, University of Barcelona40, University of Sydney41
TL;DR: Immediate completion lymph‐node dissection increased the rate of regional disease control and provided prognostic information but did not increase melanoma‐specific survival among patients with melanoma and sentinel‐node metastases.
Abstract: BackgroundSentinel-lymph-node biopsy is associated with increased melanoma-specific survival (i.e., survival until death from melanoma) among patients with node-positive intermediate-thickness melanomas (1.2 to 3.5 mm). The value of completion lymph-node dissection for patients with sentinel-node metastases is not clear. MethodsIn an international trial, we randomly assigned patients with sentinel-node metastases detected by means of standard pathological assessment or a multimarker molecular assay to immediate completion lymph-node dissection (dissection group) or nodal observation with ultrasonography (observation group). The primary end point was melanoma-specific survival. Secondary end points included disease-free survival and the cumulative rate of nonsentinel-node metastasis. ResultsImmediate completion lymph-node dissection was not associated with increased melanoma-specific survival among 1934 patients with data that could be evaluated in an intention-to-treat analysis or among 1755 patients in t...
946 citations
TL;DR: Assessment of the entire ocean oxygen inventory by analysing dissolved oxygen and supporting data for the complete oceanic water column over the past 50 years finds that the global oceanic oxygen content has decreased by more than two per cent, with large variations in oxygen loss in different ocean basins and at different depths.
Abstract: Ocean models predict a decline in the dissolved oxygen inventory of the global ocean of one to seven per cent by the year 2100, caused by a combination of a warming-induced decline in oxygen solubility and reduced ventilation of the deep ocean1, 2. It is thought that such a decline in the oceanic oxygen content could affect ocean nutrient cycles and the marine habitat, with potentially detrimental consequences for fisheries and coastal economies3, 4, 5, 6. Regional observational data indicate a continuous decrease in oceanic dissolved oxygen concentrations in most regions of the global ocean1, 7, 8, 9, 10, with an increase reported in a few limited areas, varying by study1, 10. Prior work attempting to resolve variations in dissolved oxygen concentrations at the global scale reported a global oxygen loss of 550 ± 130 teramoles (1012 mol) per decade between 100 and 1,000 metres depth based on a comparison of data from the 1970s and 1990s10. Here we provide a quantitative assessment of the entire ocean oxygen inventory by analysing dissolved oxygen and supporting data for the complete oceanic water column over the past 50 years. We find that the global oceanic oxygen content of 227.4 ± 1.1 petamoles (1015 mol) has decreased by more than two per cent (4.8 ± 2.1 petamoles) since 1960, with large variations in oxygen loss in different ocean basins and at different depths. We suggest that changes in the upper water column are mostly due to a warming-induced decrease in solubility and biological consumption. Changes in the deeper ocean may have their origin in basin-scale multi-decadal variability, oceanic overturning slow-down and a potential increase in biological consumption11, 12.
738 citations
TL;DR: Benralizumab showed significant, clinically relevant benefits, as compared with placebo, on oral glucocorticoid use and exacerbation rates and without a sustained effect on the forced expiratory volume in 1 second (FEV1).
Abstract: BackgroundMany patients with severe asthma rely on oral glucocorticoids to manage their disease We investigated whether benralizumab, a monoclonal antibody directed against the alpha subunit of the interleukin-5 receptor that significantly reduces the incidence of asthma exacerbations, was also effective as an oral glucocorticoid–sparing therapy in patients relying on oral glucocorticoids to manage severe asthma associated with eosinophilia MethodsIn a 28-week randomized, controlled trial, we assessed the effects of benralizumab (at a dose of 30 mg administered subcutaneously either every 4 weeks or every 8 weeks [with the first three doses administered every 4 weeks]) versus placebo on the reduction in the oral glucocorticoid dose while asthma control was maintained in adult patients with severe asthma The primary end point was the percentage change in the oral glucocorticoid dose from baseline to week 28 Annual asthma exacerbation rates, lung function, symptoms, and safety were assessed ResultsOf 3
699 citations
University of Göttingen1, City College of New York2, University of São Paulo3, University of Toronto4, University of Erlangen-Nuremberg5, Aalborg University6, Greifswald University Hospital7, Spaulding Rehabilitation Hospital8, Medical University of South Carolina9, University of Pennsylvania10, Technische Universität Ilmenau11, University of Oldenburg12, École Polytechnique Fédérale de Lausanne13, Paris 12 Val de Marne University14, University of New South Wales15, University of Aberdeen16, University of Trento17, University of Lisbon18, University of Kiel19, Technical University of Dortmund20, Ruhr University Bochum21, Ludwig Maximilian University of Munich22, Beth Israel Deaconess Medical Center23, Mannheim University of Applied Sciences24, University of Siena25, The Catholic University of America26, University College London27, University of Copenhagen28, Fukushima Medical University29, Massachusetts Institute of Technology30, University of Tübingen31
TL;DR: Structured interviews are provided and recommend their use in future controlled studies, in particular when trying to extend the parameters applied, to discuss recent regulatory issues, reporting practices and ethical issues.
699 citations
Wellcome Trust Centre for Human Genetics1, Imperial College London2, University of Oulu3, Agency for Science, Technology and Research4, National Institutes of Health5, King's College London6, Ealing Hospital7, National University of Singapore8, University of Turin9, University Medical Center Groningen10, University of Tartu11, University of Bristol12, University College London13, University of Eastern Finland14, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico15, University of Kiel16, Leiden University Medical Center17, Dresden University of Technology18, University of Düsseldorf19, University of Surrey20, Erasmus University Rotterdam21, Max Healthcare22, Technische Universität München23, University of Naples Federico II24, Wellcome Trust Sanger Institute25, Science for Life Laboratory26, University of Ulm27, Ludwig Maximilian University of Munich28, University of Kelaniya29, Institute of Cancer Research30, Queen Mary University of London31, King Abdulaziz University32, Massachusetts Institute of Technology33, Health Protection Agency34, University of Oxford35, Churchill Hospital36, Imperial College Healthcare37
TL;DR: In this article, the authors used epigenome-wide association to show that body mass index (BMI), a key measure of adiposity, is associated with widespread changes in DNA methylation.
Abstract: Approximately 1.5 billion people worldwide are overweight or affected by obesity, and are at risk of developing type 2 diabetes, cardiovascular disease and related metabolic and inflammatory disturbances1,2. Although the mechanisms linking adiposity to associated clinical conditions are poorly understood, recent studies suggest that adiposity may influence DNA methylation3,4,5,6, a key regulator of gene expression and molecular phenotype7. Here we use epigenome-wide association to show that body mass index (BMI; a key measure of adiposity) is associated with widespread changes in DNA methylation (187 genetic loci with P < 1 × 10−7, range P = 9.2 × 10−8 to 6.0 × 10−46; n = 10,261 samples). Genetic association analyses demonstrate that the alterations in DNA methylation are predominantly the consequence of adiposity, rather than the cause. We find that methylation loci are enriched for functional genomic features in multiple tissues (P < 0.05), and show that sentinel methylation markers identify gene expression signatures at 38 loci (P < 9.0 × 10−6, range P = 5.5 × 10−6 to 6.1 × 10−35, n = 1,785 samples). The methylation loci identify genes involved in lipid and lipoprotein metabolism, substrate transport and inflammatory pathways. Finally, we show that the disturbances in DNA methylation predict future development of type 2 diabetes (relative risk per 1 standard deviation increase in methylation risk score: 2.3 (2.07–2.56); P = 1.1 × 10−54). Our results provide new insights into the biologic pathways influenced by adiposity, and may enable development of new strategies for prediction and prevention of type 2 diabetes and other adverse clinical consequences of obesity.
667 citations
Charité1, Oregon Health & Science University2, French Institute of Health and Medical Research3, University of Western Australia4, King Edward Memorial Hospital5, Sanford Health6, Children's Hospital of Eastern Ontario7, University of Toronto8, University of Cambridge9, University College London10, Cold Spring Harbor Laboratory11, Queen Mary University of London12, Radboud University Nijmegen13, Wellcome Trust Sanger Institute14, Katholieke Universiteit Leuven15, Johns Hopkins University School of Medicine16, University of Kiel17, University of Pennsylvania18, University of Luxembourg19, Medical College of Wisconsin20, Newcastle University21, Tohoku University22, Manchester Royal Eye Hospital23, John Radcliffe Hospital24, University of Sydney25, University of Miami26, Garvan Institute of Medical Research27, Lawrence Berkeley National Laboratory28, University of Connecticut29
TL;DR: The progress of the HPO project is reviewed, including specific areas of expansion such as common (complex) disease, new algorithms for phenotype driven genomic discovery and diagnostics, integration of cross-species mapping efforts with the Mammalian Phenotype Ontology, an improved quality control pipeline, and the addition of patient-friendly terminology.
Abstract: Deep phenotyping has been defined as the precise and comprehensive analysis of phenotypic abnormalities in which the individual components of the phenotype are observed and described. The three components of the Human Phenotype Ontology (HPO; www.human-phenotype-ontology.org) project are the phenotype vocabulary, disease-phenotype annotations and the algorithms that operate on these. These components are being used for computational deep phenotyping and precision medicine as well as integration of clinical data into translational research. The HPO is being increasingly adopted as a standard for phenotypic abnormalities by diverse groups such as international rare disease organizations, registries, clinical labs, biomedical resources, and clinical software tools and will thereby contribute toward nascent efforts at global data exchange for identifying disease etiologies. This update article reviews the progress of the HPO project since the debut Nucleic Acids Research database article in 2014, including specific areas of expansion such as common (complex) disease, new algorithms for phenotype driven genomic discovery and diagnostics, integration of cross-species mapping efforts with the Mammalian Phenotype Ontology, an improved quality control pipeline, and the addition of patient-friendly terminology.
638 citations
TL;DR: The concepts and mechanisms of microbial resilience against dietary, antibiotic or bacteriotherapy-induced perturbations and the implications for human health are discussed.
Abstract: The resilience of the microbiota can protect us from disease, but a resilient dysbiotic microbiota may also cause disease. This Opinion article discusses the concepts and mechanisms of microbial resilience against dietary, antibiotic or bacteriotherapy-induced perturbations and the implications these have for human health. The composition of the intestinal microbiota varies among individuals and throughout development, and is dependent on host and environmental factors. However, although the microbiota is constantly exposed to environmental challenges, its composition and function in an individual are stable against perturbations, as microbial communities are resilient and resistant to change. The maintenance of a beneficial microbiota requires a homeostatic equilibrium within microbial communities, and also between the microorganisms and the intestinal interface of the host. The resilience of the healthy microbiota protects us from dysbiosis-related diseases, such as inflammatory bowel disease (IBD) or metabolic disorder. By contrast, a resilient dysbiotic microbiota may cause disease. In this Opinion article, we propose that microbial resilience has a key role in health and disease. We will discuss the concepts and mechanisms of microbial resilience against dietary, antibiotic or bacteriotherapy-induced perturbations and the implications for human health.
601 citations
TL;DR: Without a global political and economic effort to reduce tobacco use, to regulate environmental exposure, and to find alternatives to the massive use of biomass fuel, COPD will remain a major health-care problem for decades to come.
University of Kiel1, University of São Paulo2, Boston Children's Hospital3, Furtwangen University4, University of Mainz5, Carleton University6, Sahlgrenska University Hospital7, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico8, Guy's and St Thomas' NHS Foundation Trust9, University of Queensland10, Erasmus University Rotterdam11, RWTH Aachen University12
TL;DR: A new classification of core processes involved in chest EIT examinations and data analysis is provided, and a structured framework to categorise and understand the relationships among analysis approaches and their clinical roles is provided.
Abstract: Electrical impedance tomography (EIT) has undergone 30 years of development. Functional chest examinations with this technology are considered clinically relevant, especially for monitoring regional lung ventilation in mechanically ventilated patients and for regional pulmonary function testing in patients with chronic lung diseases. As EIT becomes an established medical technology, it requires consensus examination, nomenclature, data analysis and interpretation schemes. Such consensus is needed to compare, understand and reproduce study findings from and among different research groups, to enable large clinical trials and, ultimately, routine clinical use. Recommendations of how EIT findings can be applied to generate diagnoses and impact clinical decision-making and therapy planning are required. This consensus paper was prepared by an international working group, collaborating on the clinical promotion of EIT called TRanslational EIT developmeNt stuDy group. It addresses the stated needs by providing (1) a new classification of core processes involved in chest EIT examinations and data analysis, (2) focus on clinical applications with structured reviews and outlooks (separately for adult and neonatal/paediatric patients), (3) a structured framework to categorise and understand the relationships among analysis approaches and their clinical roles, (4) consensus, unified terminology with clinical user-friendly definitions and explanations, (5) a review of all major work in thoracic EIT and (6) recommendations for future development (193 pages of online supplements systematically linked with the chief sections of the main document). We expect this information to be useful for clinicians and researchers working with EIT, as well as for industry producers of this technology.
CEU San Pablo University1, University of Marburg2, National and Kapodistrian University of Athens3, Rush University Medical Center4, University of Toronto5, Toronto Western Hospital6, University of Pennsylvania7, Newcastle University8, University of Sydney9, University of New South Wales10, Centre national de la recherche scientifique11, Peking Union Medical College12, Columbia University13, University of Paris14, Aarhus University15, UCL Institute of Neurology16, National Institutes of Health17, Emory University18, San Francisco VA Medical Center19, University of California, San Francisco20, Veterans Health Administration21, Erasmus University Medical Center22, Baylor College of Medicine23, University of Kiel24, Hebrew University of Jerusalem25, University of Barcelona26, Columbia University Medical Center27, McGill University28, University of Alabama at Birmingham29, Northwestern University30, Icahn School of Medicine at Mount Sinai31, University of Perugia32, Vancouver Coastal Health33, University of British Columbia34
TL;DR: This multiple‐author article provides a historical state‐of‐the‐art account of what has been achieved, the current situation, and how to progress toward resolving Parkinson's disease.
Abstract: This article reviews and summarizes 200 years of Parkinson's disease. It comprises a relevant history of Dr. James Parkinson's himself and what he described accurately and what he missed from today's perspective. Parkinson's disease today is understood as a multietiological condition with uncertain etiopathogenesis. Many advances have occurred regarding pathophysiology and symptomatic treatments, but critically important issues are still pending resolution. Among the latter, the need to modify disease progression is undoubtedly a priority. In sum, this multiple-author article, prepared to commemorate the bicentenary of the shaking palsy, provides a historical state-of-the-art account of what has been achieved, the current situation, and how to progress toward resolving Parkinson's disease. © 2017 International Parkinson and Movement Disorder Society.
TL;DR: The authors of this review discuss recent progress in diagnostic and treatment approaches, including molecular characterization to determine the likelihood of a response to targeted agents and immunotherapies.
Abstract: Smoking cessation has reduced the incidence of lung cancer. The authors of this review discuss recent progress in diagnostic and treatment approaches, including molecular characterization to determine the likelihood of a response to targeted agents and immunotherapies.
TL;DR: In the last 15 years, more than 50,000 papers with zinc oxide (ZnO) in the title are listed within ISI database as mentioned in this paper, and the outstanding popularity of ZnO has many reasons; the most important one appears to be its multi-functionality resulting in applications in physics, chemistry, electrical engineering, material science, energy, textile, rubber, additive manufacturing, cosmetics, and pharmaceutical or medicine, as well as the ease to grow all kinds of nano- and microstructures.
TL;DR: The assembly of a high-quality, chromosome-scale reference genome sequence for quinoa was produced using single-molecule real-time sequencing in combination with optical, chromosomes-contact and genetic maps, which facilitated the identification of the transcription factor likely to control the production of anti-nutritional triterpenoid saponins found in quinoa seeds.
Abstract: Chenopodium quinoa (quinoa) is a highly nutritious grain identified as an important crop to improve world food security. Unfortunately, few resources are available to facilitate its genetic improvement. Here we report the assembly of a high-quality, chromosome-scale reference genome sequence for quinoa, which was produced using single-molecule real-time sequencing in combination with optical, chromosome-contact and genetic maps. We also report the sequencing of two diploids from the ancestral gene pools of quinoa, which enables the identification of sub-genomes in quinoa, and reduced-coverage genome sequences for 22 other samples of the allotetraploid goosefoot complex. The genome sequence facilitated the identification of the transcription factor likely to control the production of anti-nutritional triterpenoid saponins found in quinoa seeds, including a mutation that appears to cause alternative splicing and a premature stop codon in sweet quinoa strains. These genomic resources are an important first step towards the genetic improvement of quinoa.
TL;DR: A preliminary investigation of 5 patients with CDI shows that transfer of sterile filtrates from donor stool (FFT), rather than fecal microbiota, can be sufficient to restore normal stool habits and eliminate symptoms.
Harvard University1, Broad Institute2, University of Liège3, University of Oxford4, Wellcome Trust Sanger Institute5, Montreal Heart Institute6, University of Southern Denmark7, Katholieke Universiteit Leuven8, John Radcliffe Hospital9, Wellcome Trust Centre for Human Genetics10, Ikerbasque11, Karolinska Institutet12, Illumina13, University of Kiel14, Örebro University15, Cedars-Sinai Medical Center16, Lancaster University17, University of Western Australia18, Western General Hospital19, Norwegian University of Life Sciences20, Wellcome Trust21, University of Groningen22, University Medical Center Groningen23, University of Pittsburgh24, University of the Witwatersrand25, King's College London26, Université de Montréal27, Yale University28
TL;DR: The results of this study suggest that high-resolution fine-mapping in large samples can convert many discoveries from genome-wide association studies into statistically convincing causal variants, providing a powerful substrate for experimental elucidation of disease mechanisms.
Abstract: Inflammatory bowel diseases are chronic gastrointestinal inflammatory disorders that affect millions of people worldwide. Genome-wide association studies have identified 200 inflammatory bowel disease-associated loci, but few have been conclusively resolved to specific functional variants. Here we report fine-mapping of 94 inflammatory bowel disease loci using high-density genotyping in 67,852 individuals. We pinpoint 18 associations to a single causal variant with greater than 95% certainty, and an additional 27 associations to a single variant with greater than 50% certainty. These 45 variants are significantly enriched for protein-coding changes (n = 13), direct disruption of transcription-factor binding sites (n = 3), and tissue-specific epigenetic marks (n = 10), with the last category showing enrichment in specific immune cells among associations stronger in Crohn's disease and in gut mucosa among associations stronger in ulcerative colitis. The results of this study suggest that high-resolution fine-mapping in large samples can convert many discoveries from genome-wide association studies into statistically convincing causal variants, providing a powerful substrate for experimental elucidation of disease mechanisms.
University of Louisville1, Roswell Park Cancer Institute2, University of North Carolina at Chapel Hill3, Mayo Clinic4, University of Iowa5, University of California, Los Angeles6, University of Texas MD Anderson Cancer Center7, Icahn School of Medicine at Mount Sinai8, University of Tübingen9, Indiana University10, University of Kiel11, University of Paris12, Amgen13, University of Utah14, Rutgers University15
TL;DR: The study met its primary end point; the objective response rate was significantly higher with talimogene laherparepvec plus ipilimumab versus ipilitationab alone, indicating that the combination has greater antitumor activity without additional safety concerns versus ipILimumab.
Abstract: Purpose We evaluated the combination of talimogene laherparepvec plus ipilimumab versus ipilimumab alone in patients with advanced melanoma in a phase II study. To our knowledge, this was the first randomized trial to evaluate addition of an oncolytic virus to a checkpoint inhibitor. Methods Patients with unresectable stages IIIB to IV melanoma, with no more than one prior therapy if BRAF wild-type, no more than two prior therapies if BRAF mutant, measurable/injectable disease, and without symptomatic autoimmunity or clinically significant immunosuppression were randomly assigned 1:1 to receive talimogene laherparepvec plus ipilimumab or ipilimumab alone. Talimogene laherparepvec treatment began in week 1 (first dose, ≤ 4 mL × 106 plaque-forming units/mL; after 3 weeks, ≤ 4 mL × 108 plaque-forming units/mL every 2 weeks). Ipilimumab (3 mg/kg every 3 weeks; up to four doses) began week 1 in the ipilimumab alone arm and week 6 in the combination arm. The primary end point was objective response rate evaluated by investigators per immune-related response criteria. Results One hundred ninety-eight patients were randomly assigned to talimogene laherparepvec plus ipilimumab (n = 98), or ipilimumab alone (n = 100). Thirty-eight patients (39%) in the combination arm and 18 patients (18%) in the ipilimumab arm had an objective response (odds ratio, 2.9; 95% CI, 1.5 to 5.5; P = .002). Responses were not limited to injected lesions; visceral lesion decreases were observed in 52% of patients in the combination arm and 23% of patients in the ipilimumab arm. Frequently occurring adverse events (AEs) included fatigue (combination, 59%; ipilimumab alone, 42%), chills (combination, 53%; ipilimumab alone, 3%), and diarrhea (combination, 42%; ipilimumab alone, 35%). Incidence of grade ≥ 3 AEs was 45% and 35%, respectively. Three patients in the combination arm had fatal AEs; none were treatment related. Conclusion The study met its primary end point; the objective response rate was significantly higher with talimogene laherparepvec plus ipilimumab versus ipilimumab alone. These data indicate that the combination has greater antitumor activity without additional safety concerns versus ipilimumab.
Imperial College London1, University College London2, University of Liverpool3, University of Colorado Denver4, University of Texas Health Science Center at San Antonio5, Temple University6, University of Ferrara7, University of Kiel8, Cochrane Collaboration9, University of Bern10, University of Manchester11, Boston University12, University of Illinois at Urbana–Champaign13
TL;DR: The Task Force providedRecommendations related to corticosteroid therapy, antibiotic therapy, noninvasive mechanical ventilation, home-based management, and early pulmonary rehabilitation in patients having a COPD exacerbation should be reconsidered as new evidence becomes available.
Abstract: This document provides clinical recommendations for treatment of chronic obstructive pulmonary disease (COPD) exacerbations.Comprehensive evidence syntheses, including meta-analyses, were performed to summarise all available evidence relevant to the Task Force's questions. The evidence was appraised using the Grading of Recommendations, Assessment, Development and Evaluation approach and the results were summarised in evidence profiles. The evidence syntheses were discussed and recommendations formulated by a multidisciplinary Task Force of COPD experts.After considering the balance of desirable and undesirable consequences, quality of evidence, feasibility, and acceptability of various interventions, the Task Force made: 1) a strong recommendation for noninvasive mechanical ventilation of patients with acute or acute-on-chronic respiratory failure; 2) conditional recommendations for oral corticosteroids in outpatients, oral rather than intravenous corticosteroids in hospitalised patients, antibiotic therapy, home-based management, and the initiation of pulmonary rehabilitation within 3 weeks after hospital discharge; and 3) a conditional recommendation against the initiation of pulmonary rehabilitation during hospitalisation.The Task Force provided recommendations related to corticosteroid therapy, antibiotic therapy, noninvasive mechanical ventilation, home-based management, and early pulmonary rehabilitation in patients having a COPD exacerbation. These recommendations should be reconsidered as new evidence becomes available.
QIMR Berghofer Medical Research Institute1, University Medical Center Groningen2, University of Kiel3, Max Delbrück Center for Molecular Medicine4, Charité5, University of California, San Francisco6, University of Amsterdam7, Karolinska Institutet8, University of Bristol9, Norwegian University of Science and Technology10, University of Melbourne11, Stanford University12, University of Michigan13, Greifswald University Hospital14, University of Greifswald15, Harry Perkins Institute of Medical Research16, University Hospital Bonn17, Ludwig Maximilian University of Munich18, Kaiser Permanente19, VU University Medical Center20, Karolinska University Hospital21, GlaxoSmithKline22
TL;DR: A genome-wide association study of a broad allergic disease phenotype that considers the presence of any one of these three diseases identified 136 independent risk variants, including 73 not previously reported, which implicate 132 nearby genes in allergic disease pathophysiology.
Abstract: Asthma, hay fever (or allergic rhinitis) and eczema (or atopic dermatitis) often coexist in the same individuals, partly because of a shared genetic origin. To identify shared risk variants, we performed a genome-wide association study (GWAS; n = 360,838) of a broad allergic disease phenotype that considers the presence of any one of these three diseases. We identified 136 independent risk variants (P < 3 × 10-8), including 73 not previously reported, which implicate 132 nearby genes in allergic disease pathophysiology. Disease-specific effects were detected for only six variants, confirming that most represent shared risk factors. Tissue-specific heritability and biological process enrichment analyses suggest that shared risk variants influence lymphocyte-mediated immunity. Six target genes provide an opportunity for drug repositioning, while for 36 genes CpG methylation was found to influence transcription independently of genetic effects. Asthma, hay fever and eczema partly coexist because they share many genetic risk variants that dysregulate the expression of immune-related genes.
Boston Children's Hospital1, University of Southern Denmark2, University of Tübingen3, University of Pavia4, University of Copenhagen5, French Institute of Health and Medical Research6, Lyon College7, HCL Technologies8, Aix-Marseille University9, University of Paris10, Paris Diderot University11, University of Hamburg12, Utrecht University13, Erasmus University Medical Center14, Mayo Clinic15, University of Genoa16, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico17, University of Michigan18, Université libre de Bruxelles19, University of Kiel20, Detmold21, Aarhus University Hospital22, University Hospital Heidelberg23, University of Tartu24, University of Colorado Denver25, Centre Hospitalier de Luxembourg26, Cairo University27, Ghent University Hospital28, Katholieke Universiteit Leuven29, University of Antwerp30, Leipzig University31, Children's Hospital of Philadelphia32
TL;DR: Clinical and experimental data suggest a correlation between age at disease onset, response to sodium channel blockers and the functional properties of mutations in children with SCN2A-related epilepsy, and suggest that mutations associated with early infantile epilepsy result in increased sodium channel activity with gain-of-function.
Abstract: Mutations in SCN2A, a gene encoding the voltage-gated sodium channel Nav1.2, have been associated with a spectrum of epilepsies and neurodevelopmental disorders. Here, we report the phenotypes of 71 patients and review 130 previously reported patients. We found that (i) encephalopathies with infantile/childhood onset epilepsies (≥3 months of age) occur almost as often as those with an early infantile onset (<3 months), and are thus more frequent than previously reported; (ii) distinct phenotypes can be seen within the late onset group, including myoclonic-atonic epilepsy (two patients), Lennox-Gastaut not emerging from West syndrome (two patients), and focal epilepsies with an electrical status epilepticus during slow sleep-like EEG pattern (six patients); and (iii) West syndrome constitutes a common phenotype with a major recurring mutation (p.Arg853Gln: two new and four previously reported children). Other known phenotypes include Ohtahara syndrome, epilepsy of infancy with migrating focal seizures, and intellectual disability or autism without epilepsy. To assess the response to antiepileptic therapy, we retrospectively reviewed the treatment regimen and the course of the epilepsy in 66 patients for which well-documented medical information was available. We find that the use of sodium channel blockers was often associated with clinically relevant seizure reduction or seizure freedom in children with early infantile epilepsies (<3 months), whereas other antiepileptic drugs were less effective. In contrast, sodium channel blockers were rarely effective in epilepsies with later onset (≥3 months) and sometimes induced seizure worsening. Regarding the genetic findings, truncating mutations were exclusively seen in patients with late onset epilepsies and lack of response to sodium channel blockers. Functional characterization of four selected missense mutations using whole cell patch-clamping in tsA201 cells—together with data from the literature—suggest that mutations associated with early infantile epilepsy result in increased sodium channel activity with gain-of-function, characterized by slowing of fast inactivation, acceleration of its recovery or increased persistent sodium current. Further, a good response to sodium channel blockers clinically was found to be associated with a relatively small gain-of-function. In contrast, mutations in patients with late-onset forms and an insufficient response to sodium channel blockers were associated with loss-of-function effects, including a depolarizing shift of voltage-dependent activation or a hyperpolarizing shift of channel availability (steady-state inactivation). Our clinical and experimental data suggest a correlation between age at disease onset, response to sodium channel blockers and the functional properties of mutations in children with SCN2A-related epilepsy.
TL;DR: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases, as well as single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population.
Abstract: IMPORTANCE: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. OBJECTIVE: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. DATA SOURCES: Genomewide association studies (GWAS) published up to January 15, 2015. STUDY SELECTION: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. DATA EXTRACTION AND SYNTHESIS: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. RESULTS: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]). CONCLUSIONS AND RELEVANCE: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.
Medical University of Vienna1, Karolinska Institutet2, Stanford University3, Semmelweis University4, Hungarian Academy of Sciences5, Université catholique de Louvain6, Carl Zeiss AG7, University of Calgary8, Gunma University9, Austrian Academy of Sciences10, Royal Institute of Technology11, University of Kiel12, Yale University13
TL;DR: A catalog of neuronal subclasses provides new understanding of hypothalamic organization and function and distinguished 62 neuronal subtypes producing glutamatergic, dopaminergic or GABAergic markers for synaptic neurotransmission and harboring the ability to engage in task-dependent neurotransmitter switching.
Abstract: The hypothalamus is a brain region rich in functionally segregated neurons. Here Romanov and colleagues use single-cell RNA sequencing to distinguish 62 neuronal subtypes and define their neuropeptide and neurotransmitter makeup. They then show that onecut-3-containing dopamine neurons populate the periventricular area and are wired into the circadian circuitry.
University of Western Ontario1, University of California, San Diego2, University of Amsterdam3, University of Cambridge4, Katholieke Universiteit Leuven5, Cliniques Universitaires Saint-Luc6, Hannover Medical School7, Asan Medical Center8, University of Erlangen-Nuremberg9, University of Kiel10, Boehringer Ingelheim11
TL;DR: In this short-term study, risankizumab was more effective than placebo for inducing clinical remission in patients with active Crohn's disease and selective blockade of interleukin-23 via inhibition of p19 might be a viable therapeutic approach in Crohn’s disease.
TL;DR: autoantibodies can be classified into the following categories: mimic receptor stimulation, blocking of neural transmission, induction of altered signaling, triggering uncontrolled microthrombosis, cell lysis, neutrophil activation, and (7) induction of inflammation.
Abstract: Autoantibodies are frequently observed in healthy individuals In a minority of these individuals, they lead to manifestation of autoimmune diseases, such as rheumatoid arthritis or Graves’ disease Overall, more than 25% of the population is affected by autoantibody-driven autoimmune disease Pathways leading to autoantibody-induced pathology greatly differ among different diseases, and autoantibodies directed against the same antigen, depending on the targeted epitope, can have diverse effects To foster knowledge in autoantibody-induced pathology and to encourage development of urgently needed novel therapeutic strategies we here categorized autoantibodies according to their effects According to our algorithm, autoantibodies can be classified into the following categories: (1) Mimic receptor stimulation, (2) blocking of neural transmission, (3) induction of altered signaling, triggering uncontrolled (4) microthrombosis, (5) cell lysis, (6) neutrophil activation and (7) induction of inflammation These mechanisms in relation to disease, as well as principles of autoantibody generation and detection are reviewed herein
Max Planck Society1, Spanish National Research Council2, Catalan Institution for Research and Advanced Studies3, Helmholtz-Zentrum Dresden-Rossendorf4, University of Leeds5, University of California, San Diego6, University of California, Santa Cruz7, Lawrence Berkeley National Laboratory8, University of Kiel9, Ikerbasque10, University of Lorraine11, Kaiserslautern University of Technology12, New York University13, University of Nottingham14, Academy of Sciences of the Czech Republic15, Technische Universität Darmstadt16, Daegu Gyeongbuk Institute of Science and Technology17
TL;DR: The 2017 Magnetism Roadmap as mentioned in this paper is the most recent edition of the magnetism roadmap, which is intended to provide a reference point and guideline for emerging research directions in modern magnetism.
Abstract: Building upon the success and relevance of the 2014 Magnetism Roadmap, this 2017 Magnetism Roadmap edition follows a similar general layout, even if its focus is naturally shifted, and a different group of experts and, thus, viewpoints are being collected and presented. More importantly, key developments have changed the research landscape in very relevant ways, so that a novel view onto some of the most crucial developments is warranted, and thus, this 2017 Magnetism Roadmap article is a timely endeavour. The change in landscape is hereby not exclusively scientific, but also reflects the magnetism related industrial application portfolio. Specifically, Hard Disk Drive technology, which still dominates digital storage and will continue to do so for many years, if not decades, has now limited its footprint in the scientific and research community, whereas significantly growing interest in magnetism and magnetic materials in relation to energy applications is noticeable, and other technological fields are emerging as well. Also, more and more work is occurring in which complex topologies of magnetically ordered states are being explored, hereby aiming at a technological utilization of the very theoretical concepts that were recognised by the 2016 Nobel Prize in Physics. Given this somewhat shifted scenario, it seemed appropriate to select topics for this Roadmap article that represent the three core pillars of magnetism, namely magnetic materials, magnetic phenomena and associated characterization techniques, as well as applications of magnetism. While many of the contributions in this Roadmap have clearly overlapping relevance in all three fields, their relative focus is mostly associated to one of the three pillars. In this way, the interconnecting roles of having suitable magnetic materials, understanding (and being able to characterize) the underlying physics of their behaviour and utilizing them for applications and devices is well illustrated, thus giving an accurate snapshot of the world of magnetism in 2017. The article consists of 14 sections, each written by an expert in the field and addressing a specific subject on two pages. Evidently, the depth at which each contribution can describe the subject matter is limited and a full review of their statuses, advances, challenges and perspectives cannot be fully accomplished. Also, magnetism, as a vibrant research field, is too diverse, so that a number of areas will not be adequately represented here, leaving space for further Roadmap editions in the future. However, this 2017 Magnetism Roadmap article can provide a frame that will enable the reader to judge where each subject and magnetism research field stands overall today and which directions it might take in the foreseeable future. The first material focused pillar of the 2017 Magnetism Roadmap contains five articles, which address the questions of atomic scale confinement, 2D, curved and topological magnetic materials, as well as materials exhibiting unconventional magnetic phase transitions. The second pillar also has five contributions, which are devoted to advances in magnetic characterization, magneto-optics and magneto-plasmonics, ultrafast magnetization dynamics and magnonic transport. The final and application focused pillar has four contributions, which present non-volatile memory technology, antiferromagnetic spintronics, as well as magnet technology for energy and bio-related applications. As a whole, the 2017 Magnetism Roadmap article, just as with its 2014 predecessor, is intended to act as a reference point and guideline for emerging research directions in modern magnetism.
TL;DR: Filgotinib induced clinical remission in significantly more patients with active Crohn's disease compared with placebo, and had an acceptable safety profile.
Catherine M. Phelan, Karoline Kuchenbaecker1, Karoline Kuchenbaecker2, Jonathan Tyrer2 +440 more•Institutions (156)
TL;DR: Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.
Abstract: To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.
TL;DR: An overview of the currently available information on the natural environment of Caenorhabditis elegans focuses on the biotic environment, which is usually less predictable and thus can create high selective constraints that are likely to have had a strong impact on C. elegans evolution.
Abstract: Organisms evolve in response to their natural environment. Consideration of natural ecological parameters are thus of key importance for our understanding of an organism’s biology. Curiously, the natural ecology of the model species Caenorhabditis elegans has long been neglected, even though this nematode has become one of the most intensively studied models in biological research. This lack of interest changed ∼10 yr ago. Since then, an increasing number of studies have focused on the nematode’s natural ecology. Yet many unknowns still remain. Here, we provide an overview of the currently available information on the natural environment of C. elegans. We focus on the biotic environment, which is usually less predictable and thus can create high selective constraints that are likely to have had a strong impact on C. elegans evolution. This nematode is particularly abundant in microbe-rich environments, especially rotting plant matter such as decomposing fruits and stems. In this environment, it is part of a complex interaction network, which is particularly shaped by a species-rich microbial community. These microbes can be food, part of a beneficial gut microbiome, parasites and pathogens, and possibly competitors. C. elegans is additionally confronted with predators; it interacts with vector organisms that facilitate dispersal to new habitats, and also with competitors for similar food environments, including competitors from congeneric and also the same species. Full appreciation of this nematode’s biology warrants further exploration of its natural environment and subsequent integration of this information into the well-established laboratory-based research approaches.