Showing papers by "University of Duisburg-Essen published in 2020"
Donostia International Physics Center1, Rovira i Virgili University2, MacDiarmid Institute for Advanced Materials and Nanotechnology3, Victoria University of Wellington4, University of Cambridge5, University of California, Santa Barbara6, Queen's University Belfast7, Technical University of Denmark8, University of Victoria9, Chung-Ang University10, University of Jena11, Leibniz Institute of Photonic Technology12, Rutgers University13, University of Strathclyde14, University of Liverpool15, University of Iowa16, University of Minnesota17, Heidelberg University18, National Institute of Advanced Industrial Science and Technology19, Chalmers University of Technology20, Humboldt University of Berlin21, University of Michigan22, Jiangnan University23, Stanford University24, Xiamen University25, Ludwig Maximilian University of Munich26, Hokkaido University27, Seoul National University28, University of Illinois at Urbana–Champaign29, Kwansei Gakuin University30, University of Vigo31, Free University of Berlin32, Northwestern University33, University of Duisburg-Essen34, National Research Council35, Indian Institute of Science Education and Research, Thiruvananthapuram36, Duke University37, Northeastern University (China)38, Temple University39, Wuhan University40, Japan Advanced Institute of Science and Technology41, Jilin University42, Ikerbasque43
TL;DR: Prominent authors from all over the world joined efforts to summarize the current state-of-the-art in understanding and using SERS, as well as to propose what can be expected in the near future, in terms of research, applications, and technological development.
Abstract: The discovery of the enhancement of Raman scattering by molecules adsorbed on nanostructured metal surfaces is a landmark in the history of spectroscopic and analytical techniques. Significant experimental and theoretical effort has been directed toward understanding the surface-enhanced Raman scattering (SERS) effect and demonstrating its potential in various types of ultrasensitive sensing applications in a wide variety of fields. In the 45 years since its discovery, SERS has blossomed into a rich area of research and technology, but additional efforts are still needed before it can be routinely used analytically and in commercial products. In this Review, prominent authors from around the world joined together to summarize the state of the art in understanding and using SERS and to predict what can be expected in the near future in terms of research, applications, and technological development. This Review is dedicated to SERS pioneer and our coauthor, the late Prof. Richard Van Duyne, whom we lost during the preparation of this article.
1,768 citations
TL;DR: The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.
Abstract: Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1,2,3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10,11,12,13,14,15,16,17,18.
1,600 citations
TL;DR: The degree of lymphopenia and a proinflammatory cytokine storm is higher in severe COVID-19 patients than in mild cases, and is associated with the disease severity.
1,159 citations
TL;DR: VR seems to be a promising sphere as this study identifies 18 application domains, indicating a better reception of this technology in many disciplines, and several gaps point toward unexplored regions of VR design for education, which could motivate future work in the field.
Abstract: Researchers have explored the benefits and applications of virtual reality (VR) in different scenarios. VR possesses much potential and its application in education has seen much research interest lately. However, little systematic work currently exists on how researchers have applied immersive VR for higher education purposes that considers the usage of both high-end and budget head-mounted displays (HMDs). Hence, we propose using systematic mapping to identify design elements of existing research dedicated to the application of VR in higher education. The reviewed articles were acquired by extracting key information from documents indexed in four scientific digital libraries, which were filtered systematically using exclusion, inclusion, semi-automatic, and manual methods. Our review emphasizes three key points: the current domain structure in terms of the learning contents, the VR design elements, and the learning theories, as a foundation for successful VR-based learning. The mapping was conducted between application domains and learning contents and between design elements and learning contents. Our analysis has uncovered several gaps in the application of VR in the higher education sphere—for instance, learning theories were not often considered in VR application development to assist and guide toward learning outcomes. Furthermore, the evaluation of educational VR applications has primarily focused on usability of the VR apps instead of learning outcomes and immersive VR has mostly been a part of experimental and development work rather than being applied regularly in actual teaching. Nevertheless, VR seems to be a promising sphere as this study identifies 18 application domains, indicating a better reception of this technology in many disciplines. The identified gaps point toward unexplored regions of VR design for education, which could motivate future work in the field.
914 citations
University of Duisburg-Essen1, University of Düsseldorf2, Harvard University3, University of Warsaw4, St. Vincent's Institute of Medical Research5, University of Melbourne6, Johns Hopkins University7, Swiss Institute of Bioinformatics8, The Turing Institute9, Western General Hospital10, University of British Columbia11, BC Cancer Agency12, ETH Zurich13, Leiden University Medical Center14, Delft University of Technology15, Broad Institute16, Georgia State University17, Karlsruhe Institute of Technology18, Heidelberg Institute for Theoretical Studies19, Centrum Wiskunde & Informatica20, Utrecht University21, University of Amsterdam22, Imperial College London23, Radboud University Nijmegen24, University Medical Center Groningen25, Wageningen University and Research Centre26, University of Connecticut27, European Bioinformatics Institute28, University of Cambridge29, Wellcome Trust Sanger Institute30, Max Planck Society31, Saarland University32, Zuse Institute Berlin33, German Cancer Research Center34, Leiden University35, I.M. Sechenov First Moscow State Medical University36, Princeton University37, Memorial Sloan Kettering Cancer Center38
TL;DR: This compendium is for established researchers, newcomers, and students alike, highlighting interesting and rewarding problems for the coming years in single-cell data science.
Abstract: The recent boom in microfluidics and combinatorial indexing strategies, combined with low sequencing costs, has empowered single-cell sequencing technology. Thousands-or even millions-of cells analyzed in a single experiment amount to a data revolution in single-cell biology and pose unique data science problems. Here, we outline eleven challenges that will be central to bringing this emerging field of single-cell data science forward. For each challenge, we highlight motivating research questions, review prior work, and formulate open problems. This compendium is for established researchers, newcomers, and students alike, highlighting interesting and rewarding problems for the coming years.
677 citations
TL;DR: The characteristics and mechanism of liver injury caused by SARS‐ CoV, MERS‐CoV as well as SARS-CoV‐2 infection were summarized, which may provide help for further studies on the liver injury of COVID‐19.
Abstract: The severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2), the pathogen of 2019 novel coronavirus disease (COVID-19), has posed a serious threat to global public health. The WHO has declared the outbreak of SARS-CoV-2 infection an international public health emergency. Lung lesions have been considered as the major damage caused by SARS-CoV-2 infection. However, liver injury has also been reported to occur during the course of the disease in severe cases. Similarly, previous studies have shown that liver damage was common in the patients infected by the other two highly pathogenic coronavirus - severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV), and associated with the severity of diseases. In this review, the characteristics and mechanism of liver injury caused by SARS-CoV, MERS-CoV as well as SARS-CoV-2 infection were summarized, which may provide help for further studies on the liver injury of COVID-19.
668 citations
TL;DR: The degree of lymphopenia and a proinflammatory cytokine storm is higher in severe COVID-19 patients than in mild cases, and is associated with the disease severity.
Abstract: Background The dynamic changes of lymphocyte subsets and cytokines profiles of patients with novel coronavirus disease (COVID-19) and their correlation with the disease severity remain unclear. Method Peripheral blood samples were longitudinally collected from 40 confirmed COVID-19 patients and examined for lymphocyte subsets by flow cytometry and cytokine profiles by specific immunoassays. Findings Of the 40 COVID-19 patients enrolled, 13 severe cases showed significant and sustained decreases in lymphocyte counts but increases in neutrophil counts than 27 mild cases. Further analysis demonstrated significant decreases in the counts of T cells, especially CD8 + T cells, as well as increases in IL-6, IL-10, IL-2 and IFN-γ levels in the peripheral blood in the severe cases compared to those in the mild cases. T cell counts and cytokine levels in severe COVID-19 patients who survived the disease gradually recovered at later time points to levels that were comparable to those of the mild cases. Moreover, the neutrophil-to-CD8+ T cell ratio (N8R) were identified as the most powerful prognostic factor affecting the prognosis for severe COVID-19. Conclusion The degree of lymphopenia and a proinflammatory cytokine storm is higher in severe COVID-19 patients than in mild cases, and is associated with the disease severity. N8R may serve as a useful prognostic factor for early identification of severe COVID-19 cases.
575 citations
Eötvös Loránd University1, Yale University2, University of Cape Town3, Flinders University4, University of Calgary5, University of Queensland6, Nottingham Trent University7, Macedonian Academy of Sciences and Arts8, University of Lausanne9, University of Duisburg-Essen10, Auckland University of Technology11, University of Cambridge12, Sapienza University of Rome13, Lithuanian University of Health Sciences14, University of Porto15, University of Ulm16, Stellenbosch University17, University of Zurich18, University of Chieti-Pescara19, Catholic University of Korea20, University of Lübeck21, University of Valencia22, Tehran University of Medical Sciences23, Bellvitge University Hospital24, Tel Aviv University25, Hertfordshire Partnership University NHS Foundation Trust26
TL;DR: Although for the vast majority ICT use is adaptive and should not be pathologized, a subgroup of vulnerable individuals are at risk of developing problematic usage patterns and the present consensus guidance discusses these risks and makes some practical recommendations that may help diminish them.
501 citations
TL;DR: A brief introduction to the pathology and pathogenesis of SARS‐CoV and MERS‐ coV is provided and extrapolate this knowledge to the newly identified 2019‐nCoV.
Abstract: First reported from Wuhan, The People's Republic of China, on 31 December 2019, the ongoing outbreak of a novel coronavirus (2019-nCoV) causes great global concerns. Based on the advice of the International Health Regulations Emergency Committee and the fact that to date 24 other countries also reported cases, the WHO Director-General declared that the outbreak of 2019-nCoV constitutes a Public Health Emergency of International Concern on 30 January 2020. Together with the other two highly pathogenic coronaviruses, the severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), 2019-nCov and other yet to be identified coronaviruses pose a global threat to public health. In this mini-review, we provide a brief introduction to the pathology and pathogenesis of SARS-CoV and MERS-CoV and extrapolate this knowledge to the newly identified 2019-nCoV.
463 citations
TL;DR: The pathophysiology of myocardial ischaemia–reperfusion injury is revisits, including the role of autophagy and forms of cell death such as necrosis, apoptosis, necroptosis and pyroptosis, and the latest developments in cardioprotective interventions and the signalling pathways involved are discussed.
Abstract: Despite the increasing use and success of interventional coronary reperfusion strategies, morbidity and mortality from acute myocardial infarction are still substantial. Myocardial infarct size is a major determinant of prognosis in these patients. Therefore, cardioprotective strategies aim to reduce infarct size. However, a perplexing gap exists between the many preclinical studies reporting infarct size reduction with mechanical and pharmacological interventions and the poor translation into better clinical outcomes in patients. This Review revisits the pathophysiology of myocardial ischaemia-reperfusion injury, including the role of autophagy and forms of cell death such as necrosis, apoptosis, necroptosis and pyroptosis. Other cellular compartments in addition to cardiomyocytes are addressed, notably the coronary microcirculation. Preclinical and clinical research developments in mechanical and pharmacological approaches to induce cardioprotection, and their signal transduction pathways, are discussed. Additive cardioprotective interventions are advocated. For clinical translation into treatments for patients with acute myocardial infarction, who typically are of advanced age, have comorbidities and are receiving several medications, not only infarct size reduction but also attenuation of coronary microvascular obstruction, as well as longer-term targets including infarct repair and reverse remodelling, must be considered to improve patient outcomes. Future clinical trials must focus on patients who really need adjunct cardioprotection, that is, those with severe haemodynamic alterations.
447 citations
TL;DR: Assessment of initial data on the mental health burden of the German public during the COVID-19 pandemic found the provision of appropriate psychological interventions for those in need and the Provision of transparency and comprehensible information are crucial during the current pandemic.
Abstract: Background Since the first cases of the novel coronavirus disease SARS-CoV-2 were reported in December 2019 in China, the virus has spread in most countries. The aim of the present study was to assess initial data on the mental health burden of the German public during the COVID-19 pandemic. Methods A cross-sectional study was conducted in Germany and collected complete datasets from 15 704 German residents aged 18 years and over. Besides demographics, generalized anxiety (GAD-7), depression (PHQ-2) and psychological distress (DT) were assessed. Furthermore, COVID-19-related fear, trust in governmental actions to face COVID-19 and the subjective level of information regarding COVID-19 were covered. Results Significantly increased symptoms were highly prevalent in all dimensions: generalized anxiety (44.9%), depression (14.3%), psychological distress (65.2%) and COVID-19-related fear (59%). Females and younger people reported higher mental burden. Trust in governmental actions to face COVID-19 and the subjective level of information regarding COVID-19 are negatively associated with mental health burden. However, the subjective level of information regarding COVID-19 is positively associated with increased COVID-19-related fear. Conclusions The provision of appropriate psychological interventions for those in need and the provision of transparency and comprehensible information are crucial during the current pandemic.
TL;DR: It is demonstrated that early antigen-specific and qualitative features of SARS-CoV-2-specific antibodies, point to differences in disease trajectory, highlighting the potential importance of functional antigen- specific humoral immunity to guide patient care and vaccine development.
Umeå University1, American Museum of Natural History2, Martin Luther University of Halle-Wittenberg3, Helmholtz Centre for Environmental Research - UFZ4, Free University of Berlin5, University of Helsinki6, University of Toulouse7, Rothamsted Research8, University of Hasselt9, Academy of Sciences of the Czech Republic10, Sewanee: The University of the South11, Centre national de la recherche scientifique12, National Research Council13, University of Camerino14, University of Porto15, Flanders Marine Institute16, Bulgarian Academy of Sciences17, Lancaster University18, Spanish National Research Council19, Swedish University of Agricultural Sciences20, Forest Research Institute21, Utrecht University22, University of Oulu23, University of Warsaw24, University of Copenhagen25, University of Coimbra26, University of Latvia27, University of Sassari28, University of Nova Gorica29, Finnish Environment Institute30, Swiss Federal Institute for Forest, Snow and Landscape Research31, Norwegian Institute for Water Research32, James Hutton Institute33, University of Duisburg-Essen34, Trier University of Applied Sciences35, Swedish Meteorological and Hydrological Institute36, Research Institute for Nature and Forest37
TL;DR: A quantitative synthesis of longterm biodiversity trends across Europe is reported, showing how, despite overall increase in biodiversity metric and stability in abundance, trends differ between regions, ecosystem types, and taxa.
Abstract: Local biodiversity trends over time are likely to be decoupled from global trends, as local processes may compensate or counteract global change. We analyze 161 long-term biological time series (15–91 years) collected across Europe, using a comprehensive dataset comprising ~6,200 marine, freshwater and terrestrial taxa. We test whether (i) local long-term biodiversity trends are consistent among biogeoregions, realms and taxonomic groups, and (ii) changes in biodiversity correlate with regional climate and local conditions. Our results reveal that local trends of abundance, richness and diversity differ among biogeoregions, realms and taxonomic groups, demonstrating that biodiversity changes at local scale are often complex and cannot be easily generalized. However, we find increases in richness and abundance with increasing temperature and naturalness as well as a clear spatial pattern in changes in community composition (i.e. temporal taxonomic turnover) in most biogeoregions of Northern and Eastern Europe.
TL;DR: A gene expression signature associated with CD4+ T follicular helper cells that is associated with longer progression-free survival in HNSCC patients is defined and provided a resource for the further study of the impact of immune cells on viral- and carcinogen-induced cancers.
TL;DR: Among patients with active thyroid eye disease, teprotumumab resulted in better outcomes with respect to proptosis, Clinical Activity Score, diplopia, and quality of life than placebo; serious adverse events were uncommon.
Abstract: Background Thyroid eye disease is a debilitating, disfiguring, and potentially blinding periocular condition for which no Food and Drug Administration–approved medical therapy is available...
TL;DR: The overall seroprevalence of SARS-CoV-2 in healthcare workers of a tertiary hospital in Germany is low and the data indicate that the local hygiene standard might be effective.
TL;DR: Overall, it is foreseen that the scope of future membrane applications will become much wider, based on improved existing membrane materials and manufacturing processes, as the combination of novel, tailor-made “building blocks” and “tools” for the fabrication of next-generation membranes tuned to specific applications.
TL;DR: Inactivation of Sars-CoV-2 by UVC irradiation constitutes a reliable method for disinfection purposes in health care facilities and for preparing SARS-Cov-2 material for research purpose.
University of Duisburg-Essen1, University of Stirling2, Aarhus University3, Middle East Technical University4, University of Lisbon5, Norwegian Institute for Water Research6, Laval University7, Estonian University of Life Sciences8, Lancaster University9, Leibniz Association10, Technical University of Berlin11, University of Ljubljana12, Helmholtz Centre for Environmental Research - UFZ13, University of Natural Resources and Life Sciences, Vienna14, Cardiff University15, University of Barcelona16, Finnish Environment Institute17, DHI Water & Environment18, National Technical University of Athens19, Radboud University Nijmegen20, Free University of Berlin21, University of Koblenz and Landau22
TL;DR: A cross-scale analysis of paired-stressor effects on biological variables of European freshwater ecosystems shows that in 39% of cases, significant effects were limited to single stressors, with nutrient enrichment being the most important of these in lakes.
Abstract: Climate and land-use change drive a suite of stressors that shape ecosystems and interact to yield complex ecological responses (that is, additive, antagonistic and synergistic effects). We know little about the spatial scales relevant for the outcomes of such interactions and little about effect sizes. These knowledge gaps need to be filled to underpin future land management decisions or climate mitigation interventions for protecting and restoring freshwater ecosystems. This study combines data across scales from 33 mesocosm experiments with those from 14 river basins and 22 cross-basin studies in Europe, producing 174 combinations of paired-stressor effects on a biological response variable. Generalized linear models showed that only one of the two stressors had a significant effect in 39% of the analysed cases, 28% of the paired-stressor combinations resulted in additive effects and 33% resulted in interactive (antagonistic, synergistic, opposing or reversal) effects. For lakes, the frequencies of additive and interactive effects were similar for all spatial scales addressed, while for rivers these frequencies increased with scale. Nutrient enrichment was the overriding stressor for lakes, with effects generally exceeding those of secondary stressors. For rivers, the effects of nutrient enrichment were dependent on the specific stressor combination and biological response variable. These results vindicate the traditional focus of lake restoration and management on nutrient stress, while highlighting that river management requires more bespoke management solutions.
TL;DR: An international team of scientists with long‐standing expertise in SERS is presented by presenting considerations on reliable and quantitative SERS to increase the inter‐laboratory comparability of experimental SERS results and further establish SERS as an analytical tool.
Abstract: Experimental results obtained in different laboratories world-wide by researchers using surface-enhanced Raman scattering (SERS) can differ significantly. We, an international team of scientists with long-standing expertise in SERS, address this issue from our perspective by presenting considerations on reliable and quantitative SERS. The central idea of this joint effort is to highlight key parameters and pitfalls that are often encountered in the literature. To that end, we provide here a series of recommendations on: a) the characterization of solid and colloidal SERS substrates by correlative electron and optical microscopy and spectroscopy, b) on the determination of the SERS enhancement factor (EF), including suitable Raman reporter/probe molecules, and finally on c) good analytical practice. We hope that both newcomers and specialists will benefit from these recommendations to increase the inter-laboratory comparability of experimental SERS results and further establish SERS as an analytical tool.
TL;DR: In this paper, the authors systematically map research from 243 studies published between 2007 and 2016, with only limited research undertaken in the Global South, and largely focused on the fields of Arts & Humanities, Education, and Natural Sciences, Mathematics & Statistics.
Abstract: Digital technology has become a central aspect of higher education, inherently affecting all aspects of the student experience. It has also been linked to an increase in behavioural, affective and cognitive student engagement, the facilitation of which is a central concern of educators. In order to delineate the complex nexus of technology and student engagement, this article systematically maps research from 243 studies published between 2007 and 2016. Research within the corpus was predominantly undertaken within the United States and the United Kingdom, with only limited research undertaken in the Global South, and largely focused on the fields of Arts & Humanities, Education, and Natural Sciences, Mathematics & Statistics. Studies most often used quantitative methods, followed by mixed methods, with little qualitative research methods employed. Few studies provided a definition of student engagement, and less than half were guided by a theoretical framework. The courses investigated used blended learning and text-based tools (e.g. discussion forums) most often, with undergraduate students as the primary target group. Stemming from the use of educational technology, behavioural engagement was by far the most often identified dimension, followed by affective and cognitive engagement. This mapping article provides the grounds for further exploration into discipline-specific use of technology to foster student engagement.
TL;DR: It is shown that metabolic differences among melanoma cells confer differences in metastatic potential as a result of differences in the function of the MCT1 transporter, as metastasizing cells depend on M CT1 to manage oxidative stress.
Abstract: Metastasis requires cancer cells to undergo metabolic changes that are poorly understood1–3. Here we show that metabolic differences among melanoma cells confer differences in metastatic potential as a result of differences in the function of the MCT1 transporter. In vivo isotope tracing analysis in patient-derived xenografts revealed differences in nutrient handling between efficiently and inefficiently metastasizing melanomas, with circulating lactate being a more prominent source of tumour lactate in efficient metastasizers. Efficient metastasizers had higher levels of MCT1, and inhibition of MCT1 reduced lactate uptake. MCT1 inhibition had little effect on the growth of primary subcutaneous tumours, but resulted in depletion of circulating melanoma cells and reduced the metastatic disease burden in patient-derived xenografts and in mouse melanomas. In addition, inhibition of MCT1 suppressed the oxidative pentose phosphate pathway and increased levels of reactive oxygen species. Antioxidants blocked the effects of MCT1 inhibition on metastasis. MCT1high and MCT1−/low cells from the same melanomas had similar capacities to form subcutaneous tumours, but MCT1high cells formed more metastases after intravenous injection. Metabolic differences among cancer cells thus confer differences in metastatic potential as metastasizing cells depend on MCT1 to manage oxidative stress. Differences in MCT1 function among melanoma cells confer differences in oxidative stress resistance and metastatic potential.
TL;DR: The First International Consensus Group recommended that Corticosteroids remain first-line therapy for warm-AIHA, while the addition of rituximab should be considered early in severe cases and if no prompt response to steroids is achieved.
National Institutes of Health1, University of Amsterdam2, Utrecht University3, University of Duisburg-Essen4, University of Bordeaux5, Aix-Marseille University6, Beth Israel Deaconess Medical Center7, Ghent University Hospital8, University of Virginia9, University of Cambridge10, Xiamen University11
TL;DR: It is expected that adoption of MIFlowCyt-EV as a standard for reporting EV- FC studies will improve the ability to quantitatively compare results from different laboratories and to support the development of new instruments and assays for improved measurement of EVs.
Abstract: Extracellular vesicles (EVs) are small, heterogeneous and difficult to measure. Flow cytometry (FC) is a key technology for the measurement of individual particles, but its application to the analysis of EVs and other submicron particles has presented many challenges and has produced a number of controversial results, in part due to limitations of instrument detection, lack of robust methods and ambiguities in how data should be interpreted. These complications are exacerbated by the field's lack of a robust reporting framework, and many EV-FC manuscripts include incomplete descriptions of methods and results, contain artefacts stemming from an insufficient instrument sensitivity and inappropriate experimental design and lack appropriate calibration and standardization. To address these issues, a working group (WG) of EV-FC researchers from ISEV, ISAC and ISTH, worked together as an EV-FC WG and developed a consensus framework for the minimum information that should be provided regarding EV-FC. This framework incorporates the existing Minimum Information for Studies of EVs (MISEV) guidelines and Minimum Information about a FC experiment (MIFlowCyt) standard in an EV-FC-specific reporting framework (MIFlowCyt-EV) that supports reporting of critical information related to sample staining, EV detection and measurement and experimental design in manuscripts that report EV-FC data. MIFlowCyt-EV provides a structure for sharing EV-FC results, but it does not prescribe specific protocols, as there will continue to be rapid evolution of instruments and methods for the foreseeable future. MIFlowCyt-EV accommodates this evolution, while providing information needed to evaluate and compare different approaches. Because MIFlowCyt-EV will ensure consistency in the manner of reporting of EV-FC studies, over time we expect that adoption of MIFlowCyt-EV as a standard for reporting EV- FC studies will improve the ability to quantitatively compare results from different laboratories and to support the development of new instruments and assays for improved measurement of EVs.
Oregon Health & Science University1, Monash University2, University of Duisburg-Essen3, Leiden University Medical Center4, Katholieke Universiteit Leuven5, Institute of Cancer Research6, The Royal Marsden NHS Foundation Trust7, Mayo Clinic8, University of Miami9, Cornell University10, Memorial Sloan Kettering Cancer Center11, Harvard University12, Fox Chase Cancer Center13
TL;DR: This double-blind, randomised, placebo-controlled, phase 3 study compared the efficacy and safety of ripretinib, a switch-control tyrosine kinase inhibitor active against a broad spectrum of KIT and PDGFRA mutations, with placebo in patients with previously treated, advanced gastrointestinal stromal tumours.
Abstract: Summary Background Resistance to approved inhibitors of KIT proto-oncogene, receptor tyrosine kinase (KIT), and platelet-derived growth factor receptor α (PDGFRA) is a clinical challenge for patients with advanced gastrointestinal stromal tumours. We compared the efficacy and safety of ripretinib, a switch-control tyrosine kinase inhibitor active against a broad spectrum of KIT and PDGFRA mutations, with placebo in patients with previously treated, advanced gastrointestinal stromal tumours. Methods In this double-blind, randomised, placebo-controlled, phase 3 study, we enrolled adult patients in 29 specialised hospitals in 12 countries. We included patients aged 18 years or older who had advanced gastrointestinal stromal tumours with progression on at least imatinib, sunitinib, and regorafenib or documented intolerance to any of these treatments despite dose modifications, and who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2. Eligible patients were randomly assigned (2:1) to receive either oral ripretinib 150 mg once daily (ripretenib group) or placebo once daily (placebo group). Randomisation was done via an interactive response system using randomly permuted block sizes of six and stratified according to number of previous therapies and ECOG performance status. Patients, investigators, research staff, and the sponsor study team were masked to a patient's treatment allocation until the blinded independent central review (BICR) showed progressive disease for the patient. The primary endpoint was progression-free survival, assessed by BICR. The primary analysis was done in the intention-to-treat population and safety was assessed in patients who received at least one dose of study drug. Patients randomly assigned to placebo were permitted to cross over to ripretinib 150 mg at the time of disease progression. The INVICTUS study is registered with ClinicalTrials.gov , number NCT03353753 , and with WHO International Clinical Trials Registry Platform, number EUCTR2017-002446-76-ES; follow-up is ongoing. Findings Between Feb 27, 2018, and Nov 16, 2018, 129 of 154 assessed patients were randomly assigned to receive either ripretinib (n=85) or placebo (n=44). At data cutoff (May 31, 2019), at a median follow-up of 6·3 months (IQR 3·2–8·2) in the ripretinib group and 1·6 months (1·1–2·7) in the placebo group, 51 patients in the ripretinib group and 37 in the placebo group had had progression-free survival events. In the double-blind period, median progression-free survival was 6·3 months (95% CI 4·6–6·9) with ripretinib compared with 1·0 months (0·9–1·7) with placebo (hazard ratio 0·15, 95% CI 0·09–0·25; p 2%) grade 3 or 4 treatment-related treatment-emergent adverse events in the ripretinib group (n=85) included lipase increase (four [5%]), hypertension (three [4%]), fatigue (two [2%]), and hypophosphataemia (two (2%]); in the placebo group (n=43), the most common (>2%) grade 3 or 4 treatment-related treatment-emergent adverse events were anaemia (three [7%]), fatigue (one [2%]), diarrhoea (one [2%]), decreased appetite (one [2%]), dehydration (one [2%]), hyperkalaemia (one [2%]), acute kidney injury (one [2%]), and pulmonary oedema (one [2%]). Treatment-related serious adverse events were reported in eight (9%) of 85 patients who received ripretinib and three (7%) of 43 patients who received placebo. Treatment-related deaths occurred in one patient in the placebo group (septic shock and pulmonary oedema) and one patient in the ripretinib group (cause of death unknown; the patient died during sleep). Interpretation Ripretinib significantly improved median progression-free survival compared with placebo and had an acceptable safety profile in patients with advanced gastrointestinal stromal tumours who were resistant to approved treatments. Funding Deciphera Pharmaceuticals.
TL;DR: To ensure the reliability and safety of high-speed trains, detection and diagnosis of faults (FDD) in traction systems have become an active issue in the transportation area over the past two decades and most of the mainstream methods are reviewed.
Abstract: Recently, to ensure the reliability and safety of high-speed trains, detection and diagnosis of faults (FDD) in traction systems have become an active issue in the transportation area over the past two decades. Among these FDD methods, data-driven designs, that can be directly implemented without a logical or mathematical description of traction systems, have received special attention because of their overwhelming advantages. Based on the existing data-driven FDD methods for traction systems in high-speed trains, the first objective of this paper is to systematically review and categorize most of the mainstream methods. By analyzing the characteristic of observations from sensors equipped in traction systems, great challenges which may prevent successful FDD implementations on practical high-speed trains are then summarized in detail. Benefiting from theoretical developments of data-driven FDD strategies, instructive perspectives on this topic are further elaborately conceived by the integration of model-based FDD issues, system identification techniques, and new machine learning tools, which provide several promising solutions to FDD strategies for traction systems in high-speed trains.
Centro Nacional de Investigaciones Cardiovasculares1, Vita-Salute San Raffaele University2, Agency for Science, Technology and Research3, University of Castilla–La Mancha4, University of Oxford5, University of Mainz6, Ludwig Maximilian University of Munich7, University of Duisburg-Essen8, CEU San Pablo University9
TL;DR: This work uses a new model to track neutrophil fates and reveals that tissues co-opt neutrophils en route for elimination to induce programs that support their physiological demands, including vascular repair and hematoietic homeostasis.
TL;DR: Recent advances in understanding the molecular basis for atrial fibrillation are reviewed, with a particular emphasis on relating these new insights to opportunities for clinical translation.
Abstract: Atrial fibrillation (AF) is a highly prevalent arrhythmia, with substantial associated morbidity and mortality There have been significant management advances over the past 2 decades, but the burden of the disease continues to increase and there is certainly plenty of room for improvement in treatment options A potential key to therapeutic innovation is a better understanding of underlying fundamental mechanisms This article reviews recent advances in understanding the molecular basis for AF, with a particular emphasis on relating these new insights to opportunities for clinical translation We first review the evidence relating basic electrophysiological mechanisms to the characteristics of clinical AF We then discuss the molecular control of factors leading to some of the principal determinants, including abnormalities in impulse conduction (such as tissue fibrosis and other extra-cardiomyocyte alterations, connexin dysregulation and Na+-channel dysfunction), electrical refractoriness, and impulse generation We then consider the molecular drivers of AF progression, including a range of Ca2+-dependent intracellular processes, microRNA changes, and inflammatory signaling The concept of key interactome-related nodal points is then evaluated, dealing with systems like those associated with CaMKII (Ca2+/calmodulin-dependent protein kinase-II), NLRP3 (NACHT, LRR, and PYD domains-containing protein-3), and transcription-factors like TBX5 and PitX2c We conclude with a critical discussion of therapeutic implications, knowledge gaps and future directions, dealing with such aspects as drug repurposing, biologicals, multispecific drugs, the targeting of cardiomyocyte inflammatory signaling and potential considerations in intervening at the level of interactomes and gene-regulation The area of molecular intervention for AF management presents exciting new opportunities, along with substantial challenges