Showing papers by "University of Cologne published in 2018"
Clotilde Théry1, Kenneth W. Witwer2, Elena Aikawa3, María José Alcaraz4 +414 more•Institutions (209)
TL;DR: The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities, and a checklist is provided with summaries of key points.
Abstract: The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.
5,988 citations
Mayo Clinic1, Rush University2, University of Gothenburg3, Alzheimer's Association4, Silver Spring Networks5, Biogen Idec6, Washington University in St. Louis7, University of California, Berkeley8, University of Cologne9, University of Pennsylvania10, Stanford University11, National Institutes of Health12, University of California, San Francisco13, University of Melbourne14, VU University Medical Center15, Eli Lilly and Company16, Brigham and Women's Hospital17
TL;DR: This research framework seeks to create a common language with which investigators can generate and test hypotheses about the interactions among different pathologic processes (denoted by biomarkers) and cognitive symptoms and envision that defining AD as a biological construct will enable a more accurate characterization and understanding of the sequence of events that lead to cognitive impairment that is associated with AD.
Abstract: In 2011, the National Institute on Aging and Alzheimer's Association created separate diagnostic recommendations for the preclinical, mild cognitive impairment, and dementia stages of Alzheimer's disease. Scientific progress in the interim led to an initiative by the National Institute on Aging and Alzheimer's Association to update and unify the 2011 guidelines. This unifying update is labeled a "research framework" because its intended use is for observational and interventional research, not routine clinical care. In the National Institute on Aging and Alzheimer's Association Research Framework, Alzheimer's disease (AD) is defined by its underlying pathologic processes that can be documented by postmortem examination or in vivo by biomarkers. The diagnosis is not based on the clinical consequences of the disease (i.e., symptoms/signs) in this research framework, which shifts the definition of AD in living people from a syndromal to a biological construct. The research framework focuses on the diagnosis of AD with biomarkers in living persons. Biomarkers are grouped into those of β amyloid deposition, pathologic tau, and neurodegeneration [AT(N)]. This ATN classification system groups different biomarkers (imaging and biofluids) by the pathologic process each measures. The AT(N) system is flexible in that new biomarkers can be added to the three existing AT(N) groups, and new biomarker groups beyond AT(N) can be added when they become available. We focus on AD as a continuum, and cognitive staging may be accomplished using continuous measures. However, we also outline two different categorical cognitive schemes for staging the severity of cognitive impairment: a scheme using three traditional syndromal categories and a six-stage numeric scheme. It is important to stress that this framework seeks to create a common language with which investigators can generate and test hypotheses about the interactions among different pathologic processes (denoted by biomarkers) and cognitive symptoms. We appreciate the concern that this biomarker-based research framework has the potential to be misused. Therefore, we emphasize, first, it is premature and inappropriate to use this research framework in general medical practice. Second, this research framework should not be used to restrict alternative approaches to hypothesis testing that do not use biomarkers. There will be situations where biomarkers are not available or requiring them would be counterproductive to the specific research goals (discussed in more detail later in the document). Thus, biomarker-based research should not be considered a template for all research into age-related cognitive impairment and dementia; rather, it should be applied when it is fit for the purpose of the specific research goals of a study. Importantly, this framework should be examined in diverse populations. Although it is possible that β-amyloid plaques and neurofibrillary tau deposits are not causal in AD pathogenesis, it is these abnormal protein deposits that define AD as a unique neurodegenerative disease among different disorders that can lead to dementia. We envision that defining AD as a biological construct will enable a more accurate characterization and understanding of the sequence of events that lead to cognitive impairment that is associated with AD, as well as the multifactorial etiology of dementia. This approach also will enable a more precise approach to interventional trials where specific pathways can be targeted in the disease process and in the appropriate people.
5,126 citations
Lorenzo Galluzzi1, Lorenzo Galluzzi2, Ilio Vitale3, Stuart A. Aaronson4 +183 more•Institutions (111)
TL;DR: The Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives.
Abstract: Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.
3,301 citations
Verneri Anttila1, Verneri Anttila2, Brendan Bulik-Sullivan2, Brendan Bulik-Sullivan1 +717 more•Institutions (270)
TL;DR: It is demonstrated that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine, and it is shown that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures.
Abstract: Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.
1,357 citations
TL;DR: This review provides a comprehensive overview of the mechanisms underlying CRS pathophysiology, risk factors, clinical presentation, differential diagnoses, and prognostic factors and gives practical guidance to the management of the cytokine release syndrome.
Abstract: During the last decade the field of cancer immunotherapy has witnessed impressive progress. Highly effective immunotherapies such as immune checkpoint inhibition, and T-cell engaging therapies like bispecific T-cell engaging (BiTE) single-chain antibody constructs and chimeric antigen receptor (CAR) T cells have shown remarkable efficacy in clinical trials and some of these agents have already received regulatory approval. However, along with growing experience in the clinical application of these potent immunotherapeutic agents comes the increasing awareness of their inherent and potentially fatal adverse effects, most notably the cytokine release syndrome (CRS). This review provides a comprehensive overview of the mechanisms underlying CRS pathophysiology, risk factors, clinical presentation, differential diagnoses, and prognostic factors. In addition, based on the current evidence we give practical guidance to the management of the cytokine release syndrome.
1,056 citations
University of Cologne1, Georgetown University2, Institute of Cancer Research3, Vita-Salute San Raffaele University4, Pasteur Institute5, University of Ulm6, University of Texas MD Anderson Cancer Center7, University of Barcelona8, The Feinstein Institute for Medical Research9, Ohio State University10, University of California, Irvine11, Medical University of Łódź12, Peter MacCallum Cancer Centre13, University of California, San Diego14
TL;DR: Recommendations include a revised version of the iwCLL response criteria, an update on the use of MRD status for clinical evaluation, and recommendations regarding the assessment and prophylaxis of viral diseases during management of CLL.
940 citations
European Southern Observatory1, University of Lisbon2, University of Porto3, Max Planck Society4, University of Grenoble5, University of Geneva6, Paris Diderot University7, Leiden University8, University of Cologne9, Dublin Institute for Advanced Studies10, University of California, Berkeley11, Space Telescope Science Institute12
TL;DR: Eisenhauer et al. as mentioned in this paper detect the combined gravitational redshift and relativistic transverse Doppler effect for S2 of z = Δλ / λ ≈ 200 km s−1/c with different statistical analysis methods.
Abstract: The highly elliptical, 16-year-period orbit of the star S2 around the massive black hole candidate Sgr A✻ is a sensitive probe of the gravitational field in the Galactic centre. Near pericentre at 120 AU ≈ 1400 Schwarzschild radii, the star has an orbital speed of ≈7650 km s−1, such that the first-order effects of Special and General Relativity have now become detectable with current capabilities. Over the past 26 years, we have monitored the radial velocity and motion on the sky of S2, mainly with the SINFONI and NACO adaptive optics instruments on the ESO Very Large Telescope, and since 2016 and leading up to the pericentre approach in May 2018, with the four-telescope interferometric beam-combiner instrument GRAVITY. From data up to and including pericentre, we robustly detect the combined gravitational redshift and relativistic transverse Doppler effect for S2 of z = Δλ / λ ≈ 200 km s−1/c with different statistical analysis methods. When parameterising the post-Newtonian contribution from these effects by a factor f , with f = 0 and f = 1 corresponding to the Newtonian and general relativistic limits, respectively, we find from posterior fitting with different weighting schemes f = 0.90 ± 0.09|stat ± 0.15|sys. The S2 data are inconsistent with pure Newtonian dynamics.Key words: Galaxy: center / gravitation / black hole physics⋆ This paper is dedicated to Tal Alexander, who passed away about a week before the pericentre approach of S2.⋆⋆ GRAVITY is developed in a collaboration by the Max Planck Institute for extraterrestrial Physics, LESIA of Paris Observatory/CNRS/Sorbonne Universite/Univ. Paris Diderot and IPAG of Universite Grenoble Alpes/CNRS, the Max Planck Institute for Astronomy, the University of Cologne, the CENTRA – Centro de Astrofisica e Gravitacao, and the European Southern Observatory.⋆⋆⋆ Corresponding author: F. Eisenhauer e-mail: eisenhau@mpe.mpg.de
693 citations
TL;DR: Among patients with relapsed or refractory chronic lymphocytic leukemia, venetoclax plus rituximab resulted in significantly higher rates of progression‐free survival than bendamustine plus r ituximac, and the benefit was maintained across all clinical and biologic subgroups.
Abstract: Background Venetoclax inhibits BCL2, an antiapoptotic protein that is pathologically overexpressed and that is central to the survival of chronic lymphocytic leukemia cells. We evaluated the efficacy of venetoclax in combination with rituximab in patients with relapsed or refractory chronic lymphocytic leukemia. Methods In this randomized, open-label, phase 3 trial, we randomly assigned 389 patients to receive venetoclax for up to 2 years (from day 1 of cycle 1) plus rituximab for the first 6 months (venetoclax–rituximab group) or bendamustine plus rituximab for 6 months (bendamustine–rituximab group). The trial design did not include crossover to venetoclax plus rituximab for patients in the bendamustine–rituximab group in whom progression occurred. The primary end point was investigator-assessed progression-free survival. Results After a median follow-up period of 23.8 months, the rate of investigator-assessed progression-free survival was significantly higher in the venetoclax–rituximab group ...
615 citations
TL;DR: For the first time, specific loci that distinguish between BD and SCZ are discovered and polygenic components underlying multiple symptom dimensions are identified that point to the utility of genetics to inform symptomology and potential treatment.
569 citations
University of Alabama at Birmingham1, University of California, San Diego2, Harvard University3, Monash University4, University of California, Los Angeles5, Brigham and Women's Hospital6, University of California, San Francisco7, Emory University8, University of North Carolina at Chapel Hill9, University of Cologne10, University of Zurich11, University of Paris12
TL;DR: Advances in HIV prevention and treatment with antiretroviral drugs continue to improve clinical management and outcomes for individuals at risk for and living with HIV.
Abstract: Importance Antiretroviral therapy (ART) is the cornerstone of prevention and management of HIV infection. Objective To evaluate new data and treatments and incorporate this information into updated recommendations for initiating therapy, monitoring individuals starting therapy, changing regimens, and preventing HIV infection for individuals at risk. Evidence Review New evidence collected since the International Antiviral Society–USA 2016 recommendations via monthly PubMed and EMBASE literature searches up to April 2018; data presented at peer-reviewed scientific conferences. A volunteer panel of experts in HIV research and patient care considered these data and updated previous recommendations. Findings ART is recommended for virtually all HIV-infected individuals, as soon as possible after HIV diagnosis. Immediate initiation (eg, rapid start), if clinically appropriate, requires adequate staffing, specialized services, and careful selection of medical therapy. An integrase strand transfer inhibitor (InSTI) plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) is generally recommended for initial therapy, with unique patient circumstances (eg, concomitant diseases and conditions, potential for pregnancy, cost) guiding the treatment choice. CD4 cell count, HIV RNA level, genotype, and other laboratory tests for general health and co-infections are recommended at specified points before and during ART. If a regimen switch is indicated, treatment history, tolerability, adherence, and drug resistance history should first be assessed; 2 or 3 active drugs are recommended for a new regimen. HIV testing is recommended at least once for anyone who has ever been sexually active and more often for individuals at ongoing risk for infection. Preexposure prophylaxis with tenofovir disoproxil fumarate/emtricitabine and appropriate monitoring is recommended for individuals at risk for HIV. Conclusions and Relevance Advances in HIV prevention and treatment with antiretroviral drugs continue to improve clinical management and outcomes for individuals at risk for and living with HIV.
543 citations
University of Bern1, Institute of Cancer Research2, Oregon Health & Science University3, Cornell University4, Princess Margaret Cancer Centre5, Yonsei University6, University of Salford7, University of Copenhagen8, Monash University9, University of São Paulo10, Columbia University11, The Royal Marsden NHS Foundation Trust12, University of Texas MD Anderson Cancer Center13, University of California, Davis14, University of Bologna15, University of California, San Francisco16, University of Paris-Sud17, University of British Columbia18, Duke University19, University of Cologne20, Fred Hutchinson Cancer Research Center21, University of Birmingham22, Memorial Sloan Kettering Cancer Center23, University of Tampere24, American University of Beirut25, Medical University of Vienna26, Vanderbilt University27, Tata Memorial Hospital28, Icahn School of Medicine at Mount Sinai29, Ghent University30, University of Washington31, Université de Montréal32, Tulane University33, Tel Aviv University34, Harvard University35, Prostate Cancer Foundation36, Toho University37, University College London38, University of Toronto39, Université catholique de Louvain40, University of Milan41, University of Ulm42
TL;DR: The presented expert voting results can be used for support in areas of management of men with APC where there is no high-level evidence, but individualised treatment decisions should as always be based on all of the data available.
Harvard University1, University of Cologne2, Memorial Sloan Kettering Cancer Center3, University of Texas MD Anderson Cancer Center4, University of Bologna5, University of California, Los Angeles6, University of Oxford7, Wayne State University8, Emory University9, University of Toronto10, University of British Columbia11, Charles University in Prague12, Bristol-Myers Squibb13
TL;DR: With extended follow-up, responses to nivolumab were frequent and durable and seems to be associated with a favorable safety profile and long-term benefits across a broad spectrum of patients with relapsed/refractory cHL.
Abstract: PurposeGenetic alterations causing overexpression of programmed death-1 ligands are near universal in classic Hodgkin lymphoma (cHL). Nivolumab, a programmed death-1 checkpoint inhibitor, demonstrated efficacy in relapsed/refractory cHL after autologous hematopoietic cell transplantation (auto-HCT) in initial analyses of one of three cohorts from the CheckMate 205 study of nivolumab for cHL. Here, we assess safety and efficacy after extended follow-up of all three cohorts.MethodsThis multicenter, single-arm, phase II study enrolled patients with relapsed/refractory cHL after auto-HCT treatment failure into cohorts by treatment history: brentuximab vedotin (BV)–naive (cohort A), BV received after auto-HCT (cohort B), and BV received before and/or after auto-HCT (cohort C). All patients received nivolumab 3 mg/kg every 2 weeks until disease progression/unacceptable toxicity. The primary end point was objective response rate per independent radiology review committee.ResultsOverall, 243 patients were treated...
TL;DR: This perspective article with a focus on recent results discusses how it has been possible to efficiently create, manipulate, and destroy nanometer-size skyrmions in device-compatible materials at room-temperature by all electrical means.
Abstract: Within a decade, the field of magnetic skyrmionics has developed from a niche prediction to a huge and active research field. Not only do magnetic skyrmions—magnetic whirls with a unique topology—reveal fundamentally new physics, but they have also risen to prominence as up-and-coming candidates for next-generation high-density efficient information encoding. Within a few years, it has been possible to efficiently create, manipulate, and destroy nanometer-size skyrmions in device-compatible materials at room-temperature by all electrical means. Despite the incredibly rapid progress, several challenges still remain to obtain fully functional and competitive skyrmion devices, as discussed in this perspective article with a focus on recent results.
TL;DR: In this paper, the authors combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci associated with general cognitive function.
Abstract: General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10-8) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.
University of Sussex1, INSEAD2, University of Virginia3, University of Padua4, University of Cologne5, University of Cincinnati6, University of Economics, Prague7, Hong Kong Polytechnic University8, University of Liverpool9, Stockholm School of Economics10, Linnaeus University11, University of Hong Kong12, University of California, Berkeley13, City University of New York14, New York University15, University of Manchester16, Westat17, Temple University18, Northwestern University19, University of Zurich20, University of Sheffield21, Stockholm University22, Ludwig Maximilian University of Munich23, University of Minnesota24, Xiamen University25, Oregon State University26, Universidade Federal de Santa Catarina27, University of Washington28, Queen Mary University of London29, University of Nottingham30, Cardiff University31, University of Maryland, College Park32, Brigham Young University33, Loyola University Maryland34, University of Toronto35, University of Giessen36, United States Military Academy37, State University of New York at Oswego38, Concordia University39, University of Bamberg40, University of Amsterdam41, Center for Open Science42
TL;DR: In this paper, 29 teams involving 61 analysts used the same data set to address the same research question: whether soccer referees are more likely to give red cards to dark-skin-toned players than to light-skinned-players.
Abstract: Twenty-nine teams involving 61 analysts used the same data set to address the same research question: whether soccer referees are more likely to give red cards to dark-skin-toned players than to light-skin-toned players. Analytic approaches varied widely across the teams, and the estimated effect sizes ranged from 0.89 to 2.93 (Mdn = 1.31) in odds-ratio units. Twenty teams (69%) found a statistically significant positive effect, and 9 teams (31%) did not observe a significant relationship. Overall, the 29 different analyses used 21 unique combinations of covariates. Neither analysts’ prior beliefs about the effect of interest nor their level of expertise readily explained the variation in the outcomes of the analyses. Peer ratings of the quality of the analyses also did not account for the variability. These findings suggest that significant variation in the results of analyses of complex data may be difficult to avoid, even by experts with honest intentions. Crowdsourcing data analysis, a strategy in which numerous research teams are recruited to simultaneously investigate the same research question, makes transparent how defensible, yet subjective, analytic choices influence research results.
Florence Demenais1, Florence Demenais2, Patricia Margaritte-Jeannin1, Patricia Margaritte-Jeannin2 +213 more•Institutions (79)
TL;DR: A meta-analysis of GWAS studies for asthma from multiancestral cohorts identifies five new loci and finds that the asthma-associated loci are enriched near enhancer marks in immune cells, suggesting a major role of these loci in the regulation of immunologically related mechanisms.
Abstract: We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma loci, established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. The enrichment in enhancer marks at asthma risk loci, especially in immune cells, suggested a major role of these loci in the regulation of immunologically related mechanisms.
TL;DR: It is concluded that the combination of the anti-HIV-1 monoclonal antibodies 3BNC117 and 10-1074 can maintain long-term suppression in the absence of antiretroviral therapy in individuals with antibody-sensitive viral reservoirs.
Abstract: Individuals infected with HIV-1 require lifelong antiretroviral therapy, because interruption of treatment leads to rapid rebound viraemia Here we report on a phase 1b clinical trial in which a combination of 3BNC117 and 10-1074, two potent monoclonal anti-HIV-1 broadly neutralizing antibodies that target independent sites on the HIV-1 envelope spike, was administered during analytical treatment interruption Participants received three infusions of 30 mg kg−1 of each antibody at 0, 3 and 6 weeks Infusions of the two antibodies were generally well-tolerated The nine enrolled individuals with antibody-sensitive latent viral reservoirs maintained suppression for between 15 and more than 30 weeks (median of 21 weeks), and none developed viruses that were resistant to both antibodies We conclude that the combination of the anti-HIV-1 monoclonal antibodies 3BNC117 and 10-1074 can maintain long-term suppression in the absence of antiretroviral therapy in individuals with antibody-sensitive viral reservoirs
TL;DR: This communication provides practically useful resource tables and graphs on the new diagnostic criteria for JAK2/CALR/MPL mutation-related MPNs: PV, ET, and PMF and discusses the complementary role of mutation screening.
Abstract: The new edition of the 2016 World Health Organization (WHO) classification system for tumors of the hematopoietic and lymphoid tissues was published in September 2017. Under the category of myeloproliferative neoplasms (MPNs), the revised document includes seven subcategories: chronic myeloid leukemia, chronic neutrophilic leukemia, polycythemia vera (PV), primary myelofibrosis (PMF), essential thrombocythemia (ET), chronic eosinophilic leukemia-not otherwise specified and MPN, unclassifiable (MPN-U); of note, mastocytosis is no longer classified under the MPN category. In the current review, we focus on the diagnostic criteria for JAK2/CALR/MPL mutation-related MPNs: PV, ET, and PMF. In this regard, the 2016 changes were aimed at facilitating the distinction between masked PV and JAK2-mutated ET and between prefibrotic/early and overtly fibrotic PMF. In the current communication, we (i) provide practically useful resource tables and graphs on the new diagnostic criteria including outcome, (ii) elaborate on the rationale for the 2016 changes, (iii) discuss the complementary role of mutation screening, (iv) address ongoing controversies and propose solutions, (v) attend to the challenges of applying WHO criteria in routine clinical practice, and (vi) outline future directions from the perspectives of the clinical pathologist.
First Faculty of Medicine, Charles University in Prague1, Medical University of Vienna2, Linköping University3, Institut Gustave Roussy4, University of Cologne5, University of Milan6, University of Lausanne7, Belfast Health and Social Care Trust8, University College Hospital9, Leiden University10, Athens State University11, Medical University of Graz12
TL;DR: The European Society of Gynaecological Oncology (ESGO), the European Society for Radiotherapy and Oncologists (ESTRO), and the European Pathology (EPSP) jointly developed clinically relevant and evidence-based guidelines in order to improve the quality of care for women with cervical cancer across Europe and worldwide.
Abstract: Background Despite significant advances in the screening, detection, and treatment of preinvasive cervical lesions, invasive cervical cancer is the fifth most common cancer in European women. There are large disparities in Europe and worldwide in the incidence, management, and mortality of cervical cancer. Objective The European Society of Gynaecological Oncology (ESGO), the European Society for Radiotherapy and Oncology (ESTRO), and the European Society of Pathology (ESP) jointly develop clinically relevant and evidence-based guidelines in order to improve the quality of care for women with cervical cancer across Europe and worldwide. Methods The ESGO/ESTRO/ESP nominated an international multidisciplinary development group consisting of practicing clinicians and researchers who have demonstrated leadership and expertise in the care and research of cervical cancer (23 experts across Europe). To ensure that the guidelines are evidence based, the current literature identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 159 international reviewers, selected through ESGO/ESTRO/ESP and including patient representatives. Results The guidelines cover comprehensively staging, management, and follow-up for patients with cervical cancer. Management includes fertility sparing treatment; stage T1a, T1b1/T2a1, clinically occult cervical cancer diagnosed after simple hysterectomy; early and locally advanced cervical cancer; primary distant metastatic disease; cervical cancer in pregnancy; and recurrent disease. Principles of radiotherapy and pathological evaluation are defined.
Kanazawa University1, Kobe University2, Dalhousie University3, University of Düsseldorf4, University of Osnabrück5, University of Lyon6, University of Oxford7, University of Marburg8, Ghent University9, University of Würzburg10, Charles University in Prague11, Martin Luther University of Halle-Wittenberg12, Adelphi University13, University of Jena14, Leibniz Association15, University of Maryland, College Park16, National Institute of Genetics17, University of Tokyo18, Wageningen University and Research Centre19, John Innes Centre20, New York Botanical Garden21, University of Copenhagen22, University of Cologne23, University of Pretoria24, Institute of Science and Technology Austria25, University of New South Wales26, University of Toulouse27, Université Paris-Saclay28
TL;DR: Transcriptomic analysis of sexual reproductive structures reveals intricate control by TFs, activity of the ROS gene network, and the ancestral use of plant-like storage and stress protection proteins in the zygote.
TL;DR: This work generated high-resolution interaction neighborhood maps of the endogenously expressed DNA repair factors 53BP1, BRCA1, and MDC1 and identified a novel vertebrate-specific protein complex, shieldin, comprising REV7 plus three previously uncharacterized proteins, RINN1 (CTC-534A2.2), RINn2 (FAM35A), and RinN3 (C20ORF196).
Max Planck Society1, University of Southampton2, Durham University3, National Oceanography Centre, Southampton4, Catalan Institution for Research and Advanced Studies5, University of Barcelona6, University of Lisbon7, University of Alcalá8, Centre national de la recherche scientifique9, University of Cádiz10, University of Cologne11, Neanderthal Museum12
TL;DR: Using uranium-thorium dating of carbonate crusts to show that cave paintings from three different sites in Spain must be older than 64,000 years, this cave art is the earliest dated so far and implies Neandertal authorship.
Abstract: The extent and nature of symbolic behavior among Neandertals are obscure. Although evidence for Neandertal body ornamentation has been proposed, all cave painting has been attributed to modern humans. Here we present dating results for three sites in Spain that show that cave art emerged in Iberia substantially earlier than previously thought. Uranium-thorium (U-Th) dates on carbonate crusts overlying paintings provide minimum ages for a red linear motif in La Pasiega (Cantabria), a hand stencil in Maltravieso (Extremadura), and red-painted speleothems in Ardales (Andalucia). Collectively, these results show that cave art in Iberia is older than 64.8 thousand years (ka). This cave art is the earliest dated so far and predates, by at least 20 ka, the arrival of modern humans in Europe, which implies Neandertal authorship.
TL;DR: A comprehensive overview of the state-of-the-art of power-to-methane is presented in this paper, where the Power-To-Methane process chain is described in detail.
Abstract: Power-to-Methane is a concept that converts electrical into chemical energy using CO2 and H2O. The concept brings the possibility of connecting the power grid to different sectors, where CH4 is needed such as mobility and industry. In this review, a comprehensive overview of the state-of-the-art of Power-to-Methane is presented. The Power-to-Methane process chain is described in detail. Fundamentals of water electrolysis are highlighted and cell technologies are discussed and assessed. CO2 sources are pointed out, CO2 separation technologies are depicted and compared, and some separation projects worldwide are listed. Thermodynamics of methanation process is analyzed; catalysts and reactors used are descripted and evaluated. Finally, Power-to-Methane plants in operation and construction are addressed.
TL;DR: In this article, the position centroids exhibit clockwise looped motion on the sky, on scales of typically 150 μ as over a few tens of minutes, corresponding to about 30% the speed of light.
Abstract: We report the detection of continuous positional and polarization changes of the compact source SgrA* in high states (“flares”) of its variable near-infrared emission with the near-infrared GRAVITY-Very Large Telescope Interferometer (VLTI) beam-combining instrument. In three prominent bright flares, the position centroids exhibit clockwise looped motion on the sky, on scales of typically 150 μ as over a few tens of minutes, corresponding to about 30% the speed of light. At the same time, the flares exhibit continuous rotation of the polarization angle, with about the same 45(±15) min period as that of the centroid motions. Modelling with relativistic ray tracing shows that these findings are all consistent with a near face-on, circular orbit of a compact polarized “hot spot” of infrared synchrotron emission at approximately six to ten times the gravitational radius of a black hole of 4 million solar masses. This corresponds to the region just outside the innermost, stable, prograde circular orbit (ISCO) of a Schwarzschild–Kerr black hole, or near the retrograde ISCO of a highly spun-up Kerr hole. The polarization signature is consistent with orbital motion in a strong poloidal magnetic field.
TL;DR: An overview of the enormous morphological, taxonomical and functional diversity of soil protists is provided, and current challenges and opportunities in soil protistology are discussed.
Abstract: Protists include all eukaryotes except plants, fungi and animals. They are an essential, yet often forgotten, component of the soil microbiome. Method developments have now furthered our understanding of the real taxonomic and functional diversity of soil protists. They occupy key roles in microbial foodwebs as consumers of bacteria, fungi and other small eukaryotes. As parasites of plants, animals and even of larger protists, they regulate populations and shape communities. Pathogenic forms play a major role in public health issues as human parasites, or act as agricultural pests. Predatory soil protists release nutrients enhancing plant growth. Soil protists are of key importance for our understanding of eukaryotic evolution and microbial biogeography. Soil protists are also useful in applied research as bioindicators of soil quality, as models in ecotoxicology and as potential biofertilizers and biocontrol agents. In this review, we provide an overview of the enormous morphological, taxonomical and functional diversity of soil protists, and discuss current challenges and opportunities in soil protistology. Research in soil biology would clearly benefit from incorporating more protistology alongside the study of bacteria, fungi and animals.
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Eindhoven University of Technology1, National Scientific and Technical Research Council2, Max Planck Society3, University of Groningen4, Flinders University5, University of Oxford6, Illinois Institute of Technology7, Nottingham Trent University8, Bielefeld University9, University of Nevada, Las Vegas10, University of Wisconsin-Madison11, Missouri State University12, University of Arkansas13, Leiden University14, Katholieke Universiteit Leuven15, Linnaeus University16, Tzu Chi University17, University of British Columbia18, University of Cambridge19, University of Edinburgh20, Bangor University21, University of Glasgow22, Linköping University23, Florida State University24, Yale University25, University of Louisiana at Lafayette26, University of Texas at Austin27, St. Edward's University28, West Virginia University29, Rutgers University30, Indiana University31, RWTH Aachen University32, Keele University33, University of Tübingen34, Radboud University Nijmegen35, University of Chester36, New York University37, University of Nottingham38, Erasmus University Rotterdam39, University of Bristol40, Sahlgrenska University Hospital41, Adam Mickiewicz University in Poznań42, University of Connecticut43, Humboldt University of Berlin44, Charité45, University of Fribourg46, University of Kent47, Academy of Sciences of the Czech Republic48, RAND Corporation49, Baylor University50, Virginia Tech51, Northern Illinois University52, Open University53, King's College London54, Karolinska Institutet55, Stanford University56, Stockholm University57, Universidade Federal de Santa Catarina58, University of Tromsø59, DePaul University60, Boğaziçi University61, University of Cologne62, King Abdulaziz City for Science and Technology63, University of Leeds64, University of Virginia65, Center for Open Science66, National Institutes of Health67, University of Southern Indiana68, Autonomous University of Madrid69, Utrecht University70, Tilburg University71, Massey University72, Saint Louis University73, University of California, Davis74, Ghent University75
TL;DR: In response to recommendations to redefine statistical significance to P ≤ 0.005, it is proposed that researchers should transparently report and justify all choices they make when designing a study, including the alpha level.
Abstract: In response to recommendations to redefine statistical significance to P ≤ 0.005, we propose that researchers should transparently report and justify all choices they make when designing a study, including the alpha level.
TL;DR: Exome-wide analysis identifies rare and low-frequency coding variants associated with body mass index that confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
Abstract: Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
Harvard University1, VU University Amsterdam2, University of Cologne3, Memorial Sloan Kettering Cancer Center4, University of Texas MD Anderson Cancer Center5, Humanitas University6, University of Bologna7, University of California, Los Angeles8, University of Oxford9, Wayne State University10, Emory University11, University Health Network12, Charles University in Prague13, Mayo Clinic14, Bristol-Myers Squibb15, Brigham and Women's Hospital16
TL;DR: Genetically driven PD-L1 expression and MHC class II positivity on HRS cells are potential predictors of favorable outcome after PD-1 blockade.
Abstract: Purpose Hodgkin Reed-Sternberg (HRS) cells evade antitumor immunity by multiple means, including gains of 9p241/ CD274(PD-L1)/ PDCD1LG2(PD-L2) and perturbed antigen presentation Programmed death 1 (PD-1) receptor blockade is active in classic Hodgkin lymphoma (cHL) despite reported deficiencies of major histocompatibility complex (MHC) class I expression on HRS cells Herein, we assess bases of sensitivity to PD-1 blockade in patients with relapsed/refractory cHL who were treated with nivolumab (anti-PD-1) in the CheckMate 205 trial Methods HRS cells from archival tumor biopsies were evaluated for 9p241 alterations by fluorescence in situ hybridization and for expression of PD ligand 1 (PD-L1) and the antigen presentation pathway components-β2-microglobulin, MHC class I, and MHC class II-by immunohistochemistry These parameters were correlated with clinical responses and progression-free survival (PFS) after PD-1 blockade Results Patients with higher-level 9p241 copy gain and increased PD-L1 expression on HRS cells had superior PFS HRS cell expression of β2-microglobulin/MHC class I was not predictive for complete remission or PFS after nivolumab therapy In contrast, HRS cell expression of MHC class II was predictive for complete remission In patients with a > 12-month interval between myeloablative autologous stem-cell transplantation and nivolumab therapy, HRS cell expression of MHC class II was associated with prolonged PFS Conclusion Genetically driven PD-L1 expression and MHC class II positivity on HRS cells are potential predictors of favorable outcome after PD-1 blockade In cHL, clinical responses to nivolumab were not dependent on HRS cell expression of MHC class I
TL;DR: This work identifies two fundamental properties of digital technologies—specificity and relationality—and develops propositions that link these properties to six enabling mechanisms: compression, conservation, expansion, substitution, combination, and generation.
Abstract: We develop theory about how and when digital technologies enable new venture creation processes. We identify two fundamental properties of digital technologies—specificity and relationality—and develop propositions that link these properties to six enabling mechanisms: compression, conservation, expansion, substitution, combination, and generation. We use the linked properties and mechanisms to determine how and when in the venture creation process— from prospecting to developing to exploiting—digital technologies have enabled start-ups in the IT hardware sector and develop stage-dependent propositions about their sector-level effects. We conclude our theorizing by discussing its implications beyond digital technologies and the IT hardware sector.
University of Cologne1, Penn State Milton S. Hershey Medical Center2, University of North Carolina at Chapel Hill3, University of California, San Diego4, International Agency for Research on Cancer5, Max Planck Society6, French Institute of Health and Medical Research7, American Board of Legal Medicine8, University of Grenoble9, University of Zurich10, University of Oslo11, Oslo University Hospital12, University of Bonn13, Peter MacCallum Cancer Centre14, University of Milan15, University of Jena16, Memorial Sloan Kettering Cancer Center17, German Cancer Research Center18
TL;DR: It is shown LCNECs represent a distinct transcriptional subgroup among lung cancers and comprise two molecular subgroups, type I (TP53 and STK11/KEAP1 alterations) and type II ( TP53 and RB1 inactivation).
Abstract: Pulmonary large-cell neuroendocrine carcinomas (LCNECs) have similarities with other lung cancers, but their precise relationship has remained unclear. Here we perform a comprehensive genomic (n = 60) and transcriptomic (n = 69) analysis of 75 LCNECs and identify two molecular subgroups: “type I LCNECs” with bi-allelic TP53 and STK11/KEAP1 alterations (37%), and “type II LCNECs” enriched for bi-allelic inactivation of TP53 and RB1 (42%). Despite sharing genomic alterations with adenocarcinomas and squamous cell carcinomas, no transcriptional relationship was found; instead LCNECs form distinct transcriptional subgroups with closest similarity to SCLC. While type I LCNECs and SCLCs exhibit a neuroendocrine profile with ASCL1high/DLL3high/NOTCHlow, type II LCNECs bear TP53 and RB1 alterations and differ from most SCLC tumors with reduced neuroendocrine markers, a pattern of ASCL1low/DLL3low/NOTCHhigh, and an upregulation of immune-related pathways. In conclusion, LCNECs comprise two molecularly defined subgroups, and distinguishing them from SCLC may allow stratified targeted treatment of high-grade neuroendocrine lung tumors. The molecular nature of large-cell neuroendocrine lung carcinomas (LCNEC) has remained unclear. Here, the authors show LCNECs represent a distinct transcriptional subgroup among lung cancers and comprise two molecular subgroups, type I (TP53 and STK11/KEAP1 alterations) and type II (TP53 and RB1 inactivation).