Showing papers by "University of Würzburg published in 2016"
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TL;DR: ITOL 3 is the first tool which supports direct visualization of the recently proposed phylogenetic placements format, and its account system has been redesigned to simplify the management of trees in user-defined workspaces and projects.
Abstract: Interactive Tree Of Life (http://itol.embl.de) is a web-based tool for the display, manipulation and annotation of phylogenetic trees. It is freely available and open to everyone. The current version was completely redesigned and rewritten, utilizing current web technologies for speedy and streamlined processing. Numerous new features were introduced and several new data types are now supported. Trees with up to 100,000 leaves can now be efficiently displayed. Full interactive control over precise positioning of various annotation features and an unlimited number of datasets allow the easy creation of complex tree visualizations. iTOL 3 is the first tool which supports direct visualization of the recently proposed phylogenetic placements format. Finally, iTOL's account system has been redesigned to simplify the management of trees in user-defined workspaces and projects, as it is heavily used and currently handles already more than 500,000 trees from more than 10,000 individual users.
4,190 citations
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1,193 citations
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TL;DR: This guideline provides guidance on which surgical approach should be considered for adrenal masses with radiological findings suspicious of malignancy, and offers recommendations for the follow-up of patients with adrenal incidentalomas.
Abstract: By definition, an adrenal incidentaloma is an asymptomatic adrenal mass detected on imaging not performed for suspected adrenal disease. In most cases, adrenal incidentalomas are nonfunctioning adrenocortical adenomas, but may also represent conditions requiring therapeutic intervention (e.g. adrenocortical carcinoma, pheochromocytoma, hormone-producing adenoma or metastasis). The purpose of this guideline is to provide clinicians with best possible evidence-based recommendations for clinical management of patients with adrenal incidentalomas based on the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. We predefined four main clinical questions crucial for the management of adrenal incidentaloma patients, addressing these four with systematic literature searches: (A) How to assess risk of malignancy?; (B) How to define and manage low-level autonomous cortisol secretion, formerly called 'subclinical' Cushing's syndrome?; (C) Who should have surgical treatment and how should it be performed?; (D) What follow-up is indicated if the adrenal incidentaloma is not surgically removed? SELECTED RECOMMENDATIONS: (i) At the time of initial detection of an adrenal mass establishing whether the mass is benign or malignant is an important aim to avoid cumbersome and expensive follow-up imaging in those with benign disease. (ii) To exclude cortisol excess, a 1mg overnight dexamethasone suppression test should be performed (applying a cut-off value of serum cortisol ≤50nmol/L (1.8µg/dL)). (iii) For patients without clinical signs of overt Cushing's syndrome but serum cortisol levels post 1mg dexamethasone >138nmol/L (>5µg/dL), we propose the term 'autonomous cortisol secretion'. (iv) All patients with '(possible) autonomous cortisol' secretion should be screened for hypertension and type 2 diabetes mellitus, to ensure these are appropriately treated. (v) Surgical treatment should be considered in an individualized approach in patients with 'autonomous cortisol secretion' who also have comorbidities that are potentially related to cortisol excess. (vi) In principle, the appropriateness of surgical intervention should be guided by the likelihood of malignancy, the presence and degree of hormone excess, age, general health and patient preference. (vii) Surgery is not usually indicated in patients with an asymptomatic, nonfunctioning unilateral adrenal mass and obvious benign features on imaging studies. We provide guidance on which surgical approach should be considered for adrenal masses with radiological findings suspicious of malignancy. Furthermore, we offer recommendations for the follow-up of patients with adrenal incidentaloma who do not undergo adrenal surgery, for those with bilateral incidentalomas, for patients with extra-adrenal malignancy and adrenal masses and for young and elderly patients with adrenal incidentalomas.
1,079 citations
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TL;DR: MYC regulates the expression of two immune checkpoint proteins on the tumor cell surface: the innate immune regulator CD47 (cluster of differentiation 47) and the adaptive immune checkpoint PD-L1 (programmed death–ligand 1).
Abstract: The MYC oncogene codes for a transcription factor that is overexpressed in many human cancers. Here we show that MYC regulates the expression of two immune checkpoint proteins on the tumor cell surface: the innate immune regulator CD47 (cluster of differentiation 47) and the adaptive immune checkpoint PD-L1 (programmed death-ligand 1). Suppression of MYC in mouse tumors and human tumor cells caused a reduction in the levels of CD47 and PD-L1 messenger RNA and protein. MYC was found to bind directly to the promoters of the Cd47 and Pd-l1 genes. MYC inactivation in mouse tumors down-regulated CD47 and PD-L1 expression and enhanced the antitumor immune response. In contrast, when MYC was inactivated in tumors with enforced expression of CD47 or PD-L1, the immune response was suppressed, and tumors continued to grow. Thus, MYC appears to initiate and maintain tumorigenesis, in part, through the modulation of immune regulatory molecules.
924 citations
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Sapienza University of Rome1, Marche Polytechnic University2, University of Copenhagen3, University of Milan4, Rikshospitalet–Radiumhospitalet5, University of Oslo6, University of Edinburgh7, University of Würzburg8, Greifswald University Hospital9, University of Zurich10, Medical University of Vienna11, University of Salamanca12
TL;DR: This Consensus Statement aims to provide valuable information on classifications, pathological features, risk factors, cells of origin, genetic and epigenetic modifications and current therapies available for this cancer.
Abstract: Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies with features of biliary tract differentiation. CCA is the second most common primary liver tumour and the incidence is increasing worldwide. CCA has high mortality owing to its aggressiveness, late diagnosis and refractory nature. In May 2015, the "European Network for the Study of Cholangiocarcinoma" (ENS-CCA: www.enscca.org or www.cholangiocarcinoma.eu) was created to promote and boost international research collaboration on the study of CCA at basic, translational and clinical level. In this Consensus Statement, we aim to provide valuable information on classifications, pathological features, risk factors, cells of origin, genetic and epigenetic modifications and current therapies available for this cancer. Moreover, future directions on basic and clinical investigations and plans for the ENS-CCA are highlighted.
904 citations
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TL;DR: By s-shell pulsed resonant excitation of a Purcell-enhanced quantum dot-micropillar system, deterministically generate resonance fluorescence single photons which, at π pulse excitation, have an extraction efficiency of 66, single-photon purity of 99.1%, and photon indistinguishability of 98.5%.
Abstract: This work was supported by the National Natural Science Foundation of China, the Chinese Academy of Sciences, and the National Fundamental Research Program. We acknowledge financial support by the State of Bavaria and the German Ministry of Education and Research (BMBF) within the projects Q.com-H and the Chist-era project SSQN. N. G. acknowledges support from the Danish Research Council for Technology and Production.
839 citations
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National Institutes of Health1, European Society of Cardiology2, Ghent University3, Karolinska Institutet4, Lille University of Science and Technology5, Charles University in Prague6, Hospital Universitario La Paz7, University of Sarajevo8, Shupyk National Medical Academy of Postgraduate Education9, University of Latvia10, Ljubljana University Medical Centre11, University of Ioannina12, University of Würzburg13, Vilnius University14, University Hospital Centre Zagreb15, Nicosia General Hospital16, Jagiellonian University Medical College17, University of Zagreb18, Valve Corporation19, Hacettepe University20, University of Banja Luka21
TL;DR: A large majority of coronary patients do not achieve the guideline standards for secondary prevention with high prevalences of persistent smoking, unhealthy diets, physical inactivity and consequently most patients are overweight or obese with a high prevalence of diabetes.
Abstract: AimsTo determine whether the Joint European Societies guidelines on cardiovascular prevention are being followed in everyday clinical practice of secondary prevention and to describe the lifestyle,...
833 citations
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TL;DR: In patients with type 2 diabetes and high cardiovascular risk, empagliflozin reduced heart failure hospitalization and cardiovascular death, with a consistent benefit in patients with and without baseline heart failure.
Abstract: Aims We previously reported that in the EMPA-REG OUTCOME® trial, empagliflozin added to standard of care reduced the risk of 3-point major adverse cardiovascular events, cardiovascular and all-cause death, and hospitalization for heart failure in patients with type 2 diabetes and high cardiovascular risk. We have now further investigated heart failure outcomes in all patients and in subgroups, including patients with or without baseline heart failure.
Methods and results Patients were randomized to receive empagliflozin 10 mg, empagliflozin 25 mg, or placebo. Seven thousand and twenty patients were treated; 706 (10.1%) had heart failure at baseline. Heart failure hospitalization or cardiovascular death occurred in a significantly lower percentage of patients treated with empagliflozin \[265/4687 patients (5.7%)] than with placebo [198/2333 patients (8.5%)\] \[hazard ratio, HR: 0.66 (95% confidence interval: 0.55–0.79); P < 0.001\], corresponding to a number needed to treat to prevent one heart failure hospitalization or cardiovascular death of 35 over 3 years. Consistent effects of empagliflozin were observed across subgroups defined by baseline characteristics, including patients with vs. without heart failure, and across categories of medications to treat diabetes and/or heart failure. Empagliflozin improved other heart failure outcomes, including hospitalization for or death from heart failure [2.8 vs. 4.5%; HR: 0.61 (0.47–0.79); P < 0.001] and was associated with a reduction in all-cause hospitalization [36.8 vs. 39.6%; HR: 0.89 (0.82–0.96); P = 0.003]. Serious adverse events and adverse events leading to discontinuation were reported by a higher proportion of patients with vs. without heart failure at baseline in both treatment groups, but were no more common with empagliflozin than with placebo.
Conclusion In patients with type 2 diabetes and high cardiovascular risk, empagliflozin reduced heart failure hospitalization and cardiovascular death, with a consistent benefit in patients with and without baseline heart failure.
806 citations
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TL;DR: Although known for over 90 years, only in the past two decades has the chemistry of diboron(4) compounds been extensively explored and these compounds now feature prominently in both metal-catalyzed and metal-free methodologies for the formation of B-C bonds and other processes.
Abstract: Although known for over 90 years, only in the past two decades has the chemistry of diboron(4) compounds been extensively explored. Many interesting structural features and reaction patterns have emerged, and more importantly, these compounds now feature prominently in both metal-catalyzed and metal-free methodologies for the formation of B–C bonds and other processes.
684 citations
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TL;DR: The predominantly relapsing and often severe disease course and the short median time to second attack support the use of prophylactic long-term treatments in patients with MOG-IgG-positive ON and/or myelitis; however, treatment failure leading to rapid accumulation of disability was noted in many patients as well as flare-ups after steroid withdrawal.
Abstract: A subset of patients with neuromyelitis optica spectrum disorders (NMOSD) has been shown to be seropositive for myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) To describe the epidemiological, clinical, radiological, cerebrospinal fluid (CSF), and electrophysiological features of a large cohort of MOG-IgG-positive patients with optic neuritis (ON) and/or myelitis (n = 50) as well as attack and long-term treatment outcomes Retrospective multicenter study The sex ratio was 1:28 (m:f) Median age at onset was 31 years (range 6-70) The disease followed a multiphasic course in 80% (median time-to-first-relapse 5 months; annualized relapse rate 092) and resulted in significant disability in 40% (mean follow-up 75 ± 465 months), with severe visual impairment or functional blindness (36%) and markedly impaired ambulation due to paresis or ataxia (25%) as the most common long-term sequelae Functional blindness in one or both eyes was noted during at least one ON attack in around 70% Perioptic enhancement was present in several patients Besides acute tetra-/paraparesis, dysesthesia and pain were common in acute myelitis (70%) Longitudinally extensive spinal cord lesions were frequent, but short lesions occurred at least once in 44% Fourty-one percent had a history of simultaneous ON and myelitis Clinical or radiological involvement of the brain, brainstem, or cerebellum was present in 50%; extra-opticospinal symptoms included intractable nausea and vomiting and respiratory insufficiency (fatal in one) CSF pleocytosis (partly neutrophilic) was present in 70%, oligoclonal bands in only 13%, and blood-CSF-barrier dysfunction in 32% Intravenous methylprednisolone (IVMP) and long-term immunosuppression were often effective; however, treatment failure leading to rapid accumulation of disability was noted in many patients as well as flare-ups after steroid withdrawal Full recovery was achieved by plasma exchange in some cases, including after IVMP failure Breakthrough attacks under azathioprine were linked to the drug-specific latency period and a lack of cotreatment with oral steroids Methotrexate was effective in 5/6 patients Interferon-beta was associated with ongoing or increasing disease activity Rituximab and ofatumumab were effective in some patients However, treatment with rituximab was followed by early relapses in several cases; end-of-dose relapses occurred 9-12 months after the first infusion Coexisting autoimmunity was rare (9%) Wingerchuk’s 2006 and 2015 criteria for NMO(SD) and Barkhof and McDonald criteria for multiple sclerosis (MS) were met by 28%, 32%, 15%, 33%, respectively; MS had been suspected in 36% Disease onset or relapses were preceded by infection, vaccination, or pregnancy/delivery in several cases Our findings from a predominantly Caucasian cohort strongly argue against the concept of MOG-IgG denoting a mild and usually monophasic variant of NMOSD The predominantly relapsing and often severe disease course and the short median time to second attack support the use of prophylactic long-term treatments in patients with MOG-IgG-positive ON and/or myelitis
671 citations
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Heidelberg University1, German Cancer Research Center2, St. Jude Children's Research Hospital3, University of Toronto4, Ontario Institute for Cancer Research5, Institute of Cancer Research6, University of California, San Francisco7, Cincinnati Children's Hospital Medical Center8, Sapienza University of Rome9, University of Warsaw10, Boston Children's Hospital11, University of Bonn12, University of Hamburg13, Medical University of Vienna14, French Institute of Health and Medical Research15, Karolinska Institutet16, University of Freiburg17, Cork University Hospital18, Hadassah Medical Center19, Otto-von-Guericke University Magdeburg20, Copenhagen University Hospital21, Vanderbilt University Medical Center22, Children's Hospital of Philadelphia23, Washington University in St. Louis24, University of Göttingen25, Augsburg College26, University of Münster27, Radboud University Nijmegen28, VU University Medical Center29, University Medical Center Freiburg30, Ludwig Maximilian University of Munich31, University of Tübingen32, University of Basel33, Masaryk University34, University of Cambridge35, University of Amsterdam36, Necker-Enfants Malades Hospital37, Institut Gustave Roussy38, Aix-Marseille University39, University of Düsseldorf40, Virginia Commonwealth University41, University of Würzburg42, New York University43, Henry Ford Hospital44, University of Texas MD Anderson Cancer Center45, University of Queensland46, McGill University47
TL;DR: It is demonstrated that a significant proportion of institutionally diagnosed CNS-PNETs display molecular profiles indistinguishable from those of various other well-defined CNS tumor entities, facilitating diagnosis and appropriate therapy for patients with these tumors.
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Katholieke Universiteit Leuven1, University of Texas MD Anderson Cancer Center2, Johns Hopkins University3, University of Texas Health Science Center at San Antonio4, University of Cologne5, University of Manitoba6, Sheba Medical Center7, Université libre de Bruxelles8, University of Alabama at Birmingham9, Tel Aviv University10, University of Würzburg11, University of Strasbourg12, University of Liverpool13, München Klinik Bogenhausen14, Catholic University of Korea15, Necker-Enfants Malades Hospital16, University of Minnesota17, Technion – Israel Institute of Technology18, University of California, Davis19, Center for Global Development20
TL;DR: The results support the use of isavuconazole for the primary treatment of patients with invasive mould disease and non-inferiority was shown.
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TL;DR: It is shown that CAR-T-cell products generated from defined T-cell subsets can provide uniform potency compared with products derived from unselected T cells that vary in phenotypic composition.
Abstract: Adoptive T-cell therapy with gene-modified T cells expressing a tumor-reactive T-cell receptor or chimeric antigen receptor (CAR) is a rapidly growing field of translational medicine and has shown success in the treatment of B-cell malignancies and solid tumors. In all reported trials, patients have received T-cell products comprising random compositions of CD4(+) and CD8(+) naive and memory T cells, meaning that each patient received a different therapeutic agent. This variation may have influenced the efficacy of T-cell therapy, and complicates comparison of outcomes between different patients and across trials. We analyzed CD19 CAR-expressing effector T cells derived from different subsets (CD4(+)/CD8(+) naive, central memory, effector memory). T cells derived from each of the subsets were efficiently transduced and expanded, but showed clear differences in effector function and proliferation in vitro and in vivo. Combining the most potent CD4(+) and CD8(+) CAR-expressing subsets, resulted in synergistic antitumor effects in vivo. We show that CAR-T-cell products generated from defined T-cell subsets can provide uniform potency compared with products derived from unselected T cells that vary in phenotypic composition. These findings have important implications for the formulation of T-cell products for adoptive therapies.
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TL;DR: A review of established in vitro blood-brain barrier models with a focus on their validation regarding a set of well-established bloodbrain barrier characteristics is given in this paper, with an overview of the advantages and drawbacks of the different models described.
Abstract: The endothelial cells lining the brain capillaries separate the blood from the brain parenchyma. The endothelial monolayer of the brain capillaries serves both as a crucial interface for exchange of nutrients, gases, and metabolites between blood and brain, and as a barrier for neurotoxic components of plasma and xenobiotics. This "blood-brain barrier" function is a major hindrance for drug uptake into the brain parenchyma. Cell culture models, based on either primary cells or immortalized brain endothelial cell lines, have been developed, in order to facilitate in vitro studies of drug transport to the brain and studies of endothelial cell biology and pathophysiology. In this review, we aim to give an overview of established in vitro blood-brain barrier models with a focus on their validation regarding a set of well-established blood-brain barrier characteristics. As an ideal cell culture model of the blood-brain barrier is yet to be developed, we also aim to give an overview of the advantages and drawbacks of the different models described.
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TL;DR: Adjuvant APBI using multicatheter brachytherapy after breast-conserving surgery in patients with early breast cancer is not inferior to adjuvant whole-breast irradiation with respect to 5-year local control, disease-free survival, and overall survival.
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University of Erlangen-Nuremberg1, University of Tübingen2, University of Zurich3, University of Duisburg-Essen4, Hannover Medical School5, Heidelberg University6, Otto-von-Guericke University Magdeburg7, University Hospital Heidelberg8, Ludwig Maximilian University of Munich9, University of Münster10, RWTH Aachen University11, University of Würzburg12, Technische Universität München13
TL;DR: Anti-PD1 antibodies can induce a plethora of irAEs, and the knowledge of them will allow prompt diagnosis and improve the management resulting in decreased morbidity.
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University of Bern1, University of Jena2, Technische Universität München3, Smithsonian Conservation Biology Institute4, University of Natural Resources and Life Sciences, Vienna5, University of Tübingen6, University of Cologne7, Leibniz Association8, University of Freiburg9, Lund University10, Technische Universität Darmstadt11, University of Göttingen12, Helmholtz Centre for Environmental Research - UFZ13, University of Kiel14, University of Potsdam15, University of Münster16, University of Ulm17, University of Würzburg18, Max Planck Society19, Free University of Berlin20, Xavier University21, University of Salzburg22, Smithsonian Tropical Research Institute23, Karlsruhe Institute of Technology24, University of Giessen25
TL;DR: It is demonstrated that primary producers, herbivorous insects and microbial decomposers seem to be particularly important drivers of ecosystem functioning, as shown by the strong and frequent positive associations of their richness or abundance with multiple ecosystem services.
Abstract: Many experiments have shown that loss of biodiversity reduces the capacity of ecosystems to provide the multiple services on which humans depend. However, experiments necessarily simplify the complexity of natural ecosystems and will normally control for other important drivers of ecosystem functioning, such as the environment or land use. In addition, existing studies typically focus on the diversity of single trophic groups, neglecting the fact that biodiversity loss occurs across many taxa and that the functional effects of any trophic group may depend on the abundance and diversity of others. Here we report analysis of the relationships between the species richness and abundance of nine trophic groups, including 4,600 above- and below-ground taxa, and 14 ecosystem services and functions and with their simultaneous provision (or multifunctionality) in 150 grasslands. We show that high species richness in multiple trophic groups (multitrophic richness) had stronger positive effects on ecosystem services than richness in any individual trophic group; this includes plant species richness, the most widely used measure of biodiversity. On average, three trophic groups influenced each ecosystem service, with each trophic group influencing at least one service. Multitrophic richness was particularly beneficial for 'regulating' and 'cultural' services, and for multifunctionality, whereas a change in the total abundance of species or biomass in multiple trophic groups (the multitrophic abundance) positively affected supporting services. Multitrophic richness and abundance drove ecosystem functioning as strongly as abiotic conditions and land-use intensity, extending previous experimental results to real-world ecosystems. Primary producers, herbivorous insects and microbial decomposers seem to be particularly important drivers of ecosystem functioning, as shown by the strong and frequent positive associations of their richness or abundance with multiple ecosystem services. Our results show that multitrophic richness and abundance support ecosystem functioning, and demonstrate that a focus on single groups has led to researchers to greatly underestimate the functional importance of biodiversity.
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University of Würzburg1, University of Texas at El Paso2, University of Pennsylvania3, Pohang University of Science and Technology4, University of Manchester5, University of Missouri6, University of Sydney7, Maastricht University8, University of Toyama9, Heriot-Watt University10, University of Tokyo11, University of Pisa12, University of Otago13, Tsinghua University14, Wake Forest Institute for Regenerative Medicine15, Utrecht University16
TL;DR: A refined working definition of Biofabrication is proposed, including Bioprinting and Bioassembly as complementary strategies within Biofabrica, with special focus on its relation to and application for Tissue Engineering and Regenerative Medicine.
Abstract: Biofabrication is an evolving research field that has recently received significant attention. In particular, the adoption of Biofabrication concepts within the field of Tissue Engineering and Regenerative Medicine has grown tremendously, and has been accompanied by a growing inconsistency in terminology. This article aims at clarifying the position of Biofabrication as a research field with a special focus on its relation to and application for Tissue Engineering and Regenerative Medicine. Within this context, we propose a refined working definition of Biofabrication, including Bioprinting and Bioassembly as complementary strategies within Biofabrication.
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Brigham and Women's Hospital1, Memorial Hermann Texas Medical Center2, University of Cologne3, University of Chicago4, Duke University5, University of California, Davis6, Henry Ford Hospital7, Stanford University8, Fred Hutchinson Cancer Research Center9, University of Würzburg10, University of Strasbourg11, Katholieke Universiteit Leuven12, Rambam Health Care Campus13, University of Alabama at Birmingham14, Masaryk University15, Sheba Medical Center16, Universidade Federal de Minas Gerais17, Charité18, University of Minnesota19, Khon Kaen University20, Prince of Songkla University21, American University of Beirut22, Center for Global Development23
TL;DR: Isavuconazole showed activity against mucormycosis with efficacy similar to amphotericin B, and can be used for treatment of mucormYcosis and is well tolerated.
Abstract: Summary Background Mucormycosis is an uncommon invasive fungal disease with high mortality and few treatment options. Isavuconazole is a triazole active in vitro and in animal models against moulds of the order Mucorales. We assessed the efficacy and safety of isavuconazole for treatment of mucormycosis and compared its efficacy with amphotericin B in a matched case-control analysis. Methods In a single-arm open-label trial (VITAL study), adult patients (≥18 years) with invasive fungal disease caused by rare fungi, including mucormycosis, were recruited from 34 centres worldwide. Patients were given isavuconazole 200 mg (as its intravenous or oral water-soluble prodrug, isavuconazonium sulfate) three times daily for six doses, followed by 200 mg/day until invasive fungal disease resolution, failure, or for 180 days or more. The primary endpoint was independent data review committee-determined overall response—ie, complete or partial response (treatment success) or stable or progressive disease (treatment failure)—according to prespecified criteria. Mucormycosis cases treated with isavuconazole as primary treatment were matched with controls from the FungiScope Registry, recruited from 17 centres worldwide, who received primary amphotericin B-based treatment, and were analysed for day-42 all-cause mortality. VITAL is registered with ClinicalTrials.gov, number NCT00634049. FungiScope is registered with ClinicalTrials.gov, number NCT01731353. Findings Within the VITAL study, from April 22, 2008, to June 21, 2013, 37 patients with mucormycosis received isavuconazole for a median of 84 days (IQR 19–179, range 2–882). By day 42, four patients (11%) had a partial response, 16 (43%) had stable invasive fungal disease, one (3%) had invasive fungal disease progression, three (8%) had missing assessments, and 13 (35%) had died. 35 patients (95%) had adverse events (28 [76%] serious). Day-42 crude all-cause mortality in seven (33%) of 21 primary-treatment isavuconazole cases was similar to 13 (39%) of 33 amphotericin B-treated matched controls (weighted all-cause mortality: 33% vs 41%; p=0·595). Interpretation Isavuconazole showed activity against mucormycosis with efficacy similar to amphotericin B. Isavuconazole can be used for treatment of mucormycosis and is well tolerated. Funding Astellas Pharma Global Development, Basilea Pharmaceutica International.
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Wouter van Rheenen1, Aleksey Shatunov2, Annelot M. Dekker1, Russell L. McLaughlin3 +184 more•Institutions (54)
TL;DR: Evidence of ALS being a complex genetic trait with a polygenic architecture is established and the SNP-based heritability is estimated at 8.5%, with a distinct and important role for low-frequency variants (frequency 1–10%).
Abstract: To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.
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TL;DR: In this article, the authors show how a new quantum spin Hall (QSH) paradigm based on substrate-supported atomic monolayers of a high-Z element can be achieved by making use of a new QSH paradigm.
Abstract: Quantum spin Hall (QSH) materials promise revolutionary device applications based on dissipationless propagation of spin currents. They are two-dimensional (2D) representatives of the family of topological insulators, which exhibit conduction channels at their edges inherently protected against scattering. Initially predicted for graphene, and eventually realized in HgTe quantum wells, in the QSH systems realized so far, the decisive bottleneck preventing applications is the small bulk energy gap of less than 30 meV, requiring cryogenic operation temperatures in order to suppress detrimental bulk contributions to the edge conductance. Room-temperature functionalities, however, require much larger gaps. Here we show how this can be achieved by making use of a new QSH paradigm based on substrate-supported atomic monolayers of a high-Z element. Experimentally, the material is synthesized as honeycomb lattice of bismuth atoms, forming "bismuthene", on top of the wide-gap substrate SiC(0001). Consistent with the theoretical expectations, the spectroscopic signatures in experiment display a huge gap of ~0.8 eV in bismuthene, as well as conductive edge states. The analysis of the layer-substrate orbitals arrives at a QSH phase, whose topological gap - as a hallmark mechanism - is driven directly by the atomic spin-orbit coupling (SOC). Our results demonstrate how strained artificial lattices of heavy atoms, in contact with an insulating substrate, can be utilized to evoke a novel topological wide-gap scenario, where the chemical potential is located well within the global system gap, ensuring pure edge state conductance. We anticipate future experiments on topological signatures, such as transport measurements that probe the QSH effect via quantized universal conductance, notably at room temperature.
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University of Texas MD Anderson Cancer Center1, Massachusetts Institute of Technology2, Harvard University3, Baylor College of Medicine4, University of North Carolina at Chapel Hill5, Johns Hopkins University6, University of Michigan7, University of São Paulo8, Institute for Systems Biology9, Memorial Sloan Kettering Cancer Center10, University of Lausanne11, Translational Genomics Research Institute12, University of California, Santa Cruz13, Brigham and Women's Hospital14, University Health Network15, BC Cancer Agency16, Brown University17, Ludwig Maximilian University of Munich18, Royal North Shore Hospital19, Kolling Institute of Medical Research20, National Institutes of Health21, Arizona State University22, University of Würzburg23
TL;DR: Integrated subtype analysis identified three ACC subtypes with distinct clinical outcome and molecular alterations which could be captured by a 68-CpG probe DNA-methylation signature, proposing a strategy for clinical stratification of patients based on molecular markers.
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University of Duisburg-Essen1, University of Zurich2, University of Erlangen-Nuremberg3, University of Tübingen4, Hannover Medical School5, Heidelberg University6, Otto-von-Guericke University Magdeburg7, University Hospital Heidelberg8, University of Münster9, RWTH Aachen University10, University of Würzburg11, Technische Universität München12
TL;DR: Anti-PD-1 antibodies can induce a plethora of irAEs and the knowledge of them will allow prompt diagnosis and improve the management resulting in decreased morbidity.
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TL;DR: In this article, the performance of the ATLAS muon identification and reconstruction using the first LHC dataset recorded at s√ = 13 TeV in 2015 was evaluated using the Monte Carlo simulations.
Abstract: This article documents the performance of the ATLAS muon identification and reconstruction using the first LHC dataset recorded at s√ = 13 TeV in 2015. Using a large sample of J/ψ→μμ and Z→μμ decays from 3.2 fb−1 of pp collision data, measurements of the reconstruction efficiency, as well as of the momentum scale and resolution, are presented and compared to Monte Carlo simulations. The reconstruction efficiency is measured to be close to 99% over most of the covered phase space (|η| 2.2, the pT resolution for muons from Z→μμ decays is 2.9% while the precision of the momentum scale for low-pT muons from J/ψ→μμ decays is about 0.2%.
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TL;DR: In this paper, the MAGIC-I camera and its trigger system were replaced with a new one for low and medium zenith angles to assess the key performance parameters of MAGIC stereo system for point-like sources with Crab Nebula-like spectrum.
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University of Göttingen1, University of British Columbia2, Stanford University3, CGIAR4, University of Wisconsin-Madison5, University of Maryland, College Park6, Swedish University of Agricultural Sciences7, University of California, Berkeley8, University of Würzburg9, Centro Agronómico Tropical de Investigación y Enseñanza10, National Ecological Observatory Network11, Virginia Tech12, Cornell University13, University of California, Davis14, Institut national de la recherche agronomique15, Commonwealth Scientific and Industrial Research Organisation16, Lincoln University (New Zealand)17, International Food Policy Research Institute18
TL;DR: In this article, the authors identify five hypotheses for when and why natural habitat can fail to support biological pest control, and illustrate each with case studies from the literature: (1) pest populations have no effective natural enemies in the region, (2) natural habitat is a greater source of pests than natural enemies, (3) crops provide more resources for natural enemies than does natural habitat, (4) natural habitats is insufficient in amount, proximity, composition, or configuration to provide large enough enemy populations needed for pest control and (5) agricultural practices counteract enemy establishment and bioc
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University of Utah1, University of Michigan2, Icahn School of Medicine at Mount Sinai3, Ohio State University4, Mayo Clinic5, University of Hamburg6, Chulalongkorn University7, University of Regensburg8, Dresden University of Technology9, Emory University10, Columbia University Medical Center11, University of Würzburg12, Harvard University13, Vanderbilt University Medical Center14, University of Pennsylvania15
TL;DR: This paper developed guidelines through international expert consensus opinion to standardize the diagnosis and clinical staging of acute graft-versus-host disease (GVHD) for use in a large international GVHD research consortium.
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TL;DR: The data suggest that the intra‐articular injection of ASCs is a safe therapeutic alternative to treat severe knee OA patients and a placebo‐controlled double‐blind phase IIb study is being initiated to assess clinical and structural efficacy.
Abstract: Osteoarthritis (OA) is the most widespread musculoskeletal disorder in adults. It leads to cartilage damage associated with subchondral bone changes and synovial inflammation, causing pain and disability. The present study aimed at evaluating the safety of a dose-escalation protocol of intra-articular injected adipose-derived stromal cells (ASCs) in patients with knee OA, as well as clinical efficacy as secondary endpoint. A bicentric, uncontrolled, open phase I clinical trial was conducted in France and Germany with regulatory agency approval for ASC expansion procedure in both countries. From April 2012 to December 2013, 18 consecutive patients with symptomatic and severe knee OA were treated with a single intra-articular injection of autologous ASCs. The study design consisted of three consecutive cohorts (six patients each) with dose escalation: low dose (2 × 106 cells), medium dose (10 × 106), and high dose (50 × 106). The primary outcome parameter was safety evaluated by recording adverse events throughout the trial, and secondary parameters were pain and function subscales of the Western Ontario and McMaster Universities Arthritis Index. After 6 months of follow-up, the procedure was found to be safe, and no serious adverse events were reported. Four patients experienced transient knee joint pain and swelling after local injection. Interestingly, patients treated with low-dose ASCs experienced significant improvements in pain levels and function compared with baseline. Our data suggest that the intra-articular injection of ASCs is a safe therapeutic alternative to treat severe knee OA patients. A placebo-controlled double-blind phase IIb study is being initiated to assess clinical and structural efficacy.
Significance
Although this phase I study included a limited number of patients without a placebo arm, it showed that local injection of autologous adipose-derived stem cells was safe and well tolerated in patients with knee osteoarthritis. This study also provides encouraging preliminary evidence of efficacy. Larger and controlled long-term studies are now mandatory to confirm whether this new strategy of cell therapy can improve pain and induce structural benefit in osteoarthritis.
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TL;DR: In this article, the authors review the significant advancements in theoretic modeling of the underlying physical principles, coupled with experimental validation using a variety of technical devices and designs that allow well-controlled fiber formation using optimized material and operating parameters.