Showing papers by "University of Duisburg-Essen published in 2015"
Johns Hopkins University1, City of Hope National Medical Center2, Netherlands Cancer Institute3, University of Duisburg-Essen4, Russian Academy5, University of South Florida6, University of Chicago7, Duke University8, Harvard University9, Charles University in Prague10, Bristol-Myers Squibb11, Sarah Cannon Research Institute12, Erasmus University Rotterdam13, Autonomous University of Madrid14
TL;DR: Among patients with advanced, previously treated squamous-cell NSCLC, overall survival, response rate, and progression-free survival were significantly better with nivolumab than with docetaxel, regardless of PD-L1 expression level.
Abstract: BackgroundPatients with advanced squamous-cell non–small-cell lung cancer (NSCLC) who have disease progression during or after first-line chemotherapy have limited treatment options. This randomized, open-label, international, phase 3 study evaluated the efficacy and safety of nivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint–inhibitor antibody, as compared with docetaxel in this patient population. MethodsWe randomly assigned 272 patients to receive nivolumab, at a dose of 3 mg per kilogram of body weight every 2 weeks, or docetaxel, at a dose of 75 mg per square meter of body-surface area every 3 weeks. The primary end point was overall survival. ResultsThe median overall survival was 9.2 months (95% confidence interval [CI], 7.3 to 13.3) with nivolumab versus 6.0 months (95% CI, 5.1 to 7.3) with docetaxel. The risk of death was 41% lower with nivolumab than with docetaxel (hazard ratio, 0.59; 95% CI, 0.44 to 0.79; P<0.001). At 1 year, the overall survival rate was 42% (95% CI, 3...
6,869 citations
Memorial Sloan Kettering Cancer Center1, Institut Gustave Roussy2, Harvard University3, Roswell Park Cancer Institute4, Johns Hopkins University5, Stanford University6, University of Washington7, Vanderbilt University8, Fox Chase Cancer Center9, Macquarie University10, Aarhus University11, University of Helsinki12, The Royal Marsden NHS Foundation Trust13, University of Duisburg-Essen14, Niigata University15, Swansea University16, University of British Columbia17, Bristol-Myers Squibb18, University of Texas MD Anderson Cancer Center19
TL;DR: Overall survival was longer and fewer grade 3 or 4 adverse events occurred with nivolumab than with everolimus among patients with previously treated advanced renal-cell carcinoma.
Abstract: BackgroundNivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, was associated with encouraging overall survival in uncontrolled studies involving previously treated patients with advanced renal-cell carcinoma. This randomized, open-label, phase 3 study compared nivolumab with everolimus in patients with renal-cell carcinoma who had received previous treatment. MethodsA total of 821 patients with advanced clear-cell renal-cell carcinoma for which they had received previous treatment with one or two regimens of antiangiogenic therapy were randomly assigned (in a 1:1 ratio) to receive 3 mg of nivolumab per kilogram of body weight intravenously every 2 weeks or a 10-mg everolimus tablet orally once daily. The primary end point was overall survival. The secondary end points included the objective response rate and safety. ResultsThe median overall survival was 25.0 months (95% confidence interval [CI], 21.8 to not estimable) with nivolumab and 19.6 months (95% CI, 17.6 to 23.1) with everolimus. The haz...
4,643 citations
University of California, Los Angeles1, University of Calgary2, University of Duisburg-Essen3, University at Buffalo4, University of Toronto5, Stanford University6, University of Missouri–Kansas City7, Heidelberg University8, University of Kiel9, University of Pittsburgh10, University of Bern11, Emory University12, University of Tennessee13, Rush University Medical Center14, Goethe University Frankfurt15
TL;DR: In patients receiving intravenous t-PA for acute ischemic stroke, thrombectomy with the use of a stent retriever within 6 hours after onset improved functional outcomes at 90 days.
Abstract: BACKGROUND Among patients with acute ischemic stroke due to occlusions in the proximal anterior intracranial circulation, less than 40% regain functional independence when treated with intravenous tissue plasminogen activator (t-PA) alone. Thrombectomy with the use of a stent retriever, in addition to intravenous t-PA, increases reperfusion rates and may improve long-term functional outcome. METHODS We randomly assigned eligible patients with stroke who were receiving or had received intravenous t-PA to continue with t-PA alone (control group) or to undergo endovascular thrombectomy with the use of a stent retriever within 6 hours after symptom onset (intervention group). Patients had confirmed occlusions in the proximal anterior intracranial circulation and an absence of large ischemic-core lesions. The primary outcome was the severity of global disability at 90 days, as assessed by means of the modified Rankin scale (with scores ranging from 0 [no symptoms] to 6 [death]). RESULTS The study was stopped early because of efficacy. At 39 centers, 196 patients underwent randomization (98 patients in each group). In the intervention group, the median time from qualifying imaging to groin puncture was 57 minutes, and the rate of substantial reperfusion at the end of the procedure was 88%. Thrombectomy with the stent retriever plus intravenous t-PA reduced disability at 90 days over the entire range of scores on the modified Rankin scale (P<0.001). The rate of functional independence (modified Rankin scale score, 0 to 2) was higher in the intervention group than in the control group (60% vs. 35%, P<0.001). There were no significant between-group differences in 90-day mortality (9% vs. 12%, P = 0.50) or symptomatic intracranial hemorrhage (0% vs. 3%, P = 0.12). CONCLUSIONS In patients receiving intravenous t-PA for acute ischemic stroke due to occlusions in the proximal anterior intracranial circulation, thrombectomy with a stent retriever within 6 hours after onset improved functional outcomes at 90 days. (Funded by Covidien; SWIFT PRIME ClinicalTrials.gov number, NCT01657461.)
4,101 citations
University of Helsinki1, Semmelweis University2, Hungarian Academy of Sciences3, University of Szeged4, University of Palermo5, Institute of Molecular Pathology and Immunology of the University of Porto6, University of Porto7, Autonomous University of Barcelona8, Instituto de Biologia Molecular e Celular9, Ikerbasque10, Harvard University11, University of Duisburg-Essen12, Salk Institute for Biological Studies13, Paracelsus Private Medical University of Salzburg14, University of Colorado Denver15, Bilkent University16, Middle East Technical University17, Statens Serum Institut18, University of Southern Denmark19, Ghent University Hospital20, Oslo University Hospital21, University of Belgrade22, University of Ljubljana23, University of Mainz24, Finnish Red Cross25, University of Gothenburg26, Latvian Biomedical Research and Study centre27, University of Applied Sciences and Arts Northwestern Switzerland FHNW28, University of Valencia29, Centro Nacional de Investigaciones Cardiovasculares30, University of Freiburg31, Utrecht University32, Trinity College, Dublin33, Catalan Institution for Research and Advanced Studies34, University of Barcelona35, International University Of Catalonia36, Aarhus University Hospital37
TL;DR: A comprehensive overview of the current understanding of the physiological roles of EVs is provided, drawing on the unique EV expertise of academia-based scientists, clinicians and industry based in 27 European countries, the United States and Australia.
Abstract: In the past decade, extracellular vesicles (EVs) have been recognized as potent vehicles of intercellular communication, both in prokaryotes and eukaryotes. This is due to their capacity to transfer proteins, lipids and nucleic acids, thereby influencing various physiological and pathological functions of both recipient and parent cells. While intensive investigation has targeted the role of EVs in different pathological processes, for example, in cancer and autoimmune diseases, the EV-mediated maintenance of homeostasis and the regulation of physiological functions have remained less explored. Here, we provide a comprehensive overview of the current understanding of the physiological roles of EVs, which has been written by crowd-sourcing, drawing on the unique EV expertise of academia-based scientists, clinicians and industry based in 27 European countries, the United States and Australia. This review is intended to be of relevance to both researchers already working on EV biology and to newcomers who will encounter this universal cell biological system. Therefore, here we address the molecular contents and functions of EVs in various tissues and body fluids from cell systems to organs. We also review the physiological mechanisms of EVs in bacteria, lower eukaryotes and plants to highlight the functional uniformity of this emerging communication system.
3,690 citations
TL;DR: Dabrafenib plus trametinib, as compared with vemurafenib monotherapy, significantly improved overall survival in previously untreated patients with metastatic melanoma with BRAF V600E or V600K mutations, without increased overall toxicity.
Abstract: Background The BRAF inhibitors vemurafenib and dabrafenib have shown efficacy as monotherapies in patients with previously untreated metastatic melanoma with BRAF V600E or V600K mutations. Combining dabrafenib and the MEK inhibitor trametinib, as compared with dabrafenib alone, enhanced antitumor activity in this population of patients. Methods In this open-label, phase 3 trial, we randomly assigned 704 patients with metastatic melanoma with a BRAF V600 mutation to receive either a combination of dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) or vemurafenib (960 mg twice daily) orally as first-line therapy. The primary end point was overall survival. Results At the preplanned interim overall survival analysis, which was performed after 77% of the total number of expected events occurred, the overall survival rate at 12 months was 72% (95% confidence interval [CI], 67 to 77) in the combination-therapy group and 65% (95% CI, 59 to 70) in the vemurafenib group (hazard ratio for death in the combination-therapy group, 0.69; 95% CI, 0.53 to 0.89; P = 0.005). The prespecified interim stopping boundary was crossed, and the study was stopped for efficacy in July 2014. Median progression-free survival was 11.4 months in the combinationtherapy group and 7.3 months in the vemurafenib group (hazard ratio, 0.56; 95% CI, 0.46 to 0.69; P<0.001). The objective response rate was 64% in the combinationtherapy group and 51% in the vemurafenib group (P<0.001). Rates of severe adverse events and study-drug discontinuations were similar in the two groups. Cutaneous squamous-cell carcinoma and keratoacanthoma occurred in 1% of patients in the combination-therapy group and 18% of those in the vemurafenib group. Conclusions Dabrafenib plus trametinib, as compared with vemurafenib monotherapy, significantly improved overall survival in previously untreated patients with metastatic melanoma with BRAF V600E or V600K mutations, without increased overall toxicity. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01597908.)
2,144 citations
TL;DR: Investigating the roles of tumor-specific neoantigens and alterations in the tumor microenvironment in the response to ipilimumab found no recurrent neoantigen peptide sequences predicted responder patient populations, suggesting detailed integrated molecular characterization of large patient cohorts may be needed to identify robust determinants of response and resistance to immune checkpoint inhibitors.
Abstract: Monoclonal antibodies directed against cytotoxic T lymphocyte–associated antigen-4 (CTLA-4), such as ipilimumab, yield considerable clinical benefit for patients with metastatic melanoma by inhibiting immune checkpoint activity, but clinical predictors of response to these therapies remain incompletely characterized. To investigate the roles of tumor-specific neoantigens and alterations in the tumor microenvironment in the response to ipilimumab, we analyzed whole exomes from pretreatment melanoma tumor biopsies and matching germline tissue samples from 110 patients. For 40 of these patients, we also obtained and analyzed transcriptome data from the pretreatment tumor samples. Overall mutational load, neoantigen load, and expression of cytolytic markers in the immune microenvironment were significantly associated with clinical benefit. However, no recurrent neoantigen peptide sequences predicted responder patient populations. Thus, detailed integrated molecular characterization of large patient cohorts may be needed to identify robust determinants of response and resistance to immune checkpoint inhibitors.
2,065 citations
TL;DR: The three-part survey paper aims to give a comprehensive review of real-time fault diagnosis and fault-tolerant control, with particular attention on the results reported in the last decade.
Abstract: With the continuous increase in complexity and expense of industrial systems, there is less tolerance for performance degradation, productivity decrease, and safety hazards, which greatly necessitates to detect and identify any kinds of potential abnormalities and faults as early as possible and implement real-time fault-tolerant operation for minimizing performance degradation and avoiding dangerous situations. During the last four decades, fruitful results have been reported about fault diagnosis and fault-tolerant control methods and their applications in a variety of engineering systems. The three-part survey paper aims to give a comprehensive review of real-time fault diagnosis and fault-tolerant control, with particular attention on the results reported in the last decade. In this paper, fault diagnosis approaches and their applications are comprehensively reviewed from model- and signal-based perspectives, respectively.
2,026 citations
TL;DR: A plateau in the survival curve was observed, beginning at approximately 3 years, which was independent of prior therapy or ipilimumab dose, and added to the evidence supporting the durability of long-term survival in ipILimumab-treated patients with advanced melanoma.
Abstract: Purpose To provide a more precise estimate of long-term survival observed for ipilimumab-treated patients with advanced melanoma, we performed a pooled analysis of overall survival (OS) data from multiple studies. Methods The primary analysis pooled OS data for 1,861 patients from 10 prospective and two retrospective studies of ipilimumab, including two phase III trials. Patients were previously treated (n = 1,257) or treatment naive (n = 604), and the majority of patients received ipilimumab 3 mg/kg (n = 965) or 10 mg/kg (n = 706). We also conducted a secondary analysis of OS data (n = 4,846) with an additional 2,985 patients from an expanded access program. OS rates were estimated using the Kaplan-Meier method. Results Among 1,861 patients, median OS was 11.4 months (95% CI, 10.7 to 12.1 months), which included 254 patients with at least 3 years of survival follow-up. The survival curve began to plateau around year 3, with follow-up of up to 10 years. Three-year survival rates were 22%, 26%, and 20% for...
1,798 citations
University of Zurich1, Hannover Medical School2, University of California, Davis3, Heidelberg University4, Ludwig Maximilian University of Munich5, Charité6, University of Kentucky7, University of Cologne8, Saarland University9, University of Duisburg-Essen10, University of Göttingen11, University of Hamburg12, University of Ulm13, Technische Universität München14, Otto-von-Guericke University Magdeburg15, John Radcliffe Hospital16, Winterthur Museum, Garden and Library17, University of Turku18, Gdańsk Medical University19, University of Warmia and Mazury in Olsztyn20, Medical University of Warsaw21, University of Cambridge22, University of Basel23, Catholic University of the Sacred Heart24, Innsbruck Medical University25, University of Greifswald26, Leiden University27, University of Glasgow28
TL;DR: Patients with takotsubo cardiomyopathy had a higher prevalence of neurologic or psychiatric disorders than did those with an acute coronary syndrome and physical triggers, acute neurologics or psychiatric diseases, high troponin levels, and a low ejection fraction on admission were independent predictors for in-hospital complications.
Abstract: BackgroundThe natural history, management, and outcome of takotsubo (stress) cardiomyopathy are incompletely understood. MethodsThe International Takotsubo Registry, a consortium of 26 centers in Europe and the United States, was established to investigate clinical features, prognostic predictors, and outcome of takotsubo cardiomyopathy. Patients were compared with age- and sex-matched patients who had an acute coronary syndrome. ResultsOf 1750 patients with takotsubo cardiomyopathy, 89.8% were women (mean age, 66.8 years). Emotional triggers were not as common as physical triggers (27.7% vs. 36.0%), and 28.5% of patients had no evident trigger. Among patients with takotsubo cardiomyopathy, as compared with an acute coronary syndrome, rates of neurologic or psychiatric disorders were higher (55.8% vs. 25.7%) and the mean left ventricular ejection fraction was markedly lower (40.7±11.2% vs. 51.5±12.3%) (P<0.001 for both comparisons). Rates of severe in-hospital complications including shock and death were ...
1,721 citations
Memorial Sloan Kettering Cancer Center1, Vanderbilt University Medical Center2, University of Texas MD Anderson Cancer Center3, Harvard University4, The Royal Marsden NHS Foundation Trust5, Institut Gustave Roussy6, Autonomous University of Barcelona7, Hoffmann-La Roche8, University of Caen Lower Normandy9, German Cancer Research Center10, Heidelberg University11, Vanderbilt University12, University of Duisburg-Essen13
TL;DR: BRAF V600 appears to be a targetable oncogene in some, but not all, nonmelanoma cancers and preliminary vemurafenib activity was observed in non-small-cell lung cancer and in Erdheim-Chester disease and Langerhans'-cell histiocytosis.
Abstract: BackgroundBRAF V600 mutations occur in various nonmelanoma cancers. We undertook a histology-independent phase 2 “basket” study of vemurafenib in BRAF V600 mutation–positive nonmelanoma cancers. MethodsWe enrolled patients in six prespecified cancer cohorts; patients with all other tumor types were enrolled in a seventh cohort. A total of 122 patients with BRAF V600 mutation–positive cancer were treated, including 27 patients with colorectal cancer who received vemurafenib and cetuximab. The primary end point was the response rate; secondary end points included progression-free and overall survival. ResultsIn the cohort with non–small-cell lung cancer, the response rate was 42% (95% confidence interval [CI], 20 to 67) and median progression-free survival was 7.3 months (95% CI, 3.5 to 10.8). In the cohort with Erdheim–Chester disease or Langerhans’-cell histiocytosis, the response rate was 43% (95% CI, 18 to 71); the median treatment duration was 5.9 months (range, 0.6 to 18.6), and no patients had diseas...
1,409 citations
University of California, Los Angeles1, Vanderbilt University2, University of Zurich3, University of Duisburg-Essen4, University of Paris-Sud5, Harvard University6, Sheba Medical Center7, New York University8, University of Colorado Denver9, University of Arizona10, Netherlands Cancer Institute11, Durham University12, Seattle Cancer Care Alliance13, University of Tübingen14, University of Pennsylvania15, Temple University16, University of North Carolina at Chapel Hill17, University of Pittsburgh18, Memorial Sloan Kettering Cancer Center19, Merck & Co.20, University of California, San Francisco21
TL;DR: In this article, the efficacy and safety of two pembrolizumab doses versus investigator-choice chemotherapy in patients with ipilimumab-refractory melanoma were compared.
Abstract: Summary Background Patients with melanoma that progresses on ipilimumab and, if BRAF V600 mutant-positive, a BRAF or MEK inhibitor or both, have few treatment options. We assessed the efficacy and safety of two pembrolizumab doses versus investigator-choice chemotherapy in patients with ipilimumab-refractory melanoma. Methods We carried out a randomised phase 2 trial of patients aged 18 years or older from 73 hospitals, clinics, and academic medical centres in 12 countries who had confirmed progressive disease within 24 weeks after two or more ipilimumab doses and, if BRAF V600 mutant-positive, previous treatment with a BRAF or MEK inhibitor or both. Patients had to have resolution of all ipilimumab-related adverse events to grade 0–1 and prednisone 10 mg/day or less for at least 2 weeks, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and at least one measurable lesion to be eligible. Using a centralised interactive voice response system, we randomly assigned (1:1:1) patients in a block size of six to receive intravenous pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or investigator-choice chemotherapy (paclitaxel plus carboplatin, paclitaxel, carboplatin, dacarbazine, or oral temozolomide). Randomisation was stratified by ECOG performance status, lactate dehydrogenase concentration, and BRAF V600 mutation status. Individual treatment assignment between pembrolizumab and chemotherapy was open label, but investigators and patients were masked to assignment of the dose of pembrolizumab. We present the primary endpoint at the prespecified second interim analysis of progression-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01704287. The study is closed to enrolment but continues to follow up and treat patients. Findings Between Nov 30, 2012, and Nov 13, 2013, we enrolled 540 patients: 180 patients were randomly assigned to receive pembrolizumab 2 mg/kg, 181 to receive pembrolizumab 10 mg/kg, and 179 to receive chemotherapy. Based on 410 progression-free survival events, progression-free survival was improved in patients assigned to pembrolizumab 2 mg/kg (HR 0·57, 95% CI 0·45–0·73; p Interpretation These findings establish pembrolizumab as a new standard of care for the treatment of ipilimumab-refractory melanoma. Funding Merck Sharp & Dohme.
National Taiwan University1, Guangdong General Hospital2, University of Duisburg-Essen3, University of Mainz4, The Royal Marsden NHS Foundation Trust5, Wakayama Medical University6, Tongji University7, Central South University8, Queensland University of Technology9, Shanghai Jiao Tong University10, Kunming Medical University11, Prince of Songkla University12, Konkuk University13, Taipei Veterans General Hospital14, Russian Academy15, McGill University16, First Pavlov State Medical University of St. Peterburg17, The Chinese University of Hong Kong18, Royal Prince Alfred Hospital19, National Cheng Kung University20, Chungbuk National University21, Boehringer Ingelheim22, Harvard University23
TL;DR: In this article, the effect of Afatinib on overall survival of patients with EGFR mutation-positive lung adenocarcinoma through an analysis of data from two open-label, randomised, phase 3 trials was evaluated.
Abstract: Summary Background We aimed to assess the effect of afatinib on overall survival of patients with EGFR mutation-positive lung adenocarcinoma through an analysis of data from two open-label, randomised, phase 3 trials. Methods Previously untreated patients with EGFR mutation-positive stage IIIB or IV lung adenocarcinoma were enrolled in LUX-Lung 3 (n=345) and LUX-Lung 6 (n=364). These patients were randomly assigned in a 2:1 ratio to receive afatinib or chemotherapy (pemetrexed-cisplatin [LUX-Lung 3] or gemcitabine-cisplatin [LUX-Lung 6]), stratified by EGFR mutation (exon 19 deletion [del19], Leu858Arg, or other) and ethnic origin (LUX-Lung 3 only). We planned analyses of mature overall survival data in the intention-to-treat population after 209 (LUX-Lung 3) and 237 (LUX-Lung 6) deaths. These ongoing studies are registered with ClinicalTrials.gov, numbers NCT00949650 and NCT01121393. Findings Median follow-up in LUX-Lung 3 was 41 months (IQR 35–44); 213 (62%) of 345 patients had died. Median follow-up in LUX-Lung 6 was 33 months (IQR 31–37); 246 (68%) of 364 patients had died. In LUX-Lung 3, median overall survival was 28·2 months (95% CI 24·6–33·6) in the afatinib group and 28·2 months (20·7–33·2) in the pemetrexed-cisplatin group (HR 0·88, 95% CI 0·66–1·17, p=0·39). In LUX-Lung 6, median overall survival was 23·1 months (95% CI 20·4–27·3) in the afatinib group and 23·5 months (18·0–25·6) in the gemcitabine-cisplatin group (HR 0·93, 95% CI 0·72–1·22, p=0·61). However, in preplanned analyses, overall survival was significantly longer for patients with del19-positive tumours in the afatinib group than in the chemotherapy group in both trials: in LUX-Lung 3, median overall survival was 33·3 months (95% CI 26·8–41·5) in the afatinib group versus 21·1 months (16·3–30·7) in the chemotherapy group (HR 0·54, 95% CI 0·36–0·79, p=0·0015); in LUX-Lung 6, it was 31·4 months (95% CI 24·2–35·3) versus 18·4 months (14·6–25·6), respectively (HR 0·64, 95% CI 0·44–0·94, p=0·023). By contrast, there were no significant differences by treatment group for patients with EGFR Leu858Arg-positive tumours in either trial: in LUX-Lung 3, median overall survival was 27·6 months (19·8–41·7) in the afatinib group versus 40·3 months (24·3–not estimable) in the chemotherapy group (HR 1·30, 95% CI 0·80–2·11, p=0·29); in LUX-Lung 6, it was 19·6 months (95% CI 17·0–22·1) versus 24·3 months (19·0–27·0), respectively (HR 1·22, 95% CI 0·81–1·83, p=0·34). In both trials, the most common afatinib-related grade 3–4 adverse events were rash or acne (37 [16%] of 229 patients in LUX-Lung 3 and 35 [15%] of 239 patients in LUX-Lung 6), diarrhoea (33 [14%] and 13 [5%]), paronychia (26 [11%] in LUX-Lung 3 only), and stomatitis or mucositis (13 [5%] in LUX-Lung 6 only). In LUX-Lung 3, neutropenia (20 [18%] of 111 patients), fatigue (14 [13%]) and leucopenia (nine [8%]) were the most common chemotherapy-related grade 3–4 adverse events, while in LUX-Lung 6, the most common chemotherapy-related grade 3–4 adverse events were neutropenia (30 [27%] of 113 patients), vomiting (22 [19%]), and leucopenia (17 [15%]). Interpretation Although afatinib did not improve overall survival in the whole population of either trial, overall survival was improved with the drug for patients with del19 EGFR mutations. The absence of an effect in patients with Leu858Arg EGFR mutations suggests that EGFR del19-positive disease might be distinct from Leu858Arg-positive disease and that these subgroups should be analysed separately in future trials. Funding Boehringer Ingelheim.
TL;DR: The current manuscript is an update of the original Practical Guide, published in June 2013, and listed 15 topics of concrete clinical scenarios for which practical answers were formulated, based on available evidence.
Abstract: The current manuscript is an update of the original Practical Guide, published in June 2013[Heidbuchel H, Verhamme P, Alings M, Antz M, Hacke W, Oldgren J, et al. European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace 2013;15:625-51; Heidbuchel H, Verhamme P, Alings M, Antz M, Hacke W, Oldgren J, et al. EHRA practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation: executive summary. Eur Heart J 2013;34:2094-106]. Non-vitamin K antagonist oral anticoagulants (NOACs) are an alternative for vitamin K antagonists (VKAs) to prevent stroke in patients with non-valvular atrial fibrillation (AF). Both physicians and patients have to learn how to use these drugs effectively and safely in clinical practice. Many unresolved questions on how to optimally use these drugs in specific clinical situations remain. The European Heart Rhythm Association set out to coordinate a unified way of informing physicians on the use of the different NOACs. A writing group defined what needs to be considered as 'non-valvular AF' and listed 15 topics of concrete clinical scenarios for which practical answers were formulated, based on available evidence. The 15 topics are (i) practical start-up and follow-up scheme for patients on NOACs; (ii) how to measure the anticoagulant effect of NOACs; (iii) drug-drug interactions and pharmacokinetics of NOACs; (iv) switching between anticoagulant regimens; (v) ensuring adherence of NOAC intake; (vi) how to deal with dosing errors; (vii) patients with chronic kidney disease; (viii) what to do if there is a (suspected) overdose without bleeding, or a clotting test is indicating a risk of bleeding?; (xi) management of bleeding complications; (x) patients undergoing a planned surgical intervention or ablation; (xi) patients undergoing an urgent surgical intervention; (xii) patients with AF and coronary artery disease; (xiii) cardioversion in a NOAC-treated patient; (xiv) patients presenting with acute stroke while on NOACs; and (xv) NOACs vs. VKAs in AF patients with a malignancy. Additional information and downloads of the text and anticoagulation cards in >16 languages can be found on an European Heart Rhythm Association web site (www.NOACforAF.eu).
Paracelsus Private Medical University of Salzburg1, University of Duisburg-Essen2, Semmelweis University3, University of Turin4, Institut Gustave Roussy5, Brown University6, Pontifical Catholic University of Chile7, University of Barcelona8, Trinity College, Dublin9, Istituto Superiore di Sanità10, Ikerbasque11, Pohang University of Science and Technology12, University of Louisville13, Ghent University Hospital14, La Trobe University15, Harvard University16, National University of Singapore17, Maastricht University18, University of Mainz19, University of Cambridge20, Utrecht University21, Agency for Science, Technology and Research22, University of Gothenburg23, University of Valencia24, University of Freiburg25, Aalborg University26, National Research Council27, Paul Ehrlich Institute28, German Red Cross29, University of Oxford30, Karolinska Institutet31
TL;DR: In this paper, the authors summarize recent developments and the current knowledge of extracellular vesicles (EVs) and discuss safety and regulatory requirements that must be considered for pharmaceutical manufacturing and clinical application.
Abstract: Extracellular vesicles (EVs), such as exosomes and microvesicles, are released by different cell types and participate in physiological and pathophysiological processes. EVs mediate intercellular communication as cell-derived extracellular signalling organelles that transmit specific information from their cell of origin to their target cells. As a result of these properties, EVs of defined cell types may serve as novel tools for various therapeutic approaches, including (a) anti-tumour therapy, (b) pathogen vaccination, (c) immune-modulatory and regenerative therapies and (d) drug delivery. The translation of EVs into clinical therapies requires the categorization of EV-based therapeutics in compliance with existing regulatory frameworks. As the classification defines subsequent requirements for manufacturing, quality control and clinical investigation, it is of major importance to define whether EVs are considered the active drug components or primarily serve as drug delivery vehicles. For an effective and particularly safe translation of EV-based therapies into clinical practice, a high level of cooperation between researchers, clinicians and competent authorities is essential. In this position statement, basic and clinical scientists, as members of the International Society for Extracellular Vesicles (ISEV) and of the European Cooperation in Science and Technology (COST) program of the European Union, namely European Network on Microvesicles and Exosomes in Health and Disease (ME-HaD), summarize recent developments and the current knowledge of EV-based therapies. Aspects of safety and regulatory requirements that must be considered for pharmaceutical manufacturing and clinical application are highlighted. Production and quality control processes are discussed. Strategies to promote the therapeutic application of EVs in future clinical studies are addressed.
TL;DR: Investigating the immunogenicity of human epidermal growth factor receptor 2 -positive and triple-negative breast cancers and immunologically relevant genes in the neoadjuvant GeparSixto trial found immunologic factors were highly significant predictors of therapy response in the trial, particularly in patients treated with Cb.
Abstract: Purpose Modulation of immunologic interactions in cancer tissue is a promising therapeutic strategy. To investigate the immunogenicity of human epidermal growth factor receptor 2 (HER2) –positive and triple-negative (TN) breast cancers (BCs), we evaluated tumor-infiltrating lymphocytes (TILs) and immunologically relevant genes in the neoadjuvant GeparSixto trial. Patients and Methods GeparSixto investigated the effect of adding carboplatin (Cb) to an anthracycline-plus-taxane combination (PM) on pathologic complete response (pCR). A total of 580 tumors were evaluated before random assignment for stromal TILs and lymphocyte-predominant BC (LPBC). mRNA expression of immune-activating (CXCL9, CCL5, CD8A, CD80, CXCL13, IGKC, CD21) as well as immunosuppressive factors (IDO1, PD-1, PD-L1, CTLA4, FOXP3) was measured in 481 tumors. Results Increased levels of stromal TILs predicted pCR in univariable (P < .001) and multivariable analyses (P < .001). pCR rate was 59.9% in LPBC and 33.8% for non-LPBC (P < .001). pC...
TL;DR: Adaptive servo-ventilation had no significant effect on the primary end point in patients who had heart failure with reduced ejection fraction and predominantly central sleep apnea, but all-cause and cardiovascular mortality were both increased with this therapy.
Abstract: BACKGROUND Central sleep apnea is associated with poor prognosis and death in patients with heart failure. Adaptive servo-ventilation is a therapy that uses a noninvasive ventilator to treat central sleep apnea by delivering servo-controlled inspiratory pressure support on top of expiratory positive airway pressure. We investigated the effects of adaptive servo-ventilation in patients who had heart failure with reduced ejection fraction and predominantly central sleep apnea. METHODS We randomly assigned 1325 patients with a left ventricular ejection fraction of 45% or less, an apnea–hypopnea index (AHI) of 15 or more events (occurrences of apnea or hypopnea) per hour, and a predominance of central events to receive guideline-based medical treatment with adaptive servo-ventilation or guidelinebased medical treatment alone (control). The primary end point in the time-toevent analysis was the first event of death from any cause, lifesaving cardiovascular intervention (cardiac transplantation, implantation of a ventricular assist device, resuscitation after sudden cardiac arrest, or appropriate lifesaving shock), or unplanned hospitalization for worsening heart failure. RESULTS In the adaptive servo-ventilation group, the mean AHI at 12 months was 6.6 events per hour. The incidence of the primary end point did not differ significantly between the adaptive servo-ventilation group and the control group (54.1% and 50.8%, respectively; hazard ratio, 1.13; 95% confidence interval [CI], 0.97 to 1.31; P = 0.10). All-cause mortality and cardiovascular mortality were significantly higher in the adaptive servo-ventilation group than in the control group (hazard ratio for death from any cause, 1.28; 95% CI, 1.06 to 1.55; P = 0.01; and hazard ratio for cardiovascular death, 1.34; 95% CI, 1.09 to 1.65; P = 0.006). CONCLUSIONS Adaptive servo-ventilation had no significant effect on the primary end point in patients who had heart failure with reduced ejection fraction and predominantly central sleep apnea, but all-cause and cardiovascular mortality were both increased with this therapy. (Funded by ResMed and others; SERVE-HF ClinicalTrials.gov number, NCT00733343.) abstr act
TL;DR: This is the second-part paper of the survey on fault diagnosis and fault-tolerant techniques, where fault diagnosis methods and applications are overviewed, respectively, from the knowledge-based and hybrid/active viewpoints.
Abstract: This is the second-part paper of the survey on fault diagnosis and fault-tolerant techniques, where fault diagnosis methods and applications are overviewed, respectively, from the knowledge-based and hybrid/active viewpoints. With the aid of the first-part survey paper, the second-part review paper completes a whole overview on fault diagnosis techniques and their applications. Comments on the advantages and constraints of various diagnosis techniques, including model-based, signal-based, knowledge-based, and hybrid/active diagnosis techniques, are also given. An overlook on the future development of fault diagnosis is presented.
TL;DR: The present review characterizes the signalTransduction underlying the conditioning phenomena, including their physical and chemical triggers, intracellular signal transduction, and effector mechanisms, notably in the mitochondria, as a highly concerted spatiotemporal program.
Abstract: Reperfusion is mandatory to salvage ischemic myocardium from infarction, but reperfusion per se contributes to injury and ultimate infarct size. Therefore, cardioprotection beyond that by timely reperfusion is needed to reduce infarct size and improve the prognosis of patients with acute myocardial infarction. The conditioning phenomena provide such cardioprotection, insofar as brief episodes of coronary occlusion/reperfusion preceding (ischemic preconditioning) or following (ischemic postconditioning) sustained myocardial ischemia with reperfusion reduce infarct size. Even ischemia/reperfusion in organs remote from the heart provides cardioprotection (remote ischemic conditioning). The present review characterizes the signal transduction underlying the conditioning phenomena, including their physical and chemical triggers, intracellular signal transduction, and effector mechanisms, notably in the mitochondria. Cardioprotective signal transduction appears as a highly concerted spatiotemporal program. Although the translation of ischemic postconditioning and remote ischemic conditioning protocols to patients with acute myocardial infarction has been fairly successful, the pharmacological recruitment of cardioprotective signaling has been largely disappointing to date.
TL;DR: It is indicated that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders.
Abstract: Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from over 60,000 participants from the Psychiatric Genomics Consortium. We developed an analysis framework to rank pathways that requires only summary statistics. We combined this score across disorders to find common pathways across three adult psychiatric disorders: schizophrenia, major depression and bipolar disorder. Histone methylation processes showed the strongest association, and we also found statistically significant evidence for associations with multiple immune and neuronal signaling pathways and with the postsynaptic density. Our study indicates that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders. Our results confirm known mechanisms and suggest several novel insights into the etiology of psychiatric disorders.
TL;DR: Improved neurological impairment and long‐term neuroprotection associated with enhanced angioneurogenesis were noticed in stroke mice receiving EVs from two different bone marrow‐derived MSC lineages, providing clinically relevant evidence warranting rapid proof‐of‐concept studies in stroke patients.
Abstract: Althoughtheinitialconceptsofstemcelltherapyaimedatreplacinglosttissue,morerecentevidence has suggested that stem and progenitor cells alike promote postischemic neurological recovery by secreted factors that restore the injured brain’s capacity to reshape. Specifically, extracellular vesicles (EVs) derived from stem cells such as exosomes have recently been suggested to mediate restorative stem cell effects.In order to define whether EVs indeedimprove postischemic neurologicalimpairmentandbrainremodeling,wesystematicallycomparedtheeffectsofmesenchymalstem cell(MSC)-derivedEVs(MSC-EVs)withMSCsthatwerei.v.deliveredtomiceondays1,3,and5(MSCEVs) or on day 1 (MSCs) after focal cerebral ischemia in C57BL6 mice. For as long as 28 days after stroke, motor coordination deficits, histological brain injury, immune responses in the peripheral bloodandbrain,andcerebralangiogenesisandneurogenesiswereanalyzed.Improvedneurological impairment and long-term neuroprotection associated with enhanced angioneurogenesis were noticed in stroke mice receiving EVs from two different bone marrow-derived MSC lineages. MSC-EV administration closely resembled responses to MSCs and persisted throughout the observation period. Although cerebral immune cell infiltration was not affected by MSC-EVs, postischemic immunosuppression (i.e., B-cell, natural killer cell, and T-cell lymphopenia) was attenuated in the peripheral blood at 6 days after ischemia, providing an appropriate external milieu for successful brain remodeling. Because MSC-EVs have recently been shown to be apparently safe in humans, the present study provides clinically relevant evidence warranting rapid proof-of-concept studies in stroke patients. STEM CELLS TRANSLATIONAL MEDICINE 2015;4:1–13
TL;DR: The potential impact of the corona for NM-microbiome-(human)host interactions and the novel concept of 'nanologicals', i.e., the nanomaterial-specific targeting of molecular machines are introduced.
Abstract: Besides the wide use of engineered nanomaterials (NMs) in technical products, their applications are not only increasing in biotechnology and biomedicine, but also in the environmental field. While the physico-chemical properties and behaviour of NMs can be characterized accurately under idealized conditions, this is no longer the case in complex physiological or natural environments. Herein, proteins and other biomolecules rapidly bind to NMs, forming a protein/biomolecule corona that critically affects the NMs' (patho)biological and technical identities. As the corona impacts the in vitro and/or in vivo NM applications in humans and ecosystems, a mechanistic understanding of its relevance and of the biophysical forces regulating corona formation is mandatory. Based on recent insights, we here critically review and present an updated concept of corona formation and evolution. We comment on how corona signatures may be linked to effects at the nano–bio interface in physiological and environmental systems. In order to comprehensively analyse corona profiles and to mechanistically understand the coronas' biological/ecological impact, we present a tiered multidisciplinary approach. To stimulate progress in this field, we introduce the potential impact of the corona for NM–microbiome–(human)host interactions and the novel concept of ‘nanologicals’, i.e., the nanomaterial-specific targeting of molecular machines. We conclude by discussing the relevant challenges that still need to be resolved in this field.
University College London1, University of Helsinki2, Finnish Institute of Occupational Health3, French Institute of Health and Medical Research4, RMIT University5, Stockholm University6, Karolinska Institutet7, Stockholm County Council8, Federal Institute for Occupational Safety and Health9, Université libre de Bruxelles10, Ghent University11, University of Düsseldorf12, University of Duisburg-Essen13, Mid Sweden University14, Umeå University15, University of Copenhagen16, University of Turku17, University of Skövde18, Turku University Hospital19, Uppsala University20, Queen's University Belfast21, University of Essex22, University of Edinburgh23, University of Bristol24
TL;DR: Employees who work long hours have a higher risk of stroke than those working standard hours; the association with coronary heart disease is weaker; these findings suggest that more attention should be paid to the management of vascular risk factors in individuals whoWork long hours.
TL;DR: Remote ischemic conditioning by repeated brief inflation/deflation of a blood pressure cuff protects against endothelial dysfunction and myocardial injury in percutaneous coronary interventions, coronary artery bypass grafting, and reperfused acuteMyocardial infarction.
MedStar Washington Hospital Center1, Hebron University2, University of Texas Southwestern Medical Center3, University of Padua4, Cleveland Clinic5, Mayo Clinic6, University of Zurich7, Cornell University8, University of Duisburg-Essen9, Harvard University10, Houston Methodist Hospital11, University of Rostock12, Johns Hopkins University School of Medicine13, University of Michigan14, Yale University15
TL;DR: The aim of this work is to provide a common language for future generations to communicate effectively and effectively with one another about the importance of human rights and democracy.
Abstract: Steven A. Goldstein, MD, Co-Chair, Arturo Evangelista, MD, FESC, Co-Chair, Suhny Abbara, MD, Andrew Arai, MD, Federico M. Asch, MD, FASE, Luigi P. Badano, MD, PhD, FESC, Michael A. Bolen, MD, Heidi M. Connolly, MD, Hug Cu ellar-Cal abria, MD, Martin Czerny, MD, Richard B. Devereux, MD, Raimund A. Erbel, MD, FASE, FESC, Rossella Fattori, MD, Eric M. Isselbacher, MD, Joseph M. Lindsay, MD, Marti McCulloch, MBA, RDCS, FASE, Hector I. Michelena, MD, FASE, Christoph A. Nienaber, MD, FESC, Jae K. Oh, MD, FASE, Mauro Pepi, MD, FESC, Allen J. Taylor, MD, Jonathan W. Weinsaft, MD, Jose Luis Zamorano, MD, FESC, FASE, Contributing Editors: Harry Dietz, MD, Kim Eagle, MD, John Elefteriades, MD, Guillaume Jondeau, MD, PhD, FESC, Herv e Rousseau, MD, PhD, and Marc Schepens, MD, Washington, District of Columbia; Barcelona and Madrid, Spain; Dallas and Houston, Texas; Bethesda and Baltimore, Maryland; Padua, Pesaro, and Milan, Italy; Cleveland, Ohio; Rochester, Minnesota; Zurich, Switzerland; New York, New York; Essen and Rostock, Germany; Boston, Massachusetts; Ann Arbor, Michigan; New Haven, Connecticut; Paris and Toulouse, France; and Brugge, Belgium
University of Washington1, University of California, Los Angeles2, Johns Hopkins University3, Patient-Centered Outcomes Research Institute4, Columbia University5, Northwestern University6, University of Minnesota7, University of Texas Southwestern Medical Center8, University of Duisburg-Essen9, Vanderbilt University Medical Center10, Wake Forest University11
TL;DR: An accurate estimate of 10-year CHD risk can be obtained using traditional risk factors and CAC and the MESA risk score can be used to aid clinicians when communicating risk to patients and when determining risk-based treatment strategies.
TL;DR: The reciprocity relation between light absorption and emission is used to explore theoretical and practical performance limits for emerging technologies based on organics and perovskites, and compare them to state-of-the-art systems based on GaAs, c-Si, and CIGS.
Abstract: To compare and improve solar cells, merely knowing their percent efficiencies is insufficient; we need to be able to understand and quantify their different physical mechanisms of loss. The authors use the reciprocity relation between light absorption and emission to explore theoretical and practical performance limits for emerging technologies based on organics and perovskites, and compare them to state-of-the-art systems based on GaAs, c-Si, and CIGS. This study indicates the potential of the newer technologies, and shows the factors that limit present-day performance.
University Medical Center Freiburg1, University of Marburg2, University Hospital of Basel3, Technische Universität München4, University of Duisburg-Essen5, University of Hamburg6, Goethe University Frankfurt7, Charité8, University of Cologne9, University Hospital Bonn10, University of Düsseldorf11, Stanford University12, Sahlgrenska University Hospital13, Radboud University Nijmegen14, Utrecht University15, University of Minnesota16
TL;DR: Ruxolitinib may constitute a promising new treatment option for SR-aGVHD and SR-cGVHD that should be validated in a prospective trial.
Abstract: Despite major improvements in allogeneic hematopoietic cell transplantation over the past decades, corticosteroid-refractory (SR) acute (a) and chronic (c) graft-versus-host disease (GVHD) cause high mortality. Preclinical evidence indicates the potent anti-inflammatory properties of the JAK1/2 inhibitor ruxolitinib. In this retrospective survey, 19 stem cell transplant centers in Europe and the United States reported outcome data from 95 patients who had received ruxolitinib as salvage therapy for SR-GVHD. Patients were classified as having SR-aGVHD (n=54, all grades III or IV) or SR-cGVHD (n=41, all moderate or severe). The median number of previous GVHD-therapies was 3 for both SR-aGVHD (1-7) and SR-cGVHD (1-10). The overall response rate was 81.5% (44/54) in SR-aGVHD including 25 complete responses (46.3%), while for SR-cGVHD the ORR was 85.4% (35/41). Of those patients responding to ruxolitinib, the rate of GVHD-relapse was 6.8% (3/44) and 5.7% (2/35) for SR-aGVHD and SR-cGVHD, respectively. The 6-month-survival was 79% (67.3-90.7%, 95% confidence interval (CI)) and 97.4% (92.3-100%, 95% CI) for SR-aGVHD and SR-cGVHD, respectively. Cytopenia and cytomegalovirus-reactivation were observed during ruxolitinib treatment in both SR-aGVHD (30/54, 55.6% and 18/54, 33.3%) and SR-cGVHD (7/41, 17.1% and 6/41, 14.6%) patients. Ruxolitinib may constitute a promising new treatment option for SR-aGVHD and SR-cGVHD that should be validated in a prospective trial.
TL;DR: Atrazine, propazine, and terbuthylazine are chlorotriazine herbicides that have been frequently used in agriculture and thus are potential drinking water contaminants and are degraded more efficiently by sulfate radicals than by hydroxyl radicals.
Abstract: Atrazine, propazine, and terbuthylazine are chlorotriazine herbicides that have been frequently used in agriculture and thus are potential drinking water contaminants. Hydroxyl radicals produced by advanced oxidation processes can degrade these persistent compounds. These herbicides are also very reactive with sulfate radicals (2.2-3.5 × 10(9) M(-1) s(-1)). However, the dealkylated products of chlorotriazine pesticides are less reactive toward sulfate radicals (e.g., desethyl-desisopropyl-atrazine (DEDIA; 1.5 × 10(8) M(-1) s(-1))). The high reactivity of the herbicides is largely due to the ethyl or isopropyl group. For example, desisopropyl-atrazine (DIA) reacts quickly (k = 2 × 10(9) M(-1) s(-1)), whereas desethyl-atrazine (DEA) reacts more slowly (k = 9.6 × 10(8) M(-1) s(-1)). The tert-butyl group does not have a strong effect on reaction rate, as shown by the similar second order reaction rates between desethyl-terbuthylazine (DET; k = 3.6 × 10(8) M(-1) s(-1)) and DEDIA. Sulfate radicals degrade a significant proportion of atrazine (63%) via dealkylation, in which deethylation significantly dominates over deisopropylation (10:1). Sulfate and hydroxyl radicals react at an equally fast rate with atrazine (k (hydroxyl radical + atrazine) = 3 × 10(9) M(-1) s(-1)). However, sulfate and hydroxyl radicals differ considerably in their reaction rates with humic acids (k (sulfate radical + humic acids) = 6.8 × 10(3) L mgC(-1) s(-1) (mgC = mg carbon); k (hydroxyl radical + humic acids) = 1.4 × 10(4) L mgC(-1) s(-1)). Thus, in the presence of humic acids, atrazine is degraded more efficiently by sulfate radicals than by hydroxyl radicals.
TL;DR: The results show that the improved model is able to select an appropriate FPT and reduce random errors of the stochastic process and performs better in the RUL prediction of rolling element bearings than the original exponential model.
Abstract: The remaining useful life (RUL) prediction of rolling element bearings has attracted substantial attention recently due to its importance for the bearing health management. The exponential model is one of the most widely used methods for RUL prediction of rolling element bearings. However, two shortcomings exist in the exponential model: 1) the first predicting time (FPT) is selected subjectively; and 2) random errors of the stochastic process decrease the prediction accuracy. To deal with these two shortcomings, an improved exponential model is proposed in this paper. In the improved model, an adaptive FPT selection approach is established based on the $3\sigma$ interval, and particle filtering is utilized to reduce random errors of the stochastic process. In order to demonstrate the effectiveness of the improved model, a simulation and four tests of bearing degradation processes are utilized for the RUL prediction. The results show that the improved model is able to select an appropriate FPT and reduce random errors of the stochastic process. Consequently, it performs better in the RUL prediction of rolling element bearings than the original exponential model.
TL;DR: In this article, the authors show how the presence or absence of the Zn promoter dramatically changes not only the activity, but also unexpectedly the reaction mechanism itself, and propose two different sites for methanol synthesis, Zn-promoted and unpromoted.
Abstract: Methanol, an important chemical, fuel additive, and precursor for clean fuels, is produced by hydrogenation of carbon oxides over Cu-based catalysts. Despite the technological maturity of this process, the understanding of this apparently simple reaction is still incomplete with regard to the reaction mechanism and the active sites. Regarding the latter, recent progress has shown that stepped and ZnOx-decorated Cu surfaces are crucial for the performance of industrial catalysts. Herein, we integrate this insight with additional experiments into a full microkinetic description of methanol synthesis. In particular, we show how the presence or absence of the Zn promoter dramatically changes not only the activity, but unexpectedly the reaction mechanism itself. The Janus-faced character of Cu with two different sites for methanol synthesis, Zn-promoted and unpromoted, resolves the long-standing controversy regarding the Cu/Zn synergy and adds methanol synthesis to the few major industrial catalytic processes that are described on an atomic level.