Showing papers by "Heidelberg University published in 2015"
TL;DR: In the Global Burden of Disease Study 2013 (GBD 2013) as discussed by the authors, the authors used the GBD 2010 methods with some refinements to improve accuracy applied to an updated database of vital registration, survey, and census data.
5,792 citations
TL;DR: In the Global Burden of Disease Study 2013 (GBD 2013) as mentioned in this paper, the authors estimated the quantities for acute and chronic diseases and injuries for 188 countries between 1990 and 2013.
4,510 citations
TL;DR: Pythia 8.2 is the second main release after the complete rewrite from Fortran to C++, and now has reached such a maturity that it offers a complete replacement for most applications, notably for LHC physics studies.
4,503 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
Mayo Clinic1, University of Pennsylvania2, Anschutz Medical Campus3, Sir Charles Gairdner Hospital4, Harvard University5, University of Strasbourg6, Tohoku University7, University of Texas Southwestern Medical Center8, Walton Centre9, Heidelberg University10, Universidade Federal de Minas Gerais11, Johns Hopkins University12, Oregon Health & Science University13, University of British Columbia14, University of Oxford15
TL;DR: The International Panel for NMO Diagnosis (IPND) was convened to develop revised diagnostic criteria using systematic literature reviews and electronic surveys to facilitate consensus and achieved consensus on pediatric NMOSD diagnosis and the concepts of monophasicNMOSD and opticospinal MS.
Abstract: Neuromyelitis optica (NMO) is an inflammatory CNS syndrome distinct from multiple sclerosis (MS) that is associated with serum aquaporin-4 immunoglobulin G antibodies (AQP4-IgG). Prior NMO diagnostic criteria required optic nerve and spinal cord involvement but more restricted or more extensive CNS involvement may occur. The International Panel for NMO Diagnosis (IPND) was convened to develop revised diagnostic criteria using systematic literature reviews and electronic surveys to facilitate consensus. The new nomenclature defines the unifying term NMO spectrum disorders (NMOSD), which is stratified further by serologic testing (NMOSD with or without AQP4-IgG). The core clinical characteristics required for patients with NMOSD with AQP4-IgG include clinical syndromes or MRI findings related to optic nerve, spinal cord, area postrema, other brainstem, diencephalic, or cerebral presentations. More stringent clinical criteria, with additional neuroimaging findings, are required for diagnosis of NMOSD without AQP4-IgG or when serologic testing is unavailable. The IPND also proposed validation strategies and achieved consensus on pediatric NMOSD diagnosis and the concepts of monophasic NMOSD and opticospinal MS.
2,945 citations
Shadab Alam1, Franco D. Albareti2, Carlos Allende Prieto3, Carlos Allende Prieto4 +360 more•Institutions (102)
TL;DR: The third generation of the Sloan Digital Sky Survey (SDSS-III) took data from 2008 to 2014 using the original SDSS wide-field imager, the original and an upgraded multi-object fiber-fed optical spectrograph, a new near-infrared high-resolution spectrogram, and a novel optical interferometer.
Abstract: The third generation of the Sloan Digital Sky Survey (SDSS-III) took data from 2008 to 2014 using the original SDSS wide-field imager, the original and an upgraded multi-object fiber-fed optical spectrograph, a new near-infrared high-resolution spectrograph, and a novel optical interferometer. All the data from SDSS-III are now made public. In particular, this paper describes Data Release 11 (DR11) including all data acquired through 2013 July, and Data Release 12 (DR12) adding data acquired through 2014 July (including all data included in previous data releases), marking the end of SDSS-III observing. Relative to our previous public release (DR10), DR12 adds one million new spectra of galaxies and quasars from the Baryon Oscillation Spectroscopic Survey (BOSS) over an additional 3000 sq. deg of sky, more than triples the number of H-band spectra of stars as part of the Apache Point Observatory (APO) Galactic Evolution Experiment (APOGEE), and includes repeated accurate radial velocity measurements of 5500 stars from the Multi-Object APO Radial Velocity Exoplanet Large-area Survey (MARVELS). The APOGEE outputs now include measured abundances of 15 different elements for each star. In total, SDSS-III added 2350 sq. deg of ugriz imaging; 155,520 spectra of 138,099 stars as part of the Sloan Exploration of Galactic Understanding and Evolution 2 (SEGUE-2) survey; 2,497,484 BOSS spectra of 1,372,737 galaxies, 294,512 quasars, and 247,216 stars over 9376 sq. deg; 618,080 APOGEE spectra of 156,593 stars; and 197,040 MARVELS spectra of 5,513 stars. Since its first light in 1998, SDSS has imaged over 1/3 of the Celestial sphere in five bands and obtained over five million astronomical spectra.
2,471 citations
Institute for Health Metrics and Evaluation1, University of Washington2, Iran University of Medical Sciences3, King's College London4, Arabian Gulf University5, University of North Texas6, Auckland University of Technology7, Alaska Native Tribal Health Consortium8, Columbia University9, Wuhan University10, Imperial College London11, University of Alabama at Birmingham12, University at Albany, SUNY13, City University of New York14, University of California, San Francisco15, Griffith University16, Environment Agency17, New York University18, Southern University College19, Emory University20, University of Ottawa21, Kosin University22, University of Toronto23, University of British Columbia24, United Arab Emirates University25, Albert Einstein College of Medicine26, University of São Paulo27, Nova Southeastern University28, University of Sydney29, Heidelberg University30, Case Western Reserve University31, Cancer Treatment Centers of America32, University of Oxford33, George Mason University34, James Cook University35, University of Trieste36, University of Calgary37, Wageningen University and Research Centre38, University of Gothenburg39, University of the Witwatersrand40, Harvard University41, Jackson State University42, University of Arizona43, University of Hong Kong44, Tehran University of Medical Sciences45, University of Western Australia46, Aintree University Hospitals NHS Foundation Trust47, Veterans Health Administration48, University of Colorado Denver49, Royal Children's Hospital50, University of Melbourne51, Australian National University52, University of Marburg53, Charité54, Health Canada55, College of Health Sciences, Bahrain56, Karolinska Institutet57, University of Edinburgh58, Northumbria University59, National Research University – Higher School of Economics60, Queen Mary University of London61, Addis Ababa University62, Northwestern University63, Northeastern University64, Mario Negri Institute for Pharmacological Research65, Arak University of Medical Sciences66, University of Nottingham67, University of Tokyo68, Public Health Foundation of India69, University of Groningen70, University of the Philippines Manila71, University of Bologna72, Kyung Hee University73, Brighton and Sussex Medical School74, University of Bergen75, Stavanger University Hospital76, University of Queensland77, National Centre for Disease Control78, University of Sheffield79, Universidad Autónoma Metropolitana80, University College London81, Genentech82, Universiti Tunku Abdul Rahman83, Norwegian Institute of Public Health84
TL;DR: To estimate mortality, incidence, years lived with disability, years of life lost, and disability-adjusted life-years for 28 cancers in 188 countries by sex from 1990 to 2013, the general methodology of the Global Burden of Disease 2013 study was used.
Abstract: Importance Cancer is among the leading causes of death worldwide. Current estimates of cancer burden in individual countries and regions are necessary to inform local cancer control strategies. Objective To estimate mortality, incidence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs) for 28 cancers in 188 countries by sex from 1990 to 2013. Evidence Review The general methodology of the Global Burden of Disease (GBD) 2013 study was used. Cancer registries were the source for cancer incidence data as well as mortality incidence (MI) ratios. Sources for cause of death data include vital registration system data, verbal autopsy studies, and other sources. The MI ratios were used to transform incidence data to mortality estimates and cause of death estimates to incidence estimates. Cancer prevalence was estimated using MI ratios as surrogates for survival data; YLDs were calculated by multiplying prevalence estimates with disability weights, which were derived from population-based surveys; YLLs were computed by multiplying the number of estimated cancer deaths at each age with a reference life expectancy; and DALYs were calculated as the sum of YLDs and YLLs. Findings In 2013 there were 14.9 million incident cancer cases, 8.2 million deaths, and 196.3 million DALYs. Prostate cancer was the leading cause for cancer incidence (1.4 million) for men and breast cancer for women (1.8 million). Tracheal, bronchus, and lung (TBL) cancer was the leading cause for cancer death in men and women, with 1.6 million deaths. For men, TBL cancer was the leading cause of DALYs (24.9 million). For women, breast cancer was the leading cause of DALYs (13.1 million). Age-standardized incidence rates (ASIRs) per 100 000 and age-standardized death rates (ASDRs) per 100 000 for both sexes in 2013 were higher in developing vs developed countries for stomach cancer (ASIR, 17 vs 14; ASDR, 15 vs 11), liver cancer (ASIR, 15 vs 7; ASDR, 16 vs 7), esophageal cancer (ASIR, 9 vs 4; ASDR, 9 vs 4), cervical cancer (ASIR, 8 vs 5; ASDR, 4 vs 2), lip and oral cavity cancer (ASIR, 7 vs 6; ASDR, 2 vs 2), and nasopharyngeal cancer (ASIR, 1.5 vs 0.4; ASDR, 1.2 vs 0.3). Between 1990 and 2013, ASIRs for all cancers combined (except nonmelanoma skin cancer and Kaposi sarcoma) increased by more than 10% in 113 countries and decreased by more than 10% in 12 of 188 countries. Conclusions and Relevance Cancer poses a major threat to public health worldwide, and incidence rates have increased in most countries since 1990. The trend is a particular threat to developing nations with health systems that are ill-equipped to deal with complex and expensive cancer treatments. The annual update on the Global Burden of Cancer will provide all stakeholders with timely estimates to guide policy efforts in cancer prevention, screening, treatment, and palliation.
2,375 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
University of Washington1, University of Maryland, Baltimore2, Harvard University3, Broad Institute4, Mayo Clinic5, Yale University6, Washington University in St. Louis7, University of Texas Health Science Center at Houston8, University of Michigan9, Louisiana State University10, University of North Carolina at Charlotte11, Wellcome Trust12, University of Texas MD Anderson Cancer Center13, Boston College14, Yeshiva University15, Bilkent University16, University of California, San Diego17, National Institutes of Health18, Leiden University19, Baylor College of Medicine20, Cornell University21, Utrecht University22, University of Oxford23, Icahn School of Medicine at Mount Sinai24, Kyoto University25, Virginia Commonwealth University26, Heidelberg University27, Ewha Womans University28
TL;DR: In this paper, the authors describe an integrated set of eight structural variant classes comprising both balanced and unbalanced variants, which are constructed using short-read DNA sequencing data and statistically phased onto haplotype blocks in 26 human populations.
Abstract: Structural variants are implicated in numerous diseases and make up the majority of varying nucleotides among human genomes. Here we describe an integrated set of eight structural variant classes comprising both balanced and unbalanced variants, which we constructed using short-read DNA sequencing data and statistically phased onto haplotype blocks in 26 human populations. Analysing this set, we identify numerous gene-intersecting structural variants exhibiting population stratification and describe naturally occurring homozygous gene knockouts that suggest the dispensability of a variety of human genes. We demonstrate that structural variants are enriched on haplotypes identified by genome-wide association studies and exhibit enrichment for expression quantitative trait loci. Additionally, we uncover appreciable levels of structural variant complexity at different scales, including genic loci subject to clusters of repeated rearrangement and complex structural variants with multiple breakpoints likely to have formed through individual mutational events. Our catalogue will enhance future studies into structural variant demography, functional impact and disease association.
1,971 citations
TL;DR: This article conducted a meta-analysis of coronary artery disease (CAD) cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 millions low-frequency (0.005 < MAF < 0.5) variants.
Abstract: Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of ∼185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.
1,839 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 Ulm12, University of Hamburg13, 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 ...
Mohammad H. Forouzanfar1, Lily Alexander1, H. Ross Anderson2, Victoria F Bachman1 +718 more•Institutions (295)
TL;DR: The Global Burden of Disease, Injuries, and Risk Factor study 2013 (GBD 2013) as mentioned in this paper provides a timely opportunity to update the comparative risk assessment with new data for exposure, relative risks, and evidence on the appropriate counterfactual risk distribution.
Heidelberg University1, University of Marburg2, Queen Mary University of London3, University of Leeds4, Rutgers University5, University of New South Wales6, University of Münster7, Aarhus University8, Columbia University9, University of Chieti-Pescara10, Norwegian University of Science and Technology11, Karolinska Institutet12, Université catholique de Louvain13, University of Sydney14, University of Western Australia15, University of Dundee16, Maastricht University17, Katholieke Universiteit Leuven18, National Yang-Ming University19
TL;DR: The IASP Task Force, which comprises pain experts from across the globe, has developed a new and pragmatic classification of chronic pain for the upcoming 11th revision of the International Classification of Diseases, termed “multiple parenting.”
Abstract: Chronic pain has been recognized as pain that persists past normal healing time5 and hence lacks the acute warning function of physiological nociception.35 Usually pain is regarded as chronic when it lasts or recurs for more than 3 to 6 months.29 Chronic pain is a frequent condition, affecting an estimated 20% of people worldwide6,13,14,18 and accounting for 15% to 20% of physician visits.25,28 Chronic pain should receive greater attention as a global health priority because adequate pain treatment is a human right, and it is the duty of any health care system to provide it.4,13
The current version of the International Classification of Diseases (ICD) of the World Health Organization (WHO) includes some diagnostic codes for chronic pain conditions, but these diagnoses do not reflect the actual epidemiology of chronic pain, nor are they categorized in a systematic manner. The ICD is the preeminent tool for coding diagnoses and documenting investigations or therapeutic measures within the health care systems of many countries. In addition, ICD codes are commonly used to report target diseases and comorbidities of participants in clinical research. Consequently, the current lack of adequate coding in the ICD makes the acquisition of accurate epidemiological data related to chronic pain difficult, prevents adequate billing for health care expenses related to pain treatment, and hinders the development and implementation of new therapies.10,11,16,23,27,31,37
Responding to these shortcomings, the International Association for the Study of Pain (IASP) contacted the WHO and established a Task Force for the Classification of Chronic Pain. The IASP Task Force, which comprises pain experts from across the globe,19 has developed a new and pragmatic classification of chronic pain for the upcoming 11th revision of the ICD. The goal is to create a classification system that is applicable in primary care and in clinical settings for specialized pain management.
A major challenge in this process was finding a rational principle of classification that suits the different types of chronic pain and fits into the general ICD-11 framework. Pain categories are variably defined based on the perceived location (headache), etiology (cancer pain), or the primarily affected anatomical system (neuropathic pain). Some diagnoses of pain defy these classification principles (fibromyalgia).
This problem is not unique to the classification of pain, but exists throughout the ICD. The IASP Task Force decided to give first priority to pain etiology, followed by underlying pathophysiological mechanisms, and finally the body site. Developing this multilayered classification was greatly facilitated by a novel principle of assigning diagnostic codes in ICD-11, termed “multiple parenting.” Multiple parenting allows the same diagnosis to be subsumed under more than 1 category (for a glossary of ICD terms refer to Table Table1).1). Each diagnosis retains 1 category as primary parent, but is cross-referenced to other categories that function as secondary parents.
Table 1
Glossary of ICD-11 terms.
The new ICD category for “Chronic Pain” comprises the most common clinically relevant disorders. These disorders were divided into 7 groups (Fig. (Fig.1):1): (1) chronic primary pain, (2) chronic cancer pain, (3) chronic posttraumatic and postsurgical pain, (4) chronic neuropathic pain, (5) chronic headache and orofacial pain, (6) chronic visceral pain, and (7) chronic musculoskeletal pain. Experts assigned to each group are responsible for the definition of diagnostic criteria and the selection of the diagnoses to be included under these subcategories of chronic pain. Thanks to Bedirhan Ustun and Robert Jakob of the WHO, these pain diagnoses are now integrated in the beta version of ICD-11 (http://id.who.int/icd/entity/1581976053). The Task Force is generating content models for single entities to describe their clinical characteristics. After peer review overseen by the WHO Steering Committee,39 the classification of chronic pain will be voted into action by the World Health Assembly in 2017.
Figure 1
Organizational chart of Task Force, IASP, and WHO interactions. The IASP Task Force was created by the IASP council and its scope defined in direct consultation of the chairs (R.D.T. and W.R.) with WHO representatives in 2012. The Task Force reports to ...
2. Classification of chronic pain
Chronic pain was defined as persistent or recurrent pain lasting longer than 3 months. This definition according to pain duration has the advantage that it is clear and operationalized.
Optional specifiers for each diagnosis record evidence of psychosocial factors and the severity of the pain. Pain severity can be graded based on pain intensity, pain-related distress, and functional impairment.
2.1. Chronic primary pain
Chronic primary pain is pain in 1 or more anatomic regions that persists or recurs for longer than 3 months and is associated with significant emotional distress or significant functional disability (interference with activities of daily life and participation in social roles) and that cannot be better explained by another chronic pain condition. This is a new phenomenological definition, created because the etiology is unknown for many forms of chronic pain. Common conditions such as, eg, back pain that is neither identified as musculoskeletal or neuropathic pain, chronic widespread pain, fibromyalgia, and irritable bowel syndrome will be found in this section and biological findings contributing to the pain problem may or may not be present. The term “primary pain” was chosen in close liaison with the ICD-11 revision committee, who felt this was the most widely acceptable term, in particular, from a nonspecialist perspective.
TL;DR: A measurement of the Higgs boson mass is presented based on the combined data samples of the ATLAS and CMS experiments at the CERN LHC in the H→γγ and H→ZZ→4ℓ decay channels.
Abstract: A measurement of the Higgs boson mass is presented based on the combined data samples of the ATLAS and CMS experiments at the CERN LHC in the H→γγ and H→ZZ→4l decay channels. The results are obtained from a simultaneous fit to the reconstructed invariant mass peaks in the two channels and for the two experiments. The measured masses from the individual channels and the two experiments are found to be consistent among themselves. The combined measured mass of the Higgs boson is mH=125.09±0.21 (stat)±0.11 (syst) GeV.
University of Cologne1, Stanford University2, University of Ulsan3, Hanyang University4, Vancouver General Hospital5, University of Bonn6, University of North Carolina at Chapel Hill7, University of Rostock8, Epigenomics AG9, University of Tsukuba10, University Hospital Heidelberg11, Heidelberg University12, Schiller International University13, University of Zurich14, Vanderbilt University15, University of Belgrade16, Peter MacCallum Cancer Centre17, Casa Sollievo della Sofferenza18, University of Liverpool19, University of Zagreb20, Charité21, Oslo University Hospital22, VU University Medical Center23, Uppsala University24, Haukeland University Hospital25, Max Planck Society26, Memorial Sloan Kettering Cancer Center27, French Institute of Health and Medical Research28
TL;DR: This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer.
Abstract: We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Δex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer.
National Institutes of Health1, University of Toronto2, Martin Luther University of Halle-Wittenberg3, University of Pisa4, Medical College of Wisconsin5, Memorial Sloan Kettering Cancer Center6, Washington University in St. Louis7, University of Siena8, Heidelberg University9, University of Sydney10, University of Kentucky11, University of Naples Federico II12, Institut Gustave Roussy13, Ohio State University14
TL;DR: The revised guidelines are focused primarily on the diagnosis and treatment of patients with sporadic medullary thyroid carcinoma (MTC) and hereditary MTC and developed 67 evidence-based recommendations to assist clinicians in the care of Patients with MTC.
Abstract: Introduction: The American Thyroid Association appointed a Task Force of experts to revise the original Medullary Thyroid Carcinoma: Management Guidelines of the American Thyroid Association. Methods: The Task Force identified relevant articles using a systematic PubMed search, supplemented with additional published materials, and then created evidence-based recommendations, which were set in categories using criteria adapted from the United States Preventive Services Task Force Agency for Healthcare Research and Quality. The original guidelines provided abundant source material and an excellent organizational structure that served as the basis for the current revised document. Results: The revised guidelines are focused primarily on the diagnosis and treatment of patients with sporadic medullary thyroid carcinoma (MTC) and hereditary MTC. Conclusions: The Task Force developed 67 evidence-based recommendations to assist clinicians in the care of patients with MTC. The Task Force considers the recommendati...
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...
VU University Amsterdam1, Heidelberg University2, University of Barcelona3, Harvard University4, Complutense University of Madrid5, Lille University of Science and Technology6, Marche Polytechnic University7, Mayo Clinic8, Emory University9, Sapienza University of Rome10, University of Bologna11, University of Arkansas for Medical Sciences12, National and Kapodistrian University of Athens13, Cedars-Sinai Medical Center14, Erasmus University Rotterdam15, University of Navarra16, Centre Hospitalier Universitaire de Nantes17
TL;DR: The R-ISS is a simple and powerful prognostic staging system, and it is recommended for use in future clinical studies to stratify patients with NDMM effectively with respect to the relative risk to their survival.
Abstract: Purpose The clinical outcome of multiple myeloma (MM) is heterogeneous. A simple and reliable tool is needed to stratify patients with MM. We combined the International Staging System (ISS) with chromosomal abnormalities (CA) detected by interphase fluorescent in situ hybridization after CD138 plasma cell purification and serum lactate dehydrogenase (LDH) to evaluate their prognostic value in newly diagnosed MM (NDMM). Patients and Methods Clinical and laboratory data from 4,445 patients with NDMM enrolled onto 11 international trials were pooled together. The K-adaptive partitioning algorithm was used to define the most appropriate subgroups with homogeneous survival. Results ISS, CA, and LDH data were simultaneously available in 3,060 of 4,445 patients. We defined the following three groups: revised ISS (R-ISS) I (n = 871), including ISS stage I (serum β2-microglobulin level < 3.5 mg/L and serum albumin level ≥ 3.5 g/dL), no high-risk CA [del(17p) and/or t(4;14) and/or t(14;16)], and normal LDH level (l...
TL;DR: Idarucizumab completely reversed the anticoagulant effect of dabigatran within minutes and normalized the test results in 88 to 98% of the patients, an effect that was evident within minutes.
Abstract: BACKGROUND Specific reversal agents for non–vitamin K antagonist oral anticoagulants are lacking Idarucizumab, an antibody fragment, was developed to reverse the anticoagulant effects of dabigatran METHODS We undertook this prospective cohort study to determine the safety of 5 g of intravenous idarucizumab and its capacity to reverse the anticoagulant effects of dabigatran in patients who had serious bleeding (group A) or required an urgent procedure (group B) The primary end point was the maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab, on the basis of the determination at a central laboratory of the dilute thrombin time or ecarin clotting time A key secondary end point was the restoration of hemostasis RESULTS This interim analysis included 90 patients who received idarucizumab (51 patients in group A and 39 in group B) Among 68 patients with an elevated dilute thrombin time and 81 with an elevated ecarin clotting time at baseline, the median maximum percentage reversal was 100% (95% confidence interval, 100 to 100) Idarucizumab normalized the test results in 88 to 98% of the patients, an effect that was evident within minutes Concentrations of unbound dabigatran remained below 20 ng per milliliter at 24 hours in 79% of the patients Among 35 patients in group A who could be assessed, hemostasis, as determined by local investigators, was restored at a median of 114 hours Among 36 patients in group B who underwent a procedure, normal intraoperative hemostasis was reported in 33, and mildly or moderately abnormal hemostasis was reported in 2 patients and 1 patient, respectively One thrombotic event occurred within 72 hours after idarucizumab administration in a patient in whom anticoagulants had not been reinitiated CONCLUSIONS Idarucizumab completely reversed the anticoagulant effect of dabigatran within minutes (Funded by Boehringer Ingelheim; RE-VERSE AD ClinicalTrialsgov number, NCT02104947)
TL;DR: Strong evidence for dust and no statistically significant evidence for tensor modes is found and various model variations and extensions are probe, including adding a synchrotron component in combination with lower frequency data, and find that these make little difference to the r constraint.
Abstract: We report the results of a joint analysis of data from BICEP2/Keck Array and Planck. BICEP2 and Keck Array have observed the same approximately 400 deg2 patch of sky centered on RA 0h, Dec. −57.5deg. The combined maps reach a depth of 57 nK deg in Stokes Q and U in a band centered at 150 GHz. Planck has observed the full sky in polarization at seven frequencies from 30 to 353 GHz, but much less deeply in any given region (1.2 μK deg in Q and U at 143 GHz). We detect 150×353 cross-correlation in B-modes at high significance. We fit the single- and cross-frequency power spectra at frequencies above 150 GHz to a lensed-ΛCDM model that includes dust and a possible contribution from inflationary gravitational waves (as parameterized by the tensor-to-scalar ratio r). We probe various model variations and extensions, including adding a synchrotron component in combination with lower frequency data, and find that these make little difference to the r constraint. Finally we present an alternative analysis which is similar to a map-based cleaning of the dust contribution, and show that this gives similar constraints. The final result is expressed as a likelihood curve for r, and yields an upper limit r0.05<0.12 at 95% confidence. Marginalizing over dust and r, lensing B-modes are detected at 7.0σ significance.
Mater Health Services1, University of Sydney2, National and Kapodistrian University of Athens3, The Royal Marsden NHS Foundation Trust4, University of Tübingen5, University of Kiel6, Aix-Marseille University7, Paris Diderot University8, Sir Charles Gairdner Hospital9, Netherlands Cancer Institute10, Karolinska University Hospital11, German Cancer Research Center12, Heidelberg University13, Northwood University14, Institut Gustave Roussy15, University of Paris-Sud16, University of California, Los Angeles17, Novartis18, Merck & Co.19, Harvard University20
TL;DR: The improvement in overall survival establishes the combination of dabrafenib and trametinib as the standard targeted treatment for BRAF Val600 mutation-positive melanoma.
TL;DR: The 2015 WHO Classification of Tumors of the Lung, Pleura, Thymus and Heart features the incorporation of many exciting new advances in thoracic tumor diagnosis and classification.
TL;DR: In this paper, the performance of the various LHCb sub-detectors and the trigger system are described, using data taken from 2010 to 2012, and it is shown that the design criteria of the experiment have been met.
Abstract: The LHCb detector is a forward spectrometer at the Large Hadron Collider (LHC) at CERN. The experiment is designed for precision measurements of CP violation and rare decays of beauty and charm hadrons. In this paper the performance of the various LHCb sub-detectors and the trigger system are described, using data taken from 2010 to 2012. It is shown that the design criteria of the experiment have been met. The excellent performance of the detector has allowed the LHCb collaboration to publish a wide range of physics results, demonstrating LHCb's unique role, both as a heavy flavour experiment and as a general purpose detector in the forward region.
TL;DR: In this article, the pentaquark-charmonium states were observed in the J/ψp channel in Λ0b→J/K−p decays and the significance of these resonances is more than 9 standard deviations.
Abstract: Observations of exotic structures in the J/ψp channel, that we refer to as pentaquark-charmonium states, in Λ0b→J/ψK−p decays are presented. The data sample corresponds to an integrated luminosity of 3/fb acquired with the LHCb detector from 7 and 8 TeV pp collisions. An amplitude analysis is performed on the three-body final-state that reproduces the two-body mass and angular distributions. To obtain a satisfactory fit of the structures seen in the J/ψp mass spectrum, it is necessary to include two Breit-Wigner amplitudes that each describe a resonant state. The significance of each of these resonances is more than 9 standard deviations. One has a mass of 4380±8±29 MeV and a width of 205±18±86 MeV, while the second is narrower, with a mass of 4449.8±1.7±2.5 MeV and a width of 39±5±19 MeV. The preferred JP assignments are of opposite parity, with one state having spin 3/2 and the other 5/2.
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...
German Cancer Research Center1, Boston Children's Hospital2, University of Texas MD Anderson Cancer Center3, St. Jude Children's Research Hospital4, University of Toronto5, Max Planck Society6, Heidelberg University7, University of Utah8, Tel Aviv University9, University of Colorado Denver10, University of Bern11, Masaryk University12, University of Texas Health Science Center at San Antonio13, University of California, San Francisco14, New York University15, University of Cambridge16, University of Hamburg17, University of Bonn18
TL;DR: The molecular classification proposed herein outperforms the current histopathological classification and thus might serve as a basis for the next World Health Organization classification of CNS tumors.
TL;DR: CCTop provides the bench biologist with a tool for the rapid and efficient identification of high quality target sites and was experimentally validated for gene inactivation, non-homologous end-joining as well as homology directed repair.
Abstract: Engineering of the CRISPR/Cas9 system has opened a plethora of new opportunities for site-directed mutagenesis and targeted genome modification. Fundamental to this is a stretch of twenty nucleotides at the 5’ end of a guide RNA that provides specificity to the bound Cas9 endonuclease. Since a sequence of twenty nucleotides can occur multiple times in a given genome and some mismatches seem to be accepted by the CRISPR/Cas9 complex, an efficient and reliable in silico selection and evaluation of the targeting site is key prerequisite for the experimental success. Here we present the CRISPR/Cas9 target online predictor (CCTop, http://crispr.cos.uni-heidelberg.de) to overcome limitations of already available tools. CCTop provides an intuitive user interface with reasonable default parameters that can easily be tuned by the user. From a given query sequence, CCTop identifies and ranks all candidate sgRNA target sites according to their off-target quality and displays full documentation. CCTop was experimentally validated for gene inactivation, non-homologous end-joining as well as homology directed repair. Thus, CCTop provides the bench biologist with a tool for the rapid and efficient identification of high quality target sites.
TL;DR: In this paper, the authors conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts.
Abstract: The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.
University Hospital Heidelberg1, German Cancer Research Center2, Heidelberg University3, Ludwig Maximilian University of Munich4, University of Würzburg5, University of Bonn6, University of Bergen7, Medical University of Vienna8, Max Planck Society9, University of Tübingen10, University of Calgary11
TL;DR: It is shown that many tumour cells in astrocytomas extend ultra-long membrane protrusions, and use these distinct tumour microtubes as routes for brain invasion, proliferation, and to interconnect over long distances, which develops functional multicellular network structures.
Abstract: Astrocytic brain tumours, including glioblastomas, are incurable neoplasms characterized by diffusely infiltrative growth. Here we show that many tumour cells in astrocytomas extend ultra-long membrane protrusions, and use these distinct tumour microtubes as routes for brain invasion, proliferation, and to interconnect over long distances. The resulting network allows multicellular communication through microtube-associated gap junctions. When damage to the network occurred, tumour microtubes were used for repair. Moreover, the microtube-connected astrocytoma cells, but not those remaining unconnected throughout tumour progression, were protected from cell death inflicted by radiotherapy. The neuronal growth-associated protein 43 was important for microtube formation and function, and drove microtube-dependent tumour cell invasion, proliferation, interconnection, and radioresistance. Oligodendroglial brain tumours were deficient in this mechanism. In summary, astrocytomas can develop functional multicellular network structures. Disconnection of astrocytoma cells by targeting their tumour microtubes emerges as a new principle to reduce the treatment resistance of this disease.