Showing papers by "University of Düsseldorf published in 2015"
Alexander A. Aarts, Joanna E. Anderson1, Christopher J. Anderson2, Peter Raymond Attridge3 +287 more•Institutions (116)
TL;DR: A large-scale assessment suggests that experimental reproducibility in psychology leaves a lot to be desired, and correlational tests suggest that replication success was better predicted by the strength of original evidence than by characteristics of the original and replication teams.
Abstract: Reproducibility is a defining feature of science, but the extent to which it characterizes current research is unknown. We conducted replications of 100 experimental and correlational studies published in three psychology journals using high-powered designs and original materials when available. Replication effects were half the magnitude of original effects, representing a substantial decline. Ninety-seven percent of original studies had statistically significant results. Thirty-six percent of replications had statistically significant results; 47% of original effect sizes were in the 95% confidence interval of the replication effect size; 39% of effects were subjectively rated to have replicated the original result; and if no bias in original results is assumed, combining original and replication results left 68% with statistically significant effects. Correlational tests suggest that replication success was better predicted by the strength of original evidence than by characteristics of the original and replication teams.
5,532 citations
TL;DR: “Oxidative stress” as a concept in redox biology and medicine has been formulated in 1985; at the beginning of 2015, approx.
Abstract: “Oxidative stress” as a concept in redox biology and medicine has been formulated in 1985; at the beginning of 2015, approx. 138,000 PubMed entries show for this term. This concept has its merits and its pitfalls. Among the merits is the notion, elicited by the combined two terms of (i) aerobic metabolism as a steady-state redox balance and (ii) the associated potential strains in the balance as denoted by the term, stress, evoking biological stress responses. Current research on molecular redox switches governing oxidative stress responses is in full bloom. The fundamental importance of linking redox shifts to phosphorylation/dephosphorylation signaling is being more fully appreciated, thanks to major advances in methodology. Among the pitfalls is the fact that the underlying molecular details are to be worked out in each particular case, which is bvious for a global concept, but which is sometimes overlooked. This can lead to indiscriminate use of the term, oxidative stress, without clear relation to redox chemistry. The major role in antioxidant defense is fulfilled by antioxidant enzymes, not by small-molecule antioxidant compounds. The field of oxidative stress research embraces chemistry, biochemistry, cell biology, physiology and pathophysiology, all the way to medicine and health and disease research.
1,551 citations
TL;DR: The cocor package covers a broad range of tests including the comparisons of independent and dependent correlations with either overlapping or nonoverlapping variables, and includes an implementation of Zou’s confidence interval for all of these comparisons.
Abstract: A valid comparison of the magnitude of two correlations requires researchers to directly contrast the correlations using an appropriate statistical test. In many popular statistics packages, however, tests for the significance of the difference between correlations are missing. To close this gap, we introduce cocor, a free software package for the R programming language. The cocor package covers a broad range of tests including the comparisons of independent and dependent correlations with either overlapping or nonoverlapping variables. The package also includes an implementation of Zou’s confidence interval for all of these comparisons. The platform independent cocor package enhances the R statistical computing environment and is available for scripting. Two different graphical user interfaces—a plugin for RKWard and a web interface—make cocor a convenient and user-friendly tool.
1,292 citations
TL;DR: A concordance is identified in terms of integrity of an anterior insula/dorsal anterior cingulate-based network, which may relate to executive function deficits observed across diagnoses, which provides an organizing model that emphasizes the importance of shared neural substrates across psychopathology.
Abstract: Importance Psychiatric diagnoses are currently distinguished based on sets of specific symptoms. However, genetic and clinical analyses find similarities across a wide variety of diagnoses, suggesting that a common neurobiological substrate may exist across mental illness. Objective To conduct a meta-analysis of structural neuroimaging studies across multiple psychiatric diagnoses, followed by parallel analyses of 3 large-scale healthy participant data sets to help interpret structural findings in the meta-analysis. Data Sources PubMed was searched to identify voxel-based morphometry studies through July 2012 comparing psychiatric patients to healthy control individuals for the meta-analysis. The 3 parallel healthy participant data sets included resting-state functional magnetic resonance imaging, a database of activation foci across thousands of neuroimaging experiments, and a data set with structural imaging and cognitive task performance data. Data Extraction and Synthesis Studies were included in the meta-analysis if they reported voxel-based morphometry differences between patients with an Axis I diagnosis and control individuals in stereotactic coordinates across the whole brain, did not present predominantly in childhood, and had at least 10 studies contributing to that diagnosis (or across closely related diagnoses). The meta-analysis was conducted on peak voxel coordinates using an activation likelihood estimation approach. Main Outcomes and Measures We tested for areas of common gray matter volume increase or decrease across Axis I diagnoses, as well as areas differing between diagnoses. Follow-up analyses on other healthy participant data sets tested connectivity related to regions arising from the meta-analysis and the relationship of gray matter volume to cognition. Results Based on the voxel-based morphometry meta-analysis of 193 studies comprising 15 892 individuals across 6 diverse diagnostic groups (schizophrenia, bipolar disorder, depression, addiction, obsessive-compulsive disorder, and anxiety), we found that gray matter loss converged across diagnoses in 3 regions: the dorsal anterior cingulate, right insula, and left insula. By contrast, there were few diagnosis-specific effects, distinguishing only schizophrenia and depression from other diagnoses. In the parallel follow-up analyses of the 3 independent healthy participant data sets, we found that the common gray matter loss regions formed a tightly interconnected network during tasks and at resting and that lower gray matter in this network was associated with poor executive functioning. Conclusions and Revelance We identified a concordance across psychiatric diagnoses in terms of integrity of an anterior insula/dorsal anterior cingulate–based network, which may relate to executive function deficits observed across diagnoses. This concordance provides an organizing model that emphasizes the importance of shared neural substrates across psychopathology, despite likely diverse etiologies, which is currently not an explicit component of psychiatric nosology.
1,033 citations
Academic Medical Center1, Hartford Hospital2, University of Milan3, University at Buffalo4, University of the Witwatersrand5, University of London6, University of Düsseldorf7, Hacettepe University8, Copenhagen University Hospital9, Ghent University10, Children's Hospital Oakland Research Institute11, University of São Paulo12, University of Western Ontario13, University of Amsterdam14, University of Toronto15, Synlab Group16, New York University17, Sahlgrenska University Hospital18, Emory University19, French Institute of Health and Medical Research20, Columbia University21
TL;DR: The Panel proposes to identify SAMS by symptoms typical of statin myalgia and their temporal association with discontinuation and response to repetitive statin re-challenge, and recommends the use of a maximally tolerated statin dose combined with non-statin lipid-lowering therapies to attain recommended low-density lipoprotein cholesterol targets.
Abstract: Statin-associated muscle symptoms (SAMS) are one of the principal reasons for statin non-adherence and/or discontinuation, contributing to adverse cardiovascular outcomes. This European Atherosclerosis Society (EAS) Consensus Panel overviews current understanding of the pathophysiology of statin-associated myopathy, and provides guidance for diagnosis and management of SAMS. Statin-associated myopathy, with significant elevation of serum creatine kinase (CK), is a rare but serious side effect of statins, affecting 1 per 1000 to 1 per 10 000 people on standard statin doses. Statin-associated muscle symptoms cover a broader range of clinical presentations, usually with normal or minimally elevated CK levels, with a prevalence of 7–29% in registries and observational studies. Preclinical studies show that statins decrease mitochondrial function, attenuate energy production, and alter muscle protein degradation, thereby providing a potential link between statins and muscle symptoms; controlled mechanistic and genetic studies in humans are necessary to further understanding. The Panel proposes to identify SAMS by symptoms typical of statin myalgia (i.e. muscle pain or aching) and their temporal association with discontinuation and response to repetitive statin re-challenge. In people with SAMS, the Panel recommends the use of a maximally tolerated statin dose combined with non-statin lipid-lowering therapies to attain recommended low-density lipoprotein cholesterol targets. The Panel recommends a structured work-up to identify individuals with clinically relevant SAMS generally to at least three different statins, so that they can be offered therapeutic regimens to satisfactorily address their cardiovascular risk. Further research into the underlying pathophysiological mechanisms may offer future therapeutic potential.
988 citations
TL;DR: It is indicated that the combined action of microbe- microbe and host-microbe interactions drives microbiota differentiation at the root-soil interface.
885 citations
TL;DR: It is shown that the isolates form assemblies resembling natural microbiota on their cognate host organs, but are also capable of ectopic leaf or root colonization, which raises the possibility of reciprocal relocation between root and leaf microbiota members.
Abstract: Roots and leaves of healthy plants host taxonomically structured bacterial assemblies, and members of these communities contribute to plant growth and health. We established Arabidopsis leaf- and root-derived microbiota culture collections representing the majority of bacterial species that are reproducibly detectable by culture-independent community sequencing. We found an extensive taxonomic overlap between the leaf and root microbiota. Genome drafts of 400 isolates revealed a large overlap of genome-encoded functional capabilities between leaf- and root-derived bacteria with few significant differences at the level of individual functional categories. Using defined bacterial communities and a gnotobiotic Arabidopsis plant system we show that the isolates form assemblies resembling natural microbiota on their cognate host organs, but are also capable of ectopic leaf or root colonization. While this raises the possibility of reciprocal relocation between root and leaf microbiota members, genome information and recolonization experiments also provide evidence for microbiota specialization to their respective niche.
850 citations
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...
822 citations
University of Illinois at Urbana–Champaign1, United States Department of Agriculture2, University of California, Los Angeles3, Centre national de la recherche scientifique4, University of Oregon5, Washington University in St. Louis6, Max Planck Society7, VU University Amsterdam8, Cornell University9, University of Cambridge10, Arizona State University11, Louisiana State University12, Lawrence Berkeley National Laboratory13, University of California, Berkeley14, Rothamsted Research15, Georgia Institute of Technology16, ExxonMobil17, Iowa State University18, Australian National University19, University of Düsseldorf20, Texas A&M University21
TL;DR: This work explores an array of prospective redesigns of plant systems at various scales aimed at increasing crop yields through improved photosynthetic efficiency and performance, and suggests some proposed redesigns are certain to face obstacles that will require alternate routes.
Abstract: The world’s crop productivity is stagnating whereas population growth, rising affluence, and mandates for biofuels put increasing demands on agriculture. Meanwhile, demand for increasing cropland competes with equally crucial global sustainability and environmental protection needs. Addressing this looming agricultural crisis will be one of our greatest scientific challenges in the coming decades, and success will require substantial improvements at many levels. We assert that increasing the efficiency and productivity of photosynthesis in crop plants will be essential if this grand challenge is to be met. Here, we explore an array of prospective redesigns of plant systems at various scales, all aimed at increasing crop yields through improved photosynthetic efficiency and performance. Prospects range from straightforward alterations, already supported by preliminary evidence of feasibility, to substantial redesigns that are currently only conceptual, but that may be enabled by new developments in synthetic biology. Although some proposed redesigns are certain to face obstacles that will require alternate routes, the efforts should lead to new discoveries and technical advances with important impacts on the global problem of crop productivity and bioenergy production.
700 citations
TL;DR: It is demonstrated that synthesis of the antioxidant glutathione (GSH), driven by GCLM, is required for cancer initiation and combined inhibition of GSH and thioredoxin antioxidant pathways leads to a synergistic cancer cell death in vitro and vivo, demonstrating the importance of these two antioxidants to tumor progression and as potential targets for therapeutic intervention.
691 citations
TL;DR: Adaptation of the liver ("hepatic mitochondrial flexibility") at early stages of obesity-related insulin resistance, which is subsequently lost in NASH is suggested.
University of Edinburgh1, University of Bergen2, Harvard University3, University of Michigan4, Erasmus University Rotterdam5, Utrecht University6, University of Düsseldorf7, Katholieke Universiteit Leuven8, Swiss Tropical and Public Health Institute9, University of Basel10, National Institute for Health and Welfare11, University of Helsinki12, University of Maryland, Baltimore13, University of Sheffield14
TL;DR: An enduring positive association between long-term exposure to air pollution and total and cardiovascular mortality is established, mainly due to coronary artery disease.
Abstract: Air pollution has wide-ranging and deleterious effects on human health and is a major issue for the global community. The Global Burden of Disease study has described the worldwide impact of air pollution with as many as 3.1 million of 52.8 million all-cause and all-age deaths being attributable to ambient air pollution in the year 2010.1 Moreover, ambient air pollution ranked ninth among the modifiable disease risk factors, being listed above other commonly recognized factors, such as low physical activity, a high-sodium diet, high cholesterol, and drug use. Finally, air pollution accounts for 3.1% of global disability-adjusted life years, an index that measures the time spent in states of reduced health.1
Although it is intuitive that air pollution is an important stimulus for the development and exacerbation of respiratory diseases, such as asthma, chronic obstructive pulmonary disease, and lung cancer, there is generally less public awareness of its substantial impact on cardiovascular disease. Historically, the 1952 Great Smog of London led to an increase in cardiovascular death as well as deaths due to respiratory disease. Subsequent studies in the 1990s, such as the Harvard Six Cities2 and American Cancer Society cohort studies,2,3 established an enduring positive association between long-term exposure to air pollution and total and cardiovascular mortality, mainly due to coronary artery disease.4 In Europe, the first study that supported this association between long-term exposure and mortality was the Netherlands Cohort Study on Diet and Cancer.5 Associations with cardiovascular morbidity and mortality are also seen with short-term (e.g. day-to-day fluctuations) pollutant exposures of residents in large urban areas worldwide, including the United States of America6 …
Memorial Sloan Kettering Cancer Center1, University of Ulsan2, Johns Hopkins University3, Emory University4, University of Glasgow5, Utrecht University6, Jichi Medical University7, Japanese Foundation for Cancer Research8, Technische Universität München9, Dartmouth College10, University of Bonn11, Kyoto University12, University of Paris13, University of Düsseldorf14
TL;DR: International experts met to discuss recent advances and to revise the 2004 recommendations for assessing and reporting precursor lesions to invasive carcinomas of the pancreas, including pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasms (IPMN), mucinous cystic neoplasm, and other lesions.
Abstract: International experts met to discuss recent advances and to revise the 2004 recommendations for assessing and reporting precursor lesions to invasive carcinomas of the pancreas, including pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN), mucinous cystic neoplasm, and other lesions. Consensus recommendations include the following: (1) To improve concordance and to align with practical consequences, a 2-tiered system (low vs. high grade) is proposed for all precursor lesions, with the provision that the current PanIN-2 and neoplasms with intermediate-grade dysplasia now be categorized as low grade. Thus, "high-grade dysplasia" is to be reserved for only the uppermost end of the spectrum ("carcinoma in situ"-type lesions). (2) Current data indicate that PanIN of any grade at a margin of a resected pancreas with invasive carcinoma does not have prognostic implications; the clinical significance of dysplasia at a margin in a resected pancreas with IPMN lacking invasive carcinoma remains to be determined. (3) Intraductal lesions 0.5 to 1 cm can be either large PanINs or small IPMNs. The term "incipient IPMN" should be reserved for lesions in this size with intestinal or oncocytic papillae or GNAS mutations. (4) Measurement of the distance between an IPMN and invasive carcinoma and sampling of intervening tissue are recommended to assess concomitant versus associated status. Conceptually, concomitant invasive carcinoma (in contrast with the "associated" group) ought to be genetically distinct from an IPMN elsewhere in the gland. (5) "Intraductal spread of invasive carcinoma" (aka, "colonization") is recommended to describe lesions of invasive carcinoma invading back into and extending along the ductal system, which may morphologically mimic high-grade PanIN or even IPMN. (6) "Simple mucinous cyst" is recommended to describe cysts >1 cm having gastric-type flat mucinous lining at most minimal atypia without ovarian-type stroma to distinguish them from IPMN. (7) Human lesions resembling the acinar to ductal metaplasia and atypical flat lesions of genetically engineered mouse models exist and may reflect an alternate pathway of carcinogenesis; however, their biological significance requires further study. These revised recommendations are expected to improve our management and understanding of precursor lesions in the pancreas.
TL;DR: It is shown that there is no overlap of abundant bacterial taxa between the microbiotas of the mammalian gut and plant roots, whereas taxa overlap does exist between fish Gut and plant root communities.
TL;DR: This publication focuses on the most important changes in treatment recommendations for clinical stage I disease and the updated recommendations for follow-up, which will lead to an overall reduction in treatment burden for patients with germ cell tumours.
University of Brescia1, University of Crete2, Sheba Medical Center3, Royal National Hospital for Rheumatic Diseases4, University of Padua5, University of Düsseldorf6, University Hospital of Bern7, St Thomas' Hospital8, University of Milan9, University of Pisa10, Iuliu Hațieganu University of Medicine and Pharmacy11, Karolinska University Hospital12, National and Kapodistrian University of Athens13, Istanbul Bilim University14
TL;DR: Recommendations for women's health issues in SLE and/or APS were developed using an evidence-based approach followed by expert consensus.
Abstract: Objectives Develop recommendations for women9s health issues and family planning in systemic lupus erythematosus (SLE) and/or antiphospholipid syndrome (APS). Methods Systematic review of evidence followed by modified Delphi method to compile questions, elicit expert opinions and reach consensus. Results Family planning should be discussed as early as possible after diagnosis. Most women can have successful pregnancies and measures can be taken to reduce the risks of adverse maternal or fetal outcomes. Risk stratification includes disease activity, autoantibody profile, previous vascular and pregnancy morbidity, hypertension and the use of drugs (emphasis on benefits from hydroxychloroquine and antiplatelets/anticoagulants). Hormonal contraception and menopause replacement therapy can be used in patients with stable/inactive disease and low risk of thrombosis. Fertility preservation with gonadotropin-releasing hormone analogues should be considered prior to the use of alkylating agents. Assisted reproduction techniques can be safely used in patients with stable/inactive disease; patients with positive antiphospholipid antibodies/APS should receive anticoagulation and/or low-dose aspirin. Assessment of disease activity, renal function and serological markers is important for diagnosing disease flares and monitoring for obstetrical adverse outcomes. Fetal monitoring includes Doppler ultrasonography and fetal biometry, particularly in the third trimester, to screen for placental insufficiency and small for gestational age fetuses. Screening for gynaecological malignancies is similar to the general population, with increased vigilance for cervical premalignant lesions if exposed to immunosuppressive drugs. Human papillomavirus immunisation can be used in women with stable/inactive disease. Conclusions Recommendations for women9s health issues in SLE and/or APS were developed using an evidence-based approach followed by expert consensus.
University College London1, University of Helsinki2, Finnish Institute of Occupational Health3, French Institute of Health and Medical Research4, RMIT University5, Karolinska Institutet6, Stockholm University7, 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.
Marjolein J. Peters1, Roby Joehanes2, Luke C. Pilling3, Claudia Schurmann4 +155 more•Institutions (46)
TL;DR: Differences between transcriptomic age and chronological age are associated with biological features linked to ageing, such as blood pressure, cholesterol levels, fasting glucose, and body mass index and the transcriptomic prediction model adds biological relevance and complements existing epigenetic prediction models.
Abstract: Disease incidences increase with age, but the molecular characteristics of ageing that lead to increased disease susceptibility remain inadequately understood. Here we perform a whole-blood gene expression meta-analysis in 14,983 individuals of European ancestry (including replication) and identify 1,497 genes that are differentially expressed with chronological age. The age-associated genes do not harbor more age-associated CpG-methylation sites than other genes, but are instead enriched for the presence of potentially functional CpG-methylation sites in enhancer and insulator regions that associate with both chronological age and gene expression levels. We further used the gene expression profiles to calculate the 'transcriptomic age' of an individual, and show that differences between transcriptomic age and chronological age are associated with biological features linked to ageing, such as blood pressure, cholesterol levels, fasting glucose, and body mass index. The transcriptomic prediction model adds biological relevance and complements existing epigenetic prediction models, and can be used by others to calculate transcriptomic age in external cohorts.
TL;DR: Major clinically relevant genetic and epigenetic abnormalities in GBM are described—such as mutations in IDH1/2, EGFR, PDGFRA, and NF1 genes—altered methylation of MGMT gene promoter, and mutations in hTERT promoter.
Abstract: Recent advances in genomic technology have led to a better understanding of key molecular alterations that underlie glioblastoma (GBM). The current WHO-based classification of GBM is mainly based on histologic features of the tumor, which frequently do not reflect the molecular differences that describe the diversity in the biology of these lesions. The current WHO definition of GBM relies on the presence of high-grade astrocytic neoplasm with the presence of either microvascular proliferation and/or tumor necrosis. High-throughput analyses have identified molecular subtypes and have led to progress in more accurate classification of GBM. These findings, in turn, would result in development of more effective patient stratification, targeted therapeutics, and prediction of patient outcome. While consensus has not been reached on the precise nature and means to sub-classify GBM, it is clear that IDH-mutant GBMs are clearly distinct from GBMs without IDH1/2 mutation with respect to molecular and clinical features, including prognosis. In addition, recent findings in pediatric GBMs regarding mutations in the histone H3F3A gene suggest that these tumors may represent a 3rd major category of GBM, separate from adult primary (IDH1/2 wt), and secondary (IDH1/2 mut) GBMs. In this review, we describe major clinically relevant genetic and epigenetic abnormalities in GBM-such as mutations in IDH1/2, EGFR, PDGFRA, and NF1 genes-altered methylation of MGMT gene promoter, and mutations in hTERT promoter. These markers may be incorporated into a more refined classification system and applied in more accurate clinical decision-making process. In addition, we focus on current understanding of the biologic heterogeneity and classification of GBM and highlight some of the molecular signatures and alterations that characterize GBMs as histologically defined. We raise the question whether IDH-wild type high grade astrocytomas without microvascular proliferation or necrosis might best be classified as GBM, even if they lack the histologic hallmarks as required in the current WHO classification. Alternatively, an astrocytic tumor that fits the current histologic definition of GBM, but which shows an IDH mutation may in fact be better classified as a distinct entity, given that IDH-mutant GBM are quite distinct from a biological and clinical perspective.
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.
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TL;DR: The redox code is a set of principles that defines the positioning of the nicotinamide adenine dinucleotide and thiol/disulfide and other redox systems as well as the thiol redox proteome in space and time in biological systems.
Abstract: Significance: The redox code is a set of principles that defines the positioning of the nicotinamide adenine dinucleotide (NAD, NADP) and thiol/disulfide and other redox systems as well as the thiol redox proteome in space and time in biological systems. The code is richly elaborated in an oxygen-dependent life, where activation/deactivation cycles involving O2 and H2O2 contribute to spatiotemporal organization for differentiation, development, and adaptation to the environment. Disruption of this organizational structure during oxidative stress represents a fundamental mechanism in system failure and disease. Recent Advances: Methodology in assessing components of the redox code under physiological conditions has progressed, permitting insight into spatiotemporal organization and allowing for identification of redox partners in redox proteomics and redox metabolomics. Critical Issues: Complexity of redox networks and redox regulation is being revealed step by step, yet much still needs to be lea...
TL;DR: The H3R is an autoreceptor and heteroreceptor providing negative feedback on histaminergic and inhibition on other neurons, a block of these actions promotes waking and the development of anti-inflammatory drugs is anticipated.
Abstract: Histamine is a developmentally highly conserved autacoid found in most vertebrate tissues. Its physiological functions are mediated by four 7-transmembrane G protein–coupled receptors (H1R, H2R, H3R, H4R) that are all targets of pharmacological intervention. The receptors display molecular heterogeneity and constitutive activity. H1R antagonists are long known antiallergic and sedating drugs, whereas the H2R was identified in the 1970s and led to the development of H2R-antagonists that revolutionized stomach ulcer treatment. The crystal structure of ligand-bound H1R has rendered it possible to design new ligands with novel properties. The H3R is an autoreceptor and heteroreceptor providing negative feedback on histaminergic and inhibition on other neurons. A block of these actions promotes waking. The H4R occurs on immuncompetent cells and the development of anti-inflammatory drugs is anticipated.
TL;DR: Consensus was reached on recommendations for patients with dental implants and oral health care professionals with regard to the efficacy of measures to manage peri-implant mucositis.
Abstract: Aims: Over the past decades, the placement of dental implants has become a routine procedure in the oral rehabilitation of fully and partially edentulous patients. However, the number of patients/implants affected by peri-implant diseases is increasing. As there are – in contrast to periodontitis – at present no established and predictable concepts for the treatment of peri-implantitis, primary prevention is of key importance. The management of peri-implant mucositis is considered as a preventive measure for the onset of peri-implantitis. Therefore, the remit of this working group was to assess the prevalence of peri-implant diseases, as well as risks for peri-implant mucositis and to evaluate measures for the management of peri-implant mucositis. Methods: Discussions were informed by four systematic reviews on the current epidemiology of peri-implant diseases, on potential risks contributing to the development of peri-implant mucositis, and on the effect of patient and of professionally administered measures to manage peri-implant mucositis. This consensus report is based on the outcomes of these systematic reviews and on the expert opinion of the participants. Results: Key findings included: (i) meta-analysis estimated a weighted mean prevalence for peri-implant mucositis of 43% (CI: 32–54%) and for peri-implantitis of 22% (CI: 14–30%); (ii) bleeding on probing is considered as key clinical measure to distinguish between peri-implant health and disease; (iii) lack of regular supportive therapy in patients with peri-implant mucositis was associated with increased risk for onset of peri-implantitis; (iv) whereas plaque accumulation has been established as aetiological factor, smoking was identified as modifiable patient-related and excess cement as local risk indicator for the development of peri-implant mucositis; (v) patient-administered mechanical plaque control (with manual or powered toothbrushes) has been shown to be an effective preventive measure; (vi) professional intervention comprising oral hygiene instructions and mechanical debridement revealed a reduction in clinical signs of inflammation; (vii) adjunctive measures (antiseptics, local and systemic antibiotics, air-abrasive
University of Oulu1, Imperial College London2, Agency for Science, Technology and Research3, Wellcome Trust Centre for Human Genetics4, University of Milan5, University of Bristol6, National Institutes of Health7, Ealing Hospital8, university of lille9, Pasteur Institute of Lille10, Hammersmith Hospital11, Baker IDI Heart and Diabetes Institute12, National University of Singapore13, French Institute of Health and Medical Research14, Technische Universität München15, University of Kiel16, University of Oxford17, University of Cambridge18, University of Surrey19, Hannover Medical School20, Max Healthcare21, University of Kelaniya22, University of Mauritius23, University of Helsinki24, Imperial College Healthcare25, University of Pennsylvania26, University of Eastern Finland27, University of Düsseldorf28, Dresden University of Technology29, National Institute for Health Research30
TL;DR: A nested case-control study of DNA methylation in Indian Asians and Europeans with incident type 2 diabetes who were identified from the 8-year follow-up of 25 372 participants in the London Life Sciences Prospective Population study.
TL;DR: This paper performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry, and identified 49 distinct association signals at these loci including five mapping in or near KCNQ1.
Abstract: We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.
TL;DR: In this paper, the relationship between specific mutations in BRCA1 and cancer risk has been investigated and limited information about the relationship has been available about specific mutations for specific mutations.
Abstract: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists.
TL;DR: It is argued that primarily cognitive and not motor processes determine the take-over time, in such a way that insights can be derived for further research and the development of automated systems.
TL;DR: In this paper, the efficacy and safety of PCSK9 antibodies in adults with hypercholesterolemia were evaluated in a randomized, controlled trial (RCT) and the primary end points were all-cause and cardiovascular mortality.
Abstract: BACKGROUND Guidelines recommend statins as first-line therapy for dyslipidemia. Monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) is a new lipid-lowering approach. PURPOSE To assess the efficacy and safety of PCSK9 antibodies in adults with hypercholesterolemia. DATA SOURCES MEDLINE, PubMed Central, and Google Scholar; conference proceedings; and the ClinicalTrials.gov registry through 4 April 2015. STUDY SELECTION Phase 2 or 3 randomized, controlled trials (RCTs) comparing treatment using PCSK9 antibodies with no anti-PCSK9 therapy in adults with hypercholesterolemia. DATA EXTRACTION Two investigators independently extracted data on study characteristics and lipid and clinical outcomes, and rated risk of bias of trials. Prespecified primary end points were all-cause and cardiovascular mortality. DATA SYNTHESIS Twenty-four RCTs comprising 10 159 patients were included. Compared with no antibody, treatment with PCSK9 antibodies led to marked reductions in low-density lipoprotein cholesterol levels (mean difference, -47.49% [95% CI, -69.64% to -25.35%]; P < 0.001] and other atherogenic lipid fractions, and it reduced all-cause mortality (odds ratio [OR], 0.45 [CI, 0.23 to 0.86]; P = 0.015; heterogeneity P = 0.63; I2 = 0%) and cardiovascular mortality (OR, 0.50 [CI, 0.23 to 1.10]; P = 0.084; heterogeneity P = 0.78; I2 = 0%). The rate of myocardial infarction was significantly reduced with use of PCSK9 antibodies (OR, 0.49 [CI, 0.26 to 0.93]; P = 0.030; heterogeneity P = 0.45; I2 = 0%), and increases in the serum creatine kinase level were reduced (OR, 0.72 [CI, 0.54 to 0.96]; P = 0.026; heterogeneity P = 0.65; I2 = 0%). Serious adverse events did not increase with administration of PCSK9 antibodies. LIMITATION Results were derived from study-level data rather than patient-level data, and clinical outcome data are rare. CONCLUSION PCSK9 antibodies seem to be safe and effective for adults with dyslipidemia. PRIMARY FUNDING SOURCE CRC 1116 Masterswitches in Myocardial Ischemia, German Research Council DFG.
TL;DR: It is argued that the cortical architecture is more heterogeneous than Brodmann's map suggests, and a triple-scale concept is proposed that includes repetitive modular-like structures and micro- and meso-maps.