Showing papers by "University of Texas Health Science Center at Houston published in 2013"
John N. Weinstein1, John N. Weinstein2, Eric A. Collisson3, Gordon B. Mills1 +376 more•Institutions (31)
TL;DR: The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA with a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages.
Abstract: The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile.
5,294 citations
Jean-Charles Lambert1, Jean-Charles Lambert2, Jean-Charles Lambert3, Carla A. Ibrahim-Verbaas4 +212 more•Institutions (75)
TL;DR: In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10−8) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.
Abstract: Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10−8) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.
3,726 citations
Radboud University Nijmegen Medical Centre1, University of Michigan2, Radboud University Nijmegen3, University of Toronto4, McGill University5, University of Basel6, University of Florence7, Auckland City Hospital8, University of Pittsburgh9, Charité10, University of California, Los Angeles11, University College London12, University of Zurich13, University of Paris14, Marche Polytechnic University15, University of Texas Health Science Center at Houston16, Newcastle University17, University of Pécs18, Georgetown University19, Istanbul University20, Medical University of Białystok21, University of Giessen22, Seconda Università degli Studi di Napoli23, University College Dublin24, Stanford University25, University of Colorado Denver26, National Health Service27, Medical College of Wisconsin28, University of Alabama at Birmingham29, University of Manchester30, Rutgers University31, Thomas Jefferson University32, Amgen33, University of Toledo34, Boston University35, Medical University of South Carolina36, University of Pennsylvania37, Northwestern University38
TL;DR: The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria and should allow for more patients to be classified correctly as having the disease.
Abstract: OBJECTIVE: The 1980 American College of Rheumatology (ACR) classification criteria for systemic sclerosis (SSc) lack sensitivity for early SSc and limited cutaneous SSc. The present work, by a joint committee of the ACR and the European League Against Rheumatism (EULAR), was undertaken for the purpose of developing new classification criteria for SSc. METHODS: Using consensus methods, 23 candidate items were arranged in a multicriteria additive point system with a threshold to classify cases as SSc. The classification system was reduced by clustering items and simplifying weights. The system was tested by 1) determining specificity and sensitivity in SSc cases and controls with scleroderma-like disorders, and 2) validating against the combined view of a group of experts on a set of cases with or without SSc. RESULTS: It was determined that skin thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient for the patient to be classified as having SSc; if that is not present, 7 additive items apply, with varying weights for each: skin thickening of the fingers, fingertip lesions, telangiectasia, abnormal nailfold capillaries, interstitial lung disease or pulmonary arterial hypertension, Raynaud's phenomenon, and SSc-related autoantibodies. Sensitivity and specificity in the validation sample were, respectively, 0.91 and 0.92 for the new classification criteria and 0.75 and 0.72 for the 1980 ACR classification criteria. All selected cases were classified in accordance with consensus-based expert opinion. All cases classified as SSc according to the 1980 ACR criteria were classified as SSc with the new criteria, and several additional cases were now considered to be SSc. CONCLUSION: The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria for SSc and should allow for more patients to be classified correctly as having the disease.
2,743 citations
Cristen J. Willer1, Ellen M. Schmidt1, Sebanti Sengupta1, Gina M. Peloso2 +316 more•Institutions (87)
TL;DR: It is found that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index.
Abstract: Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.
2,585 citations
Radboud University Nijmegen1, University of Michigan2, University of Toronto3, McGill University4, University of Basel5, University of Florence6, Auckland City Hospital7, University of Pittsburgh8, Complutense University of Madrid9, Charité10, University of California, Los Angeles11, University College London12, University of Zurich13, University of Paris14, Marche Polytechnic University15, University of Texas Health Science Center at Houston16, Newcastle University17, University of Pécs18, Georgetown University19, Istanbul University20, Medical University of Białystok21, University of Giessen22, Seconda Università degli Studi di Napoli23, University College Dublin24, Stanford University25, Amgen26, University of Colorado Denver27, Medical College of Wisconsin28, University of Alabama at Birmingham29, University of Manchester30, National Health Service31, Rutgers University32, Thomas Jefferson University33, University of Toledo34, University of Pennsylvania35, Boston University36, Medical University of South Carolina37, Northwestern University38, University of Western Ontario39
TL;DR: The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria and should allow for more patients to be classified correctly as having the disease.
Abstract: Objective The 1980 American College of Rheumatology (ACR) classification criteria for systemic sclerosis (SSc) lack sensitivity for early SSc and limited cutaneous SSc. The present work, by a joint committee of the ACR and the European League Against Rheumatism (EULAR), was undertaken for the purpose of developing new classification criteria for SSc. Methods Using consensus methods, 23 candidate items were arranged in a multicriteria additive point system with a threshold to classify cases as SSc. The classification system was reduced by clustering items and simplifying weights. The system was tested by (1) determining specificity and sensitivity in SSc cases and controls with scleroderma-like disorders, and (2) validating against the combined view of a group of experts on a set of cases with or without SSc. Results It was determined that skin thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient for the patient to be classified as having SSc; if that is not present, seven additive items apply, with varying weights for each: skin thickening of the fingers, fingertip lesions, telangiectasia, abnormal nailfold capillaries, interstitial lung disease or pulmonary arterial hypertension, Raynaud9s phenomenon, and SSc-related autoantibodies. Sensitivity and specificity in the validation sample were, respectively, 0.91 and 0.92 for the new classification criteria and 0.75 and 0.72 for the 1980 ACR classification criteria. All selected cases were classified in accordance with consensus-based expert opinion. All cases classified as SSc according to the 1980 ACR criteria were classified as SSc with the new criteria, and several additional cases were now considered to be SSc. Conclusions The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria for SSc and should allow for more patients to be classified correctly as having the disease.
1,899 citations
Panos Deloukas1, Stavroula Kanoni1, Christina Willenborg2, Martin Farrall3 +201 more•Institutions (64)
TL;DR: An association analysis in CAD cases and controls identifies 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants strongly associated with CAD at a 5% false discovery rate (FDR).
Abstract: Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r(2) < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways.
1,518 citations
Duke University1, University of Melbourne2, Université de Montréal3, Royal College of Surgeons in Ireland4, University of Pennsylvania5, University of Washington6, Emory University7, Cincinnati Children's Hospital Medical Center8, Royal Children's Hospital9, Imperial College London10, New York University11, University of California, San Francisco12, University of Liverpool13, Royal Melbourne Hospital14, Columbia University15, Harvard University16, Vanderbilt University17, Cleveland Clinic18, Yeshiva University19, Mayo Clinic20, University of Pittsburgh21, University of Minnesota22, University of Virginia23, Saint Barnabas Medical Center24, University of Michigan25, Kaiser Permanente26, University of Chicago27, University of Texas Health Science Center at Houston28, Johns Hopkins University29, Children's Hospital Oakland Research Institute30, Boston Children's Hospital31, Oregon Health & Science University32, Cornell University33, United States Department of Veterans Affairs34, Washington University in St. Louis35
TL;DR: In this paper, a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms and Lennox-Gastaut syndrome (n = 115) was performed.
Abstract: Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown. Here we report a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms (n = 149) and Lennox-Gastaut syndrome (n = 115). We sequenced the exomes of 264 probands, and their parents, and confirmed 329 de novo mutations. A likelihood analysis showed a significant excess of de novo mutations in the ∼4,000 genes that are the most intolerant to functional genetic variation in the human population (P = 2.9 × 10(-3)). Among these are GABRB3, with de novo mutations in four patients, and ALG13, with the same de novo mutation in two patients; both genes show clear statistical evidence of association with epileptic encephalopathy. Given the relevant site-specific mutation rates, the probabilities of these outcomes occurring by chance are P = 4.1 × 10(-10) and P = 7.8 × 10(-12), respectively. Other genes with de novo mutations in this cohort include CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2, MTOR and NEDD4L. Finally, we show that the de novo mutations observed are enriched in specific gene sets including genes regulated by the fragile X protein (P < 10(-8)), as has been reported previously for autism spectrum disorders.
1,254 citations
TL;DR: This report summarizes the workshop discussions on key issues of the EPR effect and major gaps that need to be addressed to effectively advance nanoparticle-based drug delivery.
Abstract: Enhanced permeability of the tumor vasculature allows macromolecules to enter the tumor interstitial space, whereas the suppressed lymphatic filtration allows them to stay there. This phenomenon, enhanced permeability and retention (EPR), has been the basis of nanotechnology platforms to deliver drugs to tumors. However, progress in developing effective drugs using this approach has been hampered by heterogeneity of EPR effect in different tumors and limited experimental data from patients on effectiveness of this mechanism as related to enhanced drug accumulation. This report summarizes the workshop discussions on key issues of the EPR effect and major gaps that need to be addressed to effectively advance nanoparticle-based drug delivery.
1,247 citations
TL;DR: The roles of miRNAs and lncRNAs in cancer are summarized, with a focus on the recently identified novel mechanisms of action, and the current strategies in designing ncRNA-targeting therapeutics are discussed.
Abstract: The first cancer-targeted microRNA (miRNA) drug - MRX34, a liposome-based miR-34 mimic - entered Phase I clinical trials in patients with advanced hepatocellular carcinoma in April 2013, and miRNA therapeutics are attracting special attention from both academia and biotechnology companies. Although miRNAs are the most studied non-coding RNAs (ncRNAs) to date, the importance of long non-coding RNAs (lncRNAs) is increasingly being recognized. Here, we summarize the roles of miRNAs and lncRNAs in cancer, with a focus on the recently identified novel mechanisms of action, and discuss the current strategies in designing ncRNA-targeting therapeutics, as well as the associated challenges.
1,221 citations
TL;DR: This issue focuses on statistical methods in medical research and proposes two probabilistic models to estimate male-to-female HIV-1 transmission rate in one sexual contact.
Abstract: Since John Snow first conducted a modern epidemiological study in 1854 during a cholera epidemic in London, statistics has been associated with medical research. After Austin Bradford Hill published a series of articles on the use of statistical methodology in medical research in 1937, statistical considerations and computational tools have been paramount in conductingmedical research [1]. For the past century, statistics has played an important role in the advancement of medical research and medical research has stimulated rapid development of statistical methods. For example, the development of modern survival analysis-an important branch of statistics has aimed to solve problems encountered in clinical trials and large-scale epidemiological studies. In this era of evidence-based medicine, the development of novel statistical methods will continue to be crucial in medical research. With the expansion of computer capacity and advancement of computational techniques, it is inevitable that modern statistical methods will likely incorporate, to a greater degree, complex computational procedures. This issue focuses on statistical methods in medical research. Several novel methods aiming on solving different medical research questions are introduced. Some unique approaches of statistical analysis are also present. Hanagal and Sharma contribute two papers. The first one deals with a bivariate survival model. They examine a parameter estimation issue when the samples are taken from a bivariate log-logistic distribution with shared gamma frailty. They propose to use a Bayesian approach along with theMarkov ChainMonte Carlo computational technique for implementation. The computer simulation is conducted for performance evaluation. Two well-known datasets, one about acute leukemia and the other about kidney infection are applied as examples. The second paper contributed by Hanagal and Sharma examines the shared inverse Gaussian frailty model with the bivariate exponential baseline hazard. They first derive the likelihood of the joint survival function. In their Bayesian approach, the parameters of the baseline hazard are assumed to follow a gamma distribution while the coefficients of the regression relationship are assumed to follow an independent normal distribution. The dependence of two components of the survival function is tested. Three information criteria are used for model comparisons. The proposed method is applied to analyze diabetic retinopathy data. The paper by Chang, Lyer, Bullitt and Wang provides a method to find determinants of the brain arterial system. They represent the brain arterial system as a binary tree and apply the mixed logistic regression model to find significant covariates. The authors also demonstrate model selection methods for both fixed and random effects. A case study is presented using the method. This paper provides a rigorous approach for analyzing the binary branching structure data. It is potentially applicable to other tree structure data. Chakraborty proposes two probabilistic models to estimate male-to-female HIV-1 transmission rate in one sexual contact. One model is applicable when the transmitter cell counts are known and the other model is applicable when the receptor cell counts are known. By first uniformizing each transmitter (or receptor) cell count and assuming as a beta distribution, this paper algebraically derives the transition probability by imposing some boundary conditions based on scientific phenomena related to HIV infection. The paper by Yeh, Jiang, Garrard, Lei and Gajewski proposes to use a zero-truncated Poisson model to analyze human cancer tissues transplanted to mice when the positive counts of affected ducts is subject to right censoring. A Bayesian approach choosing a Gamma distribution as the prior is adopted. After implementing through complex computational procedures, this paper obtains the estimates of the coefficients and demonstrates model fitting through
1,127 citations
TL;DR: It is shown that nanoporous silicon particles can successfully perform all actions when they are coated with cellular membranes purified from leukocytes, and leukolike vectors retained their functions when injected in vivo, showing enhanced circulation time and improved accumulation in a tumour.
Abstract: The therapeutic efficacy of systemic drug-delivery vehicles depends on their ability to evade the immune system, cross the biological barriers of the body and localize at target tissues. White blood cells of the immune system--known as leukocytes--possess all of these properties and exert their targeting ability through cellular membrane interactions. Here, we show that nanoporous silicon particles can successfully perform all these actions when they are coated with cellular membranes purified from leukocytes. These hybrid particles, called leukolike vectors, can avoid being cleared by the immune system. Furthermore, they can communicate with endothelial cells through receptor-ligand interactions, and transport and release a payload across an inflamed reconstructed endothelium. Moreover, leukolike vectors retained their functions when injected in vivo, showing enhanced circulation time and improved accumulation in a tumour.
University of Texas Health Science Center at Houston1, University of California, San Francisco2, Oregon Health & Science University3, University of Pittsburgh4, Medical College of Wisconsin5, University of Washington6, University of Cincinnati7, University of Texas Health Science Center at San Antonio8, University of Texas Southwestern Medical Center9, San Antonio Military Medical Center10
TL;DR: Higher plasma and platelet ratios early in resuscitation were associated with decreased mortality in patients who received transfusions of at least 3 units of blood products during the first 24 hours after admission, and among survivors at 24 hours, the subsequent risk of death by day 30 was not associated with plasma or Platelet ratios.
Abstract: Objective To relate in-hospital mortality to early transfusion of plasma and/or platelets and to time-varying plasma:red blood cell (RBC) and platelet:RBC ratios. Design Prospective cohort study documenting the timing of transfusions during active resuscitation and patient outcomes. Data were analyzed using time-dependent proportional hazards models. Setting Ten US level I trauma centers. Patients Adult trauma patients surviving for 30 minutes after admission who received a transfusion of at least 1 unit of RBCs within 6 hours of admission (n = 1245, the original study group) and at least 3 total units (of RBCs, plasma, or platelets) within 24 hours (n = 905, the analysis group). Main Outcome Measure In-hospital mortality. Results Plasma:RBC and platelet:RBC ratios were not constant during the first 24 hours (P Conclusions Higher plasma and platelet ratios early in resuscitation were associated with decreased mortality in patients who received transfusions of at least 3 units of blood products during the first 24 hours after admission. Among survivors at 24 hours, the subsequent risk of death by day 30 was not associated with plasma or platelet ratios.
TL;DR: The first large-scale application of the phenome-wide association study (PheWAS) paradigm within electronic medical records (EMRs) is reported, an unbiased approach to replication and discovery that interrogates relationships between targeted genotypes and multiple phenotypes in EMR-based cohorts.
Abstract: Candidate gene and genome-wide association studies (GWAS) have identified genetic variants that modulate risk for human disease; many of these associations require further study to replicate the results. Here we report the first large-scale application of the phenome-wide association study (PheWAS) paradigm within electronic medical records (EMRs), an unbiased approach to replication and discovery that interrogates relationships between targeted genotypes and multiple phenotypes. We scanned for associations between 3,144 single-nucleotide polymorphisms (previously implicated by GWAS as mediators of human traits) and 1,358 EMR-derived phenotypes in 13,835 individuals of European ancestry. This PheWAS replicated 66% (51/77) of sufficiently powered prior GWAS associations and revealed 63 potentially pleiotropic associations with P < 4.6 × 10⁻⁶ (false discovery rate < 0.1); the strongest of these novel associations were replicated in an independent cohort (n = 7,406). These findings validate PheWAS as a tool to allow unbiased interrogation across multiple phenotypes in EMR-based cohorts and to enhance analysis of the genomic basis of human disease.
TL;DR: It is suggested that triglyceride-rich lipoproteins causally influence risk for CAD, and the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk.
Abstract: Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
University of Washington1, National University of Singapore2, Cedars-Sinai Medical Center3, National Institutes of Health4, Erasmus University Rotterdam5, University of Newcastle6, University of Wisconsin-Madison7, University of Iceland8, University of Texas Health Science Center at Houston9, University of Melbourne10, University of Sydney11, Boston University12, University of Auckland13, Group Health Cooperative14, University of Amsterdam15, Singapore National Eye Center16, Agency for Science, Technology and Research17, University of California, San Francisco18, University of Michigan19, Harvard University20
TL;DR: This genome-wide association study of retinopathy in individuals without diabetes showed little evidence of genetic associations and further studies are needed to identify genes associated with these signs in order to help unravel novel pathways and determinants of microvascular diseases.
Abstract: Background
Mild retinopathy (microaneurysms or dot-blot hemorrhages) is observed in persons without diabetes or hypertension and may reflect microvascular disease in other organs. We conducted a genome-wide association study (GWAS) of mild retinopathy in persons without diabetes.
University of Texas MD Anderson Cancer Center1, Radiation Therapy Oncology Group2, University of Lausanne3, University of Texas Health Science Center at Houston4, Medical College of Wisconsin5, Tel Aviv Sourasky Medical Center6, Johns Hopkins University7, University of Edinburgh8, Maastricht University9, University Hospitals Bristol NHS Foundation Trust10, Rambam Health Care Campus11, Ohio State University12, Emory University13, University of Maryland, Baltimore14
TL;DR: This study did not demonstrate improved efficacy for DD temozolomide for newly diagnosed GBM, regardless of methylation status, but it did confirm the prognostic significance of MGMT methylation.
Abstract: Purpose Radiotherapy with concomitant and adjuvant temozolomide is the standard of care for newly diagnosed glioblastoma (GBM) O 6 -methylguanine-DNA methyltransferase (MGMT) methylation status may be an important determinant of treatment response Dose-dense (DD) temozolomide results in prolonged depletion of MGMT in blood mononuclear cells and possibly in tumor This trial tested whether DD temozolomide improves overall survival (OS) or progression-free survival (PFS) in patients with newly diagnosed GBM Patients and Methods This phase III trial enrolled patients older than age 18 years with a Karnofsky performance score of 60 with adequate tissue Stratification included clinical factors and tumor MGMT methylation status Patients were randomly assigned to standard temozolomide (arm 1) or DD temozolomide (arm 2) for 6 to 12 cycles The primary end point was OS Secondary analyses evaluated the impact of MGMT status
TL;DR: Overall, patients treated with memantine had better cognitive function over time; specifically, memantine delayed time to cognitive decline and reduced the rate of decline in memory, executive function, and processing speed in patients receiving WBRT.
Abstract: Radiotherapy is a proven curative and palliative therapeutic tool in the treatment of a wide variety of primary and metastatic brain tumors in adults, and recent advances in multimodality therapy have led to improvements in survival. As survival has improved, more attention has been directed toward long-term treatment-related morbidity. Specifically, the effect of cerebral radiotherapy on long-term cognitive performance is a major concern.1 The vascular hypothesis of radiation injury attributes radiation-induced accelerated atherosclerosis and mineralizing microangiopathy to the vascular insufficiency and infarction that can develop after radiotherapy.2 Therefore, the mechanisms of radiation-induced injury are similar to the small vessel disease seen with vascular dementia.3,4 For this reason, there is great interest in studying vascular dementia treatments to prevent or reduce radiation-induced cognitive injury. Additionally, because treatment of cognitive decline after radiation is limited, new approaches aimed at preventing the detrimental cognitive effect of whole-brain radiotherapy (WBRT) should be developed.
Glutamate is the principal excitatory amino acid neurotransmitter in cortical and hippocampal neurons.5 One of the receptors activated by glutamate is the N-methyl-D-aspartate (NMDA) receptor, which is involved in learning and memory.6 Ischemia can induce excessive NMDA stimulation and lead to excitotoxicity, suggesting that agents that block pathologic stimulation of NMDA receptors may protect against further damage in patients with vascular dementia.7 One such agent is memantine, an NMDA receptor antagonist. Memantine is a noncompetitive, low-affinity, open-channel blocker that has been shown to be neuroprotective in preclinical models.8–10 In 2 placebo-controlled phase III trials, memantine was well tolerated and effective in treating vascular dementia, especially in patients with small vessel disease.11,12 The Radiation Therapy Oncology Group (RTOG) therefore initiated a placebo-controlled, double-blind, randomized trial to evaluate the potential protective effect of memantine on neurocognitive function in patients receiving WBRT.
TL;DR: New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.
Abstract: Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.
TL;DR: Rich functional annotations for SNVs and genes have been added into the new version, including allele frequencies observed in the 1000 Genomes Project phase 1 data and the NHLBI Exome Sequencing Project, various gene IDs from different databases, functional descriptions of genes, gene expression and gene interaction information, among others.
Abstract: dbNSFP is a database developed for functional prediction and annotation of all potential non-synonymous single-nucleotide variants (nsSNVs) in the human genome. This database significantly facilitates the process of querying predictions and annotations from different databases/web-servers for large amounts of nsSNVs discovered in exome-sequencing studies. Here we report a recent major update of the database to version 2.0. We have rebuilt the SNV collection based on GENCODE 9 and currently the database includes 87,347,043 nsSNVs and 2,270,742 essential splice site SNVs (an 18% increase compared to dbNSFP v1.0). For each nsSNV dbNSFP v2.0 has added two prediction scores (MutationAssessor and FATHMM) and two conservation scores (GERP++ and SiPhy). The original five prediction and conservation scores in v1.0 (SIFT, Polyphen2, LRT, MutationTaster and PhyloP) have been updated. Rich functional annotations for SNVs and genes have also been added into the new version, including allele frequencies observed in the 1000 Genomes Project phase 1 data and the NHLBI Exome Sequencing Project, various gene IDs from different databases, functional descriptions of genes, gene expression and gene interaction information, among others. dbNSFP v2.0 is freely available for download at http://sites.google.com/site/jpopgen/dbNSFP.
TL;DR: A genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry finds a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
Abstract: Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
TL;DR: These AMIA recommendations are intended to stimulate informed debate, provide a plan to increase understanding of the impact of usability on the effective use of health IT, and lead to safer and higher quality care with the adoption of useful and usable EHR systems.
Stig E. Bojesen1, Stig E. Bojesen2, Karen A. Pooley3, Sharon E. Johnatty4 +452 more•Institutions (129)
TL;DR: Using the Illumina custom genotyping array iCOGs, SNPs at the TERT locus in breast, ovarian and BRCA1 mutation carrier cancer cases and controls and leukocyte telomere measurements are analyzed to find associations cluster into three independent peaks.
Abstract: TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOG, we analyzed similar to 480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 x 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 x 10(-8)) and BRCA1 mutation carrier (P = 1.1 x 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 x 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 x 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 x 10(-12)) and BRCA1 mutation carrier (P = 1.6 x 10-14) breast and invasive ovarian (P = 1.3 x 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.
TL;DR: Analysis of whole-exome sequencing data from 151 tumors revealed the phosphoinositide 3-kinase (PI3K) pathway to be the most frequently mutated oncogenic pathway, suggesting that PI3K pathway mutations may serve as predictive biomarkers for treatment selection.
Abstract: Genomic findings underscore the heterogeneity of head and neck squamous cell carcinoma (HNSCC). Identification of mutations that predict therapeutic response would be a major advance. We determined the mutationally altered, targetable mitogenic pathways in a large HNSCC cohort. Analysis of whole-exome sequencing data from 151 tumors revealed the phosphoinositide 3-kinase (PI3K) pathway to be the most frequently mutated oncogenic pathway (30.5%). PI3K pathway-mutated HNSCC tumors harbored a significantly higher rate of mutations in known cancer genes. In a subset of human papillomavirus-positive tumors, PIK3CA or PIK3R1 was the only mutated cancer gene. Strikingly, all tumors with concurrent mutation of multiple PI3K pathway genes were advanced (stage IV), implicating concerted PI3K pathway aberrations in HNSCC progression. Patient-derived tumorgrafts with canonical and noncanonical PIK3CA mutations were sensitive to an mTOR/PI3K inhibitor (BEZ-235), in contrast to PIK3CA-wild-type tumorgrafts. These results suggest that PI3K pathway mutations may serve as predictive biomarkers for treatment selection.
University of Texas Health Science Center at Houston1, University of Texas at Austin2, University of Missouri–Kansas City3, University of Ottawa4, Hochschule Hannover5, Ochsner Medical Center6, Cleveland Clinic7, Harvard University8, Washington University in St. Louis9, University of Zurich10, VU University Medical Center11, University of Turku12, University of California, Los Angeles13, Ludwig Maximilian University of Munich14, Wayne State University15, University of Maryland, Baltimore16, Icahn School of Medicine at Mount Sinai17
TL;DR: The basic concepts that hold true for whatever technology measures coronary physiology directly and reliably are clarified, here focusing on positron emission tomography and its interplay with intracoronary measurements.
TL;DR: The current approaches to gene discovery and mutation detection for retinitis pigmentosa are summarized, and pitfalls and unsolved problems are indicated.
Abstract: Retinitis pigmentosa (RP) is a heterogeneous set of inherited retinopathies with many disease-causing genes, many known mutations, and highly varied clinical consequences. Progress in finding treatments is dependent on determining the genes and mutations causing these diseases, which includes both gene discovery and mutation screening in affected individuals and families. Despite the complexity, substantial progress has been made in finding RP genes and mutations. Depending on the type of RP, and the technology used, it is possible to detect mutations in 30–80% of cases. One of the most powerful approaches to genetic testing is high-throughput ‘deep sequencing’, that is, next-generation sequencing (NGS). NGS has identified several novel RP genes but a substantial fraction of previously unsolved cases have mutations in genes that are known causes of retinal disease but not necessarily RP. Apparent discrepancy between the molecular defect and clinical findings may warrant reevaluation of patients and families. In this review, we summarize the current approaches to gene discovery and mutation detection for RP, and indicate pitfalls and unsolved problems. Similar considerations apply to other forms of inherited retinal disease.
TL;DR: A list of caveats is developed to inform would-be users of such data as well as provide an informatics roadmap that aims to insure this opportunity to augment comparative effectiveness research can be best leveraged.
Abstract: The growing amount of data in operational electronic health record systems provides unprecedented opportunity for its reuse for many tasks, including comparative effectiveness research. However, there are many caveats to the use of such data. Electronic health record data from clinical settings may be inaccurate, incomplete, transformed in ways that undermine their meaning, unrecoverable for research, of unknown provenance, of insufficient granularity, and incompatible with research protocols. However, the quantity and real-world nature of these data provide impetus for their use, and we develop a list of caveats to inform would-be users of such data as well as provide an informatics roadmap that aims to insure this opportunity to augment comparative effectiveness research can be best leveraged.
California State University San Marcos1, Alfred Wegener Institute for Polar and Marine Research2, University of Alberta3, United States Department of Energy4, J. Craig Venter Institute5, Institut national de la recherche agronomique6, Ruhr University Bochum7, University of Maryland, College Park8, Monterey Bay Aquarium Research Institute9, University College London10, Centre national de la recherche scientifique11, Harvard University12, Ghent University13, Rothamsted Research14, Pierre-and-Marie-Curie University15, University of Essex16, Pontifical Catholic University of Chile17, Plymouth Marine Laboratory18, Woods Hole Oceanographic Institution19, Columbia University20, University of Cologne21, Natural History Museum22, Rutgers University23, Georgia Institute of Technology24, Moscow Institute of Physics and Technology25, University of Ostrava26, National Institutes of Health27, University of Nebraska Medical Center28, University of Southampton29, Oregon State University30, Dalhousie University31, University of Texas Health Science Center at Houston32, University of East Anglia33, University of Potsdam34, University of Bergen35, University of Washington36, University of Freiburg37, University of Marburg38, University of Los Andes39, Bigelow Laboratory For Ocean Sciences40, University of Exeter41, Oak Ridge National Laboratory42, California State University, Chico43, University of Tsukuba44
TL;DR: Comparisons across strains demonstrate that E. huxleyi, which has long been considered a single species, harbours extensive genome variability reflected in different metabolic repertoires, and reveals a pan genome (core genes plus genes distributed variably between strains) probably supported by an atypical complement of repetitive sequence in the genome.
Abstract: Coccolithophores have influenced the global climate for over 200 million years(1). These marine phytoplankton can account for 20 per cent of total carbon fixation in some systems(2). They form blooms that can occupy hundreds of thousands of square kilometres and are distinguished by their elegantly sculpted calcium carbonate exoskeletons (coccoliths), rendering them visible from space(3). Although coccolithophores export carbon in the form of organic matter and calcite to the sea floor, they also release CO2 in the calcification process. Hence, they have a complex influence on the carbon cycle, driving either CO2 production or uptake, sequestration and export to the deep ocean(4). Here we report the first haptophyte reference genome, from the coccolithophore Emiliania huxleyi strain CCMP1516, and sequences from 13 additional isolates. Our analyses reveal a pan genome (core genes plus genes distributed variably between strains) probably supported by an atypical complement of repetitive sequence in the genome. Comparisons across strains demonstrate that E. huxleyi, which has long been considered a single species, harbours extensive genome variability reflected in different metabolic repertoires. Genome variability within this species complex seems to underpin its capacity both to thrive in habitats ranging from the equator to the subarctic and to form large-scale episodic blooms under a wide variety of environmental conditions.
TL;DR: Treatment with TNFα inhibitors appears to reduce radiographic progression in patients with ankylosing spondylitis, especially with early initiation and with longer duration of followup, and the protective effect of TNF α inhibitors was stronger after propensity score matching.
Abstract: Objective
To study the effect of tumor necrosis factor α (TNFα) inhibitors on progressive spinal damage in patients with ankylosing spondylitis (AS).
Methods
All AS patients meeting the modified New York criteria who had been monitored prospectively and had at least 2 sets of spinal radiographs a minimum of 1.5 years apart were included in the study (n = 334). The patients received standard therapy, which included nonsteroidal antiinflammatory drugs and TNFα inhibitors. Radiographic severity was assessed by the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Patients with a rate of AS progression that was ≥1 mSASSS unit/year were considered progressors. Univariable and multivariable regression analyses were done. Propensity score matching and sensitivity analysis were performed. A zero-inflated negative binomial (ZINB) model was used to analyze the effect of TNFα inhibitors on the change in the mSASSS with varying followup periods. Potential confounders, such as disease activity (as assessed by the Bath Ankylosing Spondylitis Disease Activity Index), the erythrocyte sedimentation rate, C-reactive protein level, HLA–B27 positivity, sex, age at onset, smoking burden (number of pack-years), and baseline damage, were included in the model.
Results
TNFα inhibitor treatment was associated with a 50% reduction in the odds of progression, with an odds ratio (OR) of 0.52 (95% confidence interval [95% CI] 0.30–0.88, P = 0.02). Patients with a delay of >10 years in starting therapy were more likely to experience progression as compared to those who started earlier (OR 2.4 [95% CI 1.09–5.3], P = 0.03). In the ZINB model, the use of TNFα inhibitors significantly reduced disease progression when the gap between radiographs was >3.9 years. The protective effect of TNFα inhibitors was stronger after propensity score matching.
Conclusion
Treatment with TNFα inhibitors appears to reduce radiographic progression in AS patients, especially with early initiation and with longer duration of followup.
TL;DR: Data show that persisting vaccine depots can induce specific T cell sequestration, dysfunction and deletion at vaccination sites; short-lived formulations may overcome these limitations and result in greater therapeutic efficacy of peptide-based cancer vaccines.
Abstract: To understand why cancer vaccine-induced T cells often do not eradicate tumors, we studied immune responses in mice vaccinated with gp100 melanoma peptide in incomplete Freund's adjuvant (peptide/IFA), which is commonly used in clinical cancer vaccine trials. Peptide/IFA vaccination primed tumor-specific CD8(+) T cells, which accumulated not in tumors but rather at the persisting, antigen-rich vaccination site. Once there, primed T cells became dysfunctional and underwent antigen-driven, interferon-γ (IFN-γ)- and Fas ligand (FasL)-mediated apoptosis, resulting in hyporesponsiveness to subsequent vaccination. Provision of CD40-specific antibody, Toll-like receptor 7 (TLR7) agonist and interleukin-2 (IL-2) reduced T cell apoptosis but did not prevent vaccination-site sequestration. A nonpersisting vaccine formulation shifted T cell localization toward tumors, inducing superior antitumor activity while reducing systemic T cell dysfunction and promoting memory formation. These data show that persisting vaccine depots can induce specific T cell sequestration, dysfunction and deletion at vaccination sites; short-lived formulations may overcome these limitations and result in greater therapeutic efficacy of peptide-based cancer vaccines.
TL;DR: Implementation of REBOA is a feasible and effective means of proactive aortic control for patients in end-stage shock from blunt and penetrating mechanisms and can be performed by trauma and acute care surgeons who have benefited from instruction on a limited endovascular skill set.
Abstract: : BACKGROUND: A requirement for improved methods of hemorrhage control and resuscitation along with the translation of endovascular specialty skills has resulted in reappraisal of resuscitative endovascular balloon occlusion of the aorta (REBOA) for end-stage shock. The objective of this report was to describe implementation of REBOA in civilian trauma centers. METHODS: Descriptive case series of REBOA (December 2012 to March 2013) used in scenarios of end-stage hemorrhagic shock at the University of Maryland, R. Adams Cowley Shock Trauma Center, Baltimore, Maryland, and Herman Memorial Hospital, The Texas Trauma Institute, Houston, Texas. RESULTS: REBOA was performed by trauma and acute care surgeons for blunt (n 4) and penetrating (n 2) mechanisms. Three cases were REBOA in the descending thoracic aorta (Zone I) and three in the infrarenal aorta (Zone III). Mean (SD) systolic blood pressure at the time of REBOA was 59 (27) mm Hg, and mean (SD) base deficit was 13 (5). Arterial access was accomplished using both direct cutdown (n 3) and percutaneous (n 3) access to the common femoral artery. REBOA resulted in a mean (SD) increase in blood pressure of 55 (20)mmHg, and the mean (SD) aortic occlusion time was 18 (34) minutes. There were no REBOA-related complications, and there was no hemorrhage-related mortality. CONCLUSION: REBOA is a feasible and effective means of proactive aortic control for patients in end-stage shock from blunt and penetrating mechanisms. With available technology, this method of resuscitation can be performed by trauma and acute care surgeons who have benefited from instruction on a limited endovascular skill set. Future work should be aimed at devices that allow easy, fluoroscopy-free access and studies to define patients most likely to benefit from this procedure.