17516 results for "free coins in fc 26 Visit Buyfc26coins.com for latest FC 26 coins news..Y2KA"

in 55.85 milliseconds.

• A Genome-Wide Association Study in Participants Experiencing Breast Cancer Events in High-Risk Postmenopausal Women Receiving Selective Estrogen Receptor Modulators on NSABP Trials P-1 and P-2. A Collaboration Between the NIH Pharmacogenetics Research Network and the RIKEN Yokohama Institute Center for Genomic Medicine

  The primary aim of this study is to identify genes related to the occurrence of breast events, defined as occurrence of invasive breast cancer or ductal carcinoma in situ (DCIS), in women at high risk of developing breast cancer who have received a Selective Estrogen Receptor Modulator (SERM - tamoxifen or raloxifene) on the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 or P-2 trials. Cases and controls were selected from the tamoxifen arm in the P-1 and from the tamixifen and raloxifene arms in the P-2 trial. For the P-1 trial, cases and controls were required to be 50 years of age or older at time of entry. Cases were females who experienced an invasive breast cancer or DCIS on P-1 or P-2. Controls were females who did not experience an invasive breast cancer or DCIS. A nested matched case-control design was used, with matching on the following factors: 1) trial and treatment arm (P-1 tamoxifen, P-2 tamoxifen, P-2 raloxifene); 2) age at trial entry (when controls could not be exactly matched on age, we incremented the age of matching by +/- 1 year, in sequence until a match was obtained without exceeding +/- 5 years); 5-year predicted breast cancer risk based on the Gail model ( <2.00%, 2.01-3.00, 3.01-5.00, >5.01), 3) history of lobular carcinoma in situ (yes vs. no); 4) history of atypical hyperplasia in breast (yes vs. no); 5) time on study (controls must be on study at least as long as the time to diagnosis of the breast event for the case). Because 94.2% of the participants on P-1 and P-2 treated with tamoxifen or raloxifene were Caucasian, this study was restricted to only Caucasians. Two cases and two controls were randomly chosen as duplicates for quality control of genotype concordance. The DNA samples were plated into 96-well plates, with cases and controls randomly distributed across the plates. A Caucasian parent-child CEPH trio from the HapMap project was included to check for Mendelian transmission of alleles. Genotypes were determined by the RIKEN Center for Genomic Medicine with the Illumina Human610-Quad.

  Study phs000305

• Evolution of a FLT3-TKD mutated subclone at meningeal relapse in acute promyelocytic leukemia (H021)

  Here we report the case of an acute promyelocytic leukemia (APL) patient who, though negative for FLT3 mutations at diagnosis, developed isolated FLT3-TKD positive meningeal relapse, which, in retrospect, could be traced back to a minute bone marrow subclone present at first diagnosis. Initially, the 48-year old female diagnosed with high-risk APL had achieved complete molecular remission after standard treatment with all-trans retinoic acid (ATRA) and chemotherapy according to the AIDA protocol. 13 months after start of ATRA maintenance the patient suffered clinically overt meningeal relapse along with minute molecular traces of PML/RARA in the bone marrow. Following treatment with arsenic trioxide (ATO) and ATRA in combination with intrathecal cytarabine and methotrexate, the patient achieved a complete molecular remission in both cerebrospinal fluid (CSF) and bone marrow, which currently lasts for two years after completion of therapy. Whole exome sequencing and subsequent ultradeep targeted re-sequencing revealed a heterozygous FLT3-TKD mutation in CSF leukemic cells (p.D835Y, c.2503G>T, 1000/1961 reads (51%)), which was undetectable in the concurrent bone marrow sample. Interestingly, the FLT3-TKD mutated meningeal clone originated from a small bone marrow subclone present in a variant allele frequency of 0.4% (6/1553 reads) at initial diagnosis. This case highlights the concept of clonal evolution with a subclone harboring an additional mutation being selected as the “fittest” and leading to meningeal relapse. It also further supports earlier suggestions that FLT3 mutations may play a role for migration and clonal expansion in the CSF sanctuary site.H021

  Study EGAS00001001848

• A Randomized, Double-Blind, Crossover Study of Sodium Phenylbutyrate (Buphenyl) and Low-Dose Arginine (100 mg/kg/day) Compared to High-Dose Arginine (500 mg/kg/day) Alone on Liver Function, Ureagenesis and Subsequent Nitric Oxide Production in Patients with Argininosuccinic Aciduria (ASA)

  Individuals with Urea Cycle Disorders (UCD) cannot remove ammonia, a waste product, from the blood. At present there is little information on the use of sodium phenylbutyrate (Buphenyl™) in children with argininosuccinic aciduria (ASA). It is hoped that this drug may help lower ammonia and argininosuccinic acid levels in patients with ASA. Through this study we hope to learn whether the use of sodium phenylbutyrate (Buphenyl™) in patients with ASA, in addition to diet and arginine therapy, will decrease liver damage and the number of periods during which ammonia levels are high. The primary study objective is to determine if the treatment of ASA patients with sodium phenylbutyrate (Buphenyl™) in conjunction with lowered doses of arginine improves liver function as measured by short-term assessment of synthetic activity and the use of stable isotope tracers to assess ureagenesis and nitric oxide production. Twelve patients with ASA will be studied using a randomized, cross-over design. Medical records will be reviewed to confirm the diagnosis prior to enrollment. Patients will be on the each arm of the study for one week each preceded by a three day washout period. Patients will come to the Baylor College of Medicine General Clinical Research Center in Texas Children's Hospital for an inpatient hospitalization. This hospitalization is for diet control, clinical evaluation, and stable isotope infusions for measurement of in vivo rates of ureagenesis and nitric oxide production. During the washout periods Buphenyl™ or other alternative route medications, e.g., benzoate, will be discontinued and arginine will be administered at the standard therapeutic dose of 500 mg/kg/day or 10 grams/m2. Following randomization, subjects will be maintained on either high-dose arginine (500 mg/kg/day or 10 grams/m2) alone, or the alternative of low-dose arginine (100 mg/kg/d or 2 grams/m2) along with sodium phenylbutyrate (500 mg/kg/day or 10 grams/m2). For the second week they will be crossed over to the other arm of the study preceded by another three day washout. Previous medications and dietary protein intake (0.6 g/kg/day or current metabolic diet) will be continued during both arms of the study. The two arms may be performed as separate ten-day admissions. The decision to design the study with two arms, high-dose arginine and low-dose arginine/Buphenyl™, was reached after weighing several considerations. First, the current accepted practice for treatment of ASA is high-dose arginine. Based on metabolic flux studies, we have quantified the effects of this dose of arginine as compared to standard doses of Buphenyl™/phenylacetate on ureagenesis. Since the study is not designed or intended to address the independent effects of Buphenyl™ as compared to arginine alone, Buphenyl™ was added for safety reasons to accommodate loss of clearance of nitrogen by decreasing the arginine dose. Moreover, based on our experience with recruiting for previous versions of this study, most ASA patients with liver dysfunction are on an alternative route ammonia scavenger medication in addition to arginine. We found that this has in fact become an accepted practice. Hence, when considering study design from both a safety and recruitment perspective, it was most reasonable to design the study to investigate specifically the hypothesis that the production and presence of argininosuccinic acid leads to liver dysfunction. Since both low-dose arginine with Buphenyl™ and high-dose arginine alone lead to a decreased production of argininosuccinic acid, and both are currently accepted therapies in ASA and UCDs in general, the need to address their effects distinctly is not being investigated at this time. Sodium phenylbutyrate dosage will be 500 mg/kg/day in patients weighing less than 20kg and 10 g/m2/day in larger patients. Daily dosage will be given in equally divided doses 4 times per day. In order to ensure that the study remains double-blind to investigators, study staff and subjects, the Investigational Pharmacy Service at Texas Children's Hospital will dispense both the Buphenyl™ and arginine in powder form which is compounded into capsules or will be mixed with syrpalta (up to 5 grams will dissolve in 10cc liquid) and administered orally or through nasogastric or gastrostomy tube. No nasogastric tube should be placed or gastrostomy performed solely for the purpose of inclusion in this study. Because the reported adverse effects of sodium phenylbutyrate include gastritis, participants will be started on a standard dose of ranitidine (Zantac™), or comparable drug, during both arms of the study.

  Study phs001305

• HudsonAlpha Institute for Biotechnology Clinical Sequencing Exploratory Research (CSER): Genomic Diagnosis in Children with Developmental Delay

  The overarching goal of this project is to explore the ability for whole exome and genome sequencing technologies to identify the genetic causes of unexplained developmental delay, intellectual disability (DD/ID), and related congenital anomalies in children. Such information may be useful as an endpoint to the otherwise fruitless "diagnostic odyssey" that many DD/ID affected families undergo and in some cases, identification of these genetic variants may point to better therapeutic or educational options by precisely defining the root cause(s) of the child's condition. We seek to identify causal, diagnostically relevant, genetic variants in children with developmental delay and/or intellectual disability (DD/ID). In addition, because our analytical approach includes sequencing probands and their parents (parent-offspring trios and duos; parents are sequenced when available), secondary findings will be returned to adults (parents) at their request. The aims of this research project include: 1) Use exome and whole genome sequencing to identify genetic variation that results in DD/ID. 2) Return primary genetic results (DD/ID causative) as well as secondary findings to probands and their parents, respectively. 3) Understand how the return of genomic test results affects the health and well-being of study participants. The children participating in this study are patients at, or referrals to, North Alabama Children's Specialist (NACS) in Huntsville, Alabama. All blood samples from probands and their parents will be collected at NACS (project 1). Sequencing will be completed at the HudsonAlpha Institute for Biotechnology, with validation (via Sanger sequencing) conducted at Emory University for all returned variants (project 2). The University of Louisville will oversee questionnaires, surveys and interviews aimed at understanding study participants' perception of, and response to, genetic test results, in addition to assessment of secondary findings preferences (project 3).A subset of variants, largely those determined to be diagnostic or variants of uncertain significance for study participants at the time of disclosure, have been submitted to ClinVar. These variants are listed as part of the "CSER-HudsonAlpha" study within the database.

  Study phs001089

• A Genome-Wide Association Study of Heroin Dependence

  This collaboration of Australian and American investigators aims to identify genes associated with liability for heroin dependence. The project uses a case-control design in which cases met lifetime DSM-IV criteria for heroin dependence. Controls included assessed individuals who did not meet DSM-IV heroin dependence criteria and unassessed general population controls. Cases and controls were obtained from the several large investigations including: The Comorbidity and Trauma Study, Heroin Dependence in Western Australia, the OZ-ALC Study, a Twin Study of Mole Development in Adolescence, and ongoing genetic studies of substance dependence conducted by investigators at Yale and collaborating institutions. These projects are briefly described below. The Comorbidity and Trauma Study (PI: Elliot Nelson), a retrospective case-control study examining genetic and environmental factors contributing to heroin dependence liability. The study was funded by the National Institute on Drug Abuse (NIDA), and was run in collaboration with Washington University, the Queensland Institute of Medical Research (QIMR), and the National Drug and Alcohol Research Centre (NDARC), University of New South Wales. Case participants were recruited from maintenance clinics in the greater Sydney area. Control participants were recruited from employment centres and community centres, open street malls, and local press servicing the same geographical area as the opioid maintenance treatment clinics and either denied recreational use of opioids or had used these drugs recreationally fewer than 11 times lifetime. The prevalence in these individuals of non-opioid licit drug dependence and illicit drug dependence as well as childhood trauma exposure and other psychiatric disorders is elevated considerably versus estimates of similar measures in Australian general population samples. Participants provided blood samples as a source of DNA and completed a comprehensive psychiatric diagnostic interview based on the Semi-Structured Assessment of the Genetics of Alcoholism - Australia (SSAGA-OZ) augmented with sections drawn from other instruments assessing childhood trauma exposure, family history, and screening for borderline personality disorder. Heroin Dependence in Western Australia (PI: Sybille Schwab) is a study focusing both on genetic contributions to heroin dependence and response to naltrexone treatment of the disorder. Participants completed a clinical assessment and provided blood samples during their treatment at the Perth Naltrexone Clinic now name as the Fresh Start Recovery Programme. Funding for the project was provided by the Australia Government's National Health and Medical Research Council (Grant # 513862; PI: Sybille Schwab) Affected subjects from ongoing genetic studies of substance dependence conducted by investigators at Yale (PI: Joel Gelernter) and collaborating institutions were collected in the course of several NIDA-funded studies. Those included in the current set were assessed by means of the SSADDA (Semi-Structured Assessment for Drug Dependence and Alcoholism). All are opioid dependent European-Americans, and all list heroin as the opioid must used. Most were collected at Yale University School of Medicine or University of CT School of Medicine under the supervision of Drs Joel Gelernter and Henry Kranzler. Control subjects were also collected in the course of several NIDA- and NIAAA-funded studies. Those included in the current set were assessed by means of the SSADDA (Semi-structured Assessment for Drug Dependence and Alcoholism). Most were collected at Yale University School of Medicine or University of Connecticut School of Medicine under the supervision of Drs Joel Gelernter and Henry Kranzler. The OZ-ALC Study (PI: Andrew Heath) consists of a large group of twins and their family members ascertained from the general population Australian Twin Registry who have participated in ongoing research projects. For the control investigation, we have selected individuals who do meet criteria for illicit drug dependence who have had GWAS genotyping with the Illumina Human CNV370-Quad. Inclusion of individuals with alcohol dependence or nicotine dependence was minimized. For a more detailed description of the study, please see: http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000181.v1.p1 The Twin Study of Mole Development in Adolescence (PI: Nick Martin) is an ongoing investigation of melanocytic naevi funded by the Australian Government's National Health and Medical Research Council (Grant # 389891; PI: Nick Martin). For the current project, unassessed parents of these twins will serve as a control group. These individuals will either have been previously genotyped with the Illumina Human 610-Quad BeadChip or will be genotyped as part of the current project. Parents have largely survived the period of risk for heroin dependence and, by virtue of their participation in this research, are very likely to have a prevalence of heroin dependence lower than that in the general population (i.e., <0.7%). In order to understand the immune modulatory effect of opioids across peripheral blood immune populations, a second study (PI: Christine S. Cheng) analyzed single cell RNA-seq profiles from the PBMCs of a subset of case participants and control participants from the Comorbidity and Trauma Study (PI: Elliot Nelson). The study assessed and identified transcriptional changes between opioid dependent and control samples across naive and LPS stimulated immune populations.

  Study phs000277

• Field Studies of Human Immunity to Amebiasis in Bangladesh (NIH Birth Cohort) and Exploration of the Biologic Basis for Underperformance of Oral Polio and Rotavirus Vaccines in Bangladesh (PROVIDE)

  NIH birth cohort study Amebiasis is a common cause of diarrhea and is associated with malnutrition in grade-school aged children in an urban slum of Dhaka, Bangladesh. Field Studies of Human Immunity to Amebiasis in Bangladesh was designed to determine the contribution of amebiasis to illness in the first 2 years of life when most deaths due to diarrhea occur, and understand the immunologic and genetic factors that protect children from amebiasis. The hypothesis underlying the study is that susceptibility to amebiasis is determined by host innate and acquired immune responses that vary between individuals in part due to: human genetic polymorphisms; environmental influences including malnutrition and concurrent geohelminth infection; and virulence differences among Entamoeba histolytica genotypes. Specific aims proposed in the design of the study were to: a) Measure the incidence of amebiasis and correlate it with human and parasite genetic polymorphisms, immune responses, and environmental factors such as geohelminth infection and malnutrition; b) Test the hypothesis that protective immunity is mediated both by innate immune responses initiated via TLR stimulation as well as by mucosal IgA against the Gal/GalNAc lectin and systemic IFN-γ; c) Test for the association of common genetic polymorphisms in host innate and acquired immune genes with incidence of amebiasis. 629 newborn babies were enrolled and followed regularly through bi-weekly surveillance for diarrheal episodes, anthropometry at 3-month interval until 60 months of age. The infants that were consented for GWAS analysis were genotyped in 3 separate batches at different times, on 3 different arrays. Quality control was performed on the 3 separate data sets and then jointly after merging. Genetic data available on 447 infants together with their phenotype data is made available in this submission PROVIDE (Performance of Rotavirus and Oral Polio Vaccines in Developing Countries) Study Oral polio and rotavirus vaccines are significantly less effective in children living in the developing world. Environmental enteropathy, which is associated with intestinal inflammation, decreased absorption and increased permeability, may contribute substantially to oral vaccine failure in developing country settings. The primary objective of the study was to determine the association of environmental enteropathy with the efficacy of oral polio and rotavirus vaccines in children in Bangladesh. Secondary and exploratory objectives were designed to address other possible causes of oral vaccine underperformance including malnutrition, interference with maternal or breastmilk antibodies, changes in gut microbiota, and genetic susceptibility. The PROVIDE study was structured as a 2x2 clinical trial with a prospective birth cohort enrollment of 700 infants and their mothers in the urban slum of Mirpur, Dhaka, Bangladesh. All children received the full series of Bangladesh's Expanded Program on Immunization vaccines, including oral polio vaccine (OPV) and followed for their first 2 years of life. Half the children were randomized to receive an inactivated polio vaccine (IPV) for their 4th dose at 39 weeks instead of the standard OPV dose. In the other trial, half the infants received the 2-dose rotavirus vaccine (Rotarix) with delayed dosing at 10 and 17 weeks of age. A detailed description of the study design and procedures can be obtained from PROVIDE methods publication: Kirkpatrick B.D., Colgate R.E., Mychaleckyj J.C., Haque R., Dorothy D.M., Carmolli M.P., et al. (2015) Am J Trop Med Hyg 92, 744-751 The Poliovirus trial and results are described in Mychaleckyj et al, Vaccine 2016 The Rotavirus trial and results are described in Colgate et al, Clin Infect Dis 2016 The PROVIDE infants were genotyped on a custom Affymetrix Axiom array (30K SNPs) at the University of Virginia Center for Public Health Genomics; and on a pre-production version of the Illumina MEGA v2 chip at the Wellcome Trust Sanger Institute, UK. The latter genotyping was performed under the auspices of the VaccGene Consortium. Analyses are ongoing to identify variants associated with the included phenotypes. A manuscript describing the genotyping methods and analysis is in preparation for the initial phenotypes. The Infection Malnutrition Bangladesh Cohort is utilized in the following dbGaP sub-studies. To view genotypes, other molecular data, and derived variables collected in these sub-studies, please click on the following sub-studies below or in the "Sub-studies" box located on the right hand side of this top-level study page phs001475 Infection Malnutrition Bangladesh Cohort. phs001476 Amebiasis Immunity phs001478 Polio Rotavirus Vaccines phs001665 Cryptosporidiosis Enteropathogens

  Study phs001475

• Molecular analysis of diffuse cerebellar gliomas

  Among diffuse gliomas, oligodendrogliomas show relatively better prognosis, respond well to radiotherapy and chemotherapy, and seldom progress to very aggressive tumors. To elucidate the genetic and epigenetic background for such behavior and tumor evolution during tumor relapse, we comparatively analyzed 12 pairs of primary and recurrent oligodendrogliomas with 1p/19q-codeletion. Initial treatment for these patients was mostly chemotherapy alone. Temozolomide was used for 3, and procarbazine, nimustine and vincristine (PAV chemotherapy) were used for 7 patients. World Health Organization histological grade at recurrence was mostly stable; it was increased in 2, the same in 9, and decreased in 1 cases. Whole-exome sequencing demonstrated that the rate of shared mutation between the primary and recurrent tumors was relatively low, ranging from 3.2-57.9% (average, 33.3%), indicating a branched evolutionary pattern. The trunk alterations that existed throughout the course were restricted to IDH1 mutation, 1p/19q-codeletion, and TERT promoter mutation, and mutation of the known candidate tumor suppressor genes CIC and FUBP1 were not consistently observed between primary and recurrent tumors. Multiple sampling from different regions within a tumor showed marked intratumoral heterogeneity. Notably, in general, the number of mutations was not significantly different after recurrence, remaining under 100, and no hypermutator phenotype was observed. FUBP1 mutation, loss of chr. 9p21, and TCF12 mutation were among a few recurrent de novo alterations that were found at recurrence, indicating that these events were clonally selected at recurrence but were not enough to enhance malignancy. Genome-wide methylation status, measured by Illumina 450 K arrays, was stable between recurrence and the primary tumor. In summary, although oligodendroglioma displays marked mutational heterogeneity, histological malignant transformation accompanying events such as considerable increase in mutation number and epigenetic profile change were not observed at recurrence, indicating that noticeable temporal and spatial genetic heterogeneity in oligodendrogliomas does not result in rapid tumor progression.

  Study JGAS000106

• eIMPACT Trial: Modernized Collaborative Care to Reduce the Excess CVD Risk of Older Depressed Patients

  Cardiovascular disease (CVD) is the #1 killer of American men and women, and its economic burden is substantial and on the rise. Adults with depression are at elevated risk of CVD events and poor CVD prognosis. Unfortunately, past clinical trials of depression treatments have not observed the anticipated cardiovascular benefits. A novel explanation for these null results is that the depression interventions in these trials, which all involved patients with preexisting CVD, were delivered too late in the natural history of CVD. Accordingly, the objective of this single-center, parallel-group, assessor-blinded randomized controlled trial was to determine whether successful depression treatment before, versus after, the onset of clinical CVD reduces CVD risk in depression. Primary care patients with depression and elevated CVD risk from a safety net healthcare system (N = 216, Mage = 59 years, 78% female, 50% Black, 46% with income <$10,000/year) were randomized 1:1 to 12 months of the eIMPACT intervention (a modernized collaborative stepped care program involving internet cognitive-behavioral therapy [CBT], telephonic CBT, and/or select antidepressants) or usual primary care for depression (primary care providers supported by embedded behavioral health clinicians and psychiatrists). The primary outcome was endothelial dysfunction (brachial flow-mediated dilation) at 12 months, and the secondary outcomes were self-reported depressive symptoms (Hopkins Symptom Checklist-20), autonomic dysfunction (high-frequency heart rate variability), systemic inflammation (interleukin-6 and high-sensitivity C-reactive protein), and platelet activation (β-thromboglobulin and platelet factor 4) at 12 months. The central hypothesis was that the eIMPACT intervention would improve endothelial dysfunction in depressed adults by decreasing depressive symptoms, autonomic dysfunction, systemic inflammation, and platelet activation. Primary results are posted to ClinicalTrials.gov at NCT02458690. The de-identified limited dataset available on BDC consists of only the individual phenotypic data needed to confirm this trial’s primary results – i.e., randomization status, primary and secondary outcome variables, and participant characteristics utilized in the hypothesis-testing models (age, sex, race, education, income, and systolic blood pressure). We also provide the SAS code to replicate the results of the hypothesis-testing models reported in Table 4 and Supplemental Tables 1-3 in the main outcomes paper (#2 in Selected Publications). Of note, the user will need to specify the file path for the dataset to run the SAS code. Instructions for requesting individual-level data are available on BDC at https://biodatacatalyst.nhlbi.nih.gov/resources/data/. Apply for data access in dbGaP. Upon approval, users may begin accessing requested data in BDC. For questions about availability, you may contact the BDC team at https://biodatacatalyst.nhlbi.nih.gov/contact.

  Study phs003283

• Heart Failure Network Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy - (HFN ATHENA-BioLINCC)

  ObjectiveTo assess whether high-dose spironolactone treatment for patients with acute heart failure lowers natriuretic peptide levels and improves outcomes better than usual care.BackgroundAcute heart failure (AHF) accounts for more than a million hospitalizations in the United States annually. The role of low-dose mineralocorticoid receptors antagonists (MRAs) therapy as a neurohormonal antagonist is well established for the treatment of chronic heart failure and reduced ejection fraction. However, the role of high-dose MRA therapy in AHF remained uncertain. A previous clinical trial suggested that the benefits of high-dose MRA therapy in AHF included lower natriuretic peptide levels, less congestion, better renal function, and less need for an intravenous diuretic. The use of intravenous loop diuretics can intensify secondary hyperaldosteronism among AHF patients, and hyperaldosteronism directly contributes to diuretic resistance in AHF. Elevated aldosterone levels in AHF are associated with an increased risk of cardiovascular mortality and HF readmission. Hospitalizations for heart failure are associated with increased risk of mortality and/or readmission.The HFN-ATHENA trial was conducted to determine if mineralocorticoid receptor antagonists administered at high doses relieved congestion, decreased diuretic resistance, and mitigated the effects of adverse neurohormonal activation in AHF.SubjectsThe ATHENA trial enrolled 360 participants. Of these, 178 participants were randomized to usual care treatment (placebo or low-dose spironolactone) and 182 participants were randomized to high-dose spironolactone.DesignThe study intervention was initiated within 24 hours of patients receiving the first dose of intravenous diuretics. Participants not taking spironolactone at enrollment were randomized to 100 mg spironolactone or a placebo. Participants taking low-dose spironolactone before their hospital admission were randomized to 100 mg or 25 mg per day in the usual care treatment arm. Prescription of all other medications, including diuretics, was left at the discretion of the treating physician. The study drug was discontinued after 96 hours and further MRA use was left to the treating physician's discretion. The primary end point was the proportional change in the log NT-proBNP levels from randomization to 96 hours (or at the hospital discharge if the discharge occurred earlier than 96 hours). Secondary endpoints included: (1) a clinical congestion score; (2) dyspnea relief; (3) daily cumulative net urine output for up to 96 hours; (4) net weight change from baseline to 96 hours or discharge (whichever came first); (5) furosemide equivalents of the loop diuretic dosage at discharge; and (6) the development of in-hospital worsening HF, with signs and symptoms requiring additional therapy.ConclusionsThere was no significant difference in the primary or secondary endpoints between the high-dose treatment arm and the usual care treatment arm.

  Study phs003506

• Prediction of Trastuzumab Benefit in Adjuvant Breast Cancer: Gene Expression Profiling in NSABP B31

  Background National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-31 suggested the efficacy of adjuvant trastuzumab, even in HER2-negative breast cancer. This finding prompted us to develop a predictive model for degree of benefit from trastuzumab using archived tumor blocks from B-31. Methods Case subjects with tumor blocks were randomly divided into discovery (n = 588) and confirmation cohorts (n = 991). A predictive model was built from the discovery cohort through gene expression profiling of 462 genes with nCounter assay. A predefined cut point for the predictive model was tested in the confirmation cohort. Gene-by-treatment interaction was tested with Cox models, and correlations between variables were assessed with Spearman correlation. Principal component analysis was performed on the final set of selected genes. All statistical tests were two-sided. Results Eight predictive genes associated with HER2 (ERBB2, c17orf37, GRB7) or ER (ESR1, NAT1, GATA3, CA12, IGF1R) were selected for model building. Three-dimensional subset treatment effect pattern plot using two principal components of these genes was used to identify a subset with no benefit from trastuzumab, characterized by intermediate-level ERBB2 and high-level ESR1 mRNA expression. In the confirmation set, the predefined cut points for this model classified patients into three subsets with differential benefit from trastuzumab with hazard ratios of 1.58 (95% confidence interval [CI] = 0.67 to 3.69; P = .29; n = 100), 0.60 (95% CI = 0.41 to 0.89; P = .01; n = 449), and 0.28 (95% CI = 0.20 to 0.41; P < .001; n = 442; P interaction between the model and trastuzumab < .001). Conclusions We developed a gene expression-based predictive model for degree of benefit from trastuzumab and demostrated that HER2-negative tumors belong to the moderate benefit group, thus providing justification for testing trastuzumab in HER2-negative patients (NSABP B-47). ** Reprinted from J Natl Cancer Inst;2013;105:1782-1788 with permission from Oxford University Press.

  Study phs000826

• Proteomic Analysis of Non-Muscle Invasive and Muscle Invasive Bladder Cancer Highlights Distinct Subgroups With Metabolic, Matrisomal, and Immune Hallmarks

  We present the proteome biology of bladder cancer based on a cohort comprising treatment-naïve non-muscle invasive (NMIBC, N=17) and treatment-naïve muscle-invasive bladder cancer (MIBC, N=51), as well as neoadjuvant-treated MIBC (N=11); using formalin-fixed, paraffin-embedded samples and data-independent acquisition yielding >8,000 protein identifications. The NMIBC proteome reveals two subgroups that represent cell adhesion or lipid metabolism biology. MIBC, compared to NMIBC, shows an altered metabolic proteome together with enrichment of extracellular matrix (ECM), immune response, and complement proteins; in line with three proteomic MIBC subgroups that represent ECM, metabolic, or immune signatures. The ECM and immune subgroups are enriched for markers of M2-like tumor-associated macrophages and dendritic cells, while markers for natural killer cells are exclusive for the ECM subgroup, and markers for cytotoxic T-cells are a hallmark of the immune subgroup. Infiltration of CD8+ PD1+ positive cytotoxic T cells correlated with PD-L1 expression of MIBC, as demonstrated by multiplex immunofluorescence analysis. The metabolic subgroup presents a comparably immune-depleted microenvironment. YAP1 signaling is particularly prominent in the ECM subgroup. The protein BSCL2 emerges as a prognostic marker for MIBC. We highlight increased endogenous proteolysis in MIBC alongside the upregulation of matrix metalloproteases exceeding the upregulation of their endogenous inhibitors. Genomic panel sequencing underlines prevalent FGFR3 mutations in NMIBC and prevalent TP53 mutations in MIBC, but a genomic underpinning of the MIBC subgroups remains elusive. Proteogenomic analysis yields protein-level evidence for more than 1,300 single amino acid variants. The proteomes of neoadjuvant-treated MIBC resembled treatment-naïve MIBC. Tumor-stroma interaction of MIBC was further investigated by proteomic analysis of patient-derived xenografts of MIBC. Our study adds to the proteome-level understanding of bladder cancer.

  Study EGAS00001007290

• SardiNIA Medical Sequencing Discovery Project

  The SardiNIA Medical Sequencing Discovery Project studies the genetics of blood lipid levels and personality in a Sardinian population cohort. The project has generated draft genome sequences for approximately 2,000 individuals using whole genome shotgun sequencing. The draft sequences will allow investigators to evaluate the contribution of common and rare single nucleotide polymorphisms, short insertions and deletions, large copy number polymorphisms and other structural variants to blood levels of low density lipoprotein cholesterol (LDL-c), high density lipoprotein cholesterol (HDL-c) and triglycerides (TG), all of which are key risk factors for cardiovascular disease, and to the 5 domains of personality as assessed by the NEO-PI-R questionnaire. The two traits represent different ends of the spectrum of medically interesting complex traits. Blood lipid levels are a risk factor for cardiovascular disease for which genetic studies have been very successful. In contrast, personality traits and other behavioral phenotypes represent a set of phenotypes that have proven more challenging to dissect using standard genetic tools. In both cases, we expect whole genome sequencing to improve our understanding of the underlying biology. The isolated Sardinian population is ideal for this type of study for several reasons, in particular because: (i) the bottleneck that occurred after colonization of the island attenuated natural selection against alleles with phenotypic consequences, increasing the odds that functional alleles will reach modest frequencies (0.5 - 5.0%) and will be detected in the present study and (ii) sharing of long haplotype stretches surrounding rare variants will facilitate imputation based analyses of shotgun sequence data, which improve the accuracy of individual genotype calls and thus increase power. This research helps advance NIH's mission by furthering our understanding of the genetic factors contributing to blood lipid levels and coronary heart disease and to personality, behavior and mental health. In addition, these data should facilitate development of analysis tools and strategies that can be used to study the genomes of hundreds to thousands of individuals and further our understanding of the genetics and biology of many different traits and conditions.

  Study phs000313

• SNP Genotype Data: Subpopulations of Filipino, Malaysian, and Papua New Guinea

  In the context of the study 'Exploring Adaptive Phenotypes for the Human Calcium-Sensing Receptor Polymorphism R990G,' this repository contains 11 VCF files. Each file includes genetic data from 22 autosomes, representing distinct subpopulations. The subpopulations are as follows: Malaysian: Aeta (15 samples) Agta (11 samples) Batak (10 samples) Mamanwa (6 samples) Filipino: Jehai (13 samples) Kintaq (6 samples) Temiar (5 samples) Papua New Guinea: Highlands (2 samples) Koinambe (10 samples) Kosipe (10 samples) Sepik (2 samples) The numbers in parentheses indicate the sample size for each respective subpopulation.

  Study EGAS50000000044

• Evaluation of Local Response of Prostate Cancer to Irradiation Using Multiparametric MRI and MR-Guided Biopsies

  The purpose of this study was to determine the rate of local recurrence in patients with intermediate and high risk prostate cancer treated with radiotherapy. In this study, multiparametric MRI was first performed, and biopsy tissue was acquired from cancerous regions detected on MRI. Blood samples were also taken. DNA and RNA were extracted from tissue taken at baseline. DNA was used for whole exome sequencing (WES). RNA was used for gene expression microarray. Each patient then received radiation therapy with androgen deprivation therapy.

  Study phs001821

• Epigenetic profiling of primary human thymocyte subsets

  Dynamic changes of the DNA methylation (DNAmeth) landscape drive differentiation of mature T lymphocytes. However, the role of DNAmeth-mediated regulation in thymocyte development remains unclear. Thus, we generated genome-wide DNAmeth and transcriptomic profiles of eight defined, ex vivo isolated primary human thymocyte subsets, to assess the epigenetic remodling taking place during human thymic T cell development. The generated data may also serve as a reference for the analysis of T cell-based inborn errors of immunity or for quality control purposes of in vitro generated T cell populations.

  Study EGAS50000001106

• Epigenetics/genetics of the patient-derived xenografts of pediatric T-cell leukemia

  We compared 12 pediatric T cell acute lymphoblastic leukemias collected at initial diagnosis and relapse with their corresponding PDX models. The analysis was performed on genomic level (whole genome sequencing (WGS), whole exome sequencing (WES), multiplex ligation probe amplification (MLPA), targeted sequencing) and the epigenetic level (DNA methylation, Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq)). In sum, this study underlines the remarkable genomic stability, and for the first time documents the preservation of the epigenomic landscape in T-ALL-derived PDX models.

  Study EGAS00001003248

• Anaplastic_Meningioma_WGS_X10

  Anaplastic meningiomas are a rare, malignant variant of meningioma. At present there is no effective treatment for this cancer. The aim of the study is to identify somatic mutations in anaplastic meningiomas. We plan to sequence a set of 500 known cancer genes in 50 anaplastic meningioma and corresponding peripheral blood DNA samples. Bioinformatics will be used to analyse the results to assess the probability of these mutations being causal and so likely of critical importance for the tumour growth. Identification of these mutations will guide selection of appropriate compounds to effectively treat the disease.

  Study EGAS00001000859

• Immuno-genomic landscape of osteosarcoma

  Osteosarcoma is an orphan disease affecting children and young adults that has seen little to no progress in survival outcomes for >30 years. Despite having heavily rearranged genomes, to date, clinical trials with immunotherapy have shown no benefit for patients with osteosarcoma. In this study, we conducted the first multi-platform immune profiling (whole genome, transcriptome, T-cell receptor sequencing, immunohistochemistry and reverse phase protein array) on every available pediatric and adult osteosarcoma patients from our institution (N = 48) with the goal of describing immune features that may contribute to immunotherapy resistance.

  Study EGAS00001004197

• Immuno-genomic landscape of osteosarcoma

  Osteosarcoma is an orphan disease affecting children and young adults that has seen little to no progress in survival outcomes for >30 years. Despite having heavily rearranged genomes, to date, clinical trials with immunotherapy have shown no benefit for patients with osteosarcoma. In this study, we conducted the first multi-platform immune profiling (whole genome, transcriptome, T-cell receptor sequencing, immunohistochemistry and reverse phase protein array) on every available pediatric and adult osteosarcoma patients from our institution (N = 48) with the goal of describing immune features that may contribute to immunotherapy resistance.

  Study EGAS00001003887

• Cystic fibrosis multi-omics study

  Cystic fibrosis (CF) is a genetic disorder affecting approximately 1 in 2,500 people in the UK. Here, we generated a number of high-throughput sequence data sets for monocytes and neutrophils from CF patients and matched healthy volunteers (HV); including ChIP-Seq (H3K27Ac), chromatin accessibility (ATAC-Seq), and transcript/gene expression (RNA-Seq) data. Analysis of gene expression and epigenetic profiles demonstrates a robust innate immune gene expression profile that distinguishes CF and HV during periods of disease exacerbation. Upregulation of pathways responsible for the production of proinflammatory cytokines is described.

  Study EGAS00001006421

• Women's Health Study Accelerometry Dataset

  Background The Women's Health Study (WHS) was a randomized trial testing low-dose aspirin and vitamin E for preventing cancer and CVD among 39,876 women aged ≥45 years throughout the US from 1992-2004. When the trial ended as planned, women who were willing to participate continued in an observational follow-up study. Participants in Accelerometer Study From 2011-2015, an ancillary study collected data on physical activity and sedentary behavior using accelerometers. Women were mailed a triaxial accelerometer (ActiGraph GT3X+, ActiGraph Corp) with a wear log, and asked to wear this on their hip for seven consecutive days, removing it only during sleep and water-based activities. Further details have previously been published (PMID: 30666321). A total of 17,708 women wore and returned their devices, and data were downloaded from the devices of 17,466 women; no data were available from the other 242 (device failure). By convention, a "valid day" of wear has data on at least 10 hours (PMID: 22698174). Among these 17,466 women, 17,062 had at least one valid day of wear. The data are provided for all 17,062 women. Additionally, "compliant wear" is conventionally defined for participants wearing the device for at least 10 hours, on at least 4 days (PMID: 22698174). Of the 17,062 women, 16,741 had compliant wear (PMID: 29109088). Self-reported Physical Activity and Sedentary Behavior After we received the accelerometer from a WHS participant, she was sent a questionnaire asking her to report the time she spent in different physical activities during the week that the accelerometer was worn (see questionnaire below). A total of 15,514 women (91% of participants in the Accelerometer Study) returned their physical activity questionnaires. In addition, beginning in October 2012, we included questions on sedentary behavior; a total of 9,430 women returned questionnaires that included questions on both physical activity and sedentary behavior.

  Study phs001964

• Small RNA Contents of Extracellular Vesicles from Patients with Cognitive Decline

  In this proposal, we examined samples from living neurologically normal individuals (n=72), cognitively normal Parkinson's disease (PD; n=21), PD with mild cognitive impairment (PD-MCI; n=18), PD with dementia (PDD; n=23), and dementia with Lewy-bodies (DLB; n=18), Alzheimer’s disease (AD; n=33) and mild cognitive impairment (MCI, n=38). The main goal for this study was to assess the diagnostic utility of small RNA contents from extracellular vesicles (EVs) for the prediction of cognitive decline. Plasma samples were collected and the RNA from extracellular vesicles (EVs) was isolated using the Qiagen exoRNeasy kit, and the small RNA contents were sequenced using the PerkinElmer NextFlex kit (v2). While PD is typically thought of as a motor disorder, there are significant non-motor symptoms that can be devastating. One of the most common non-motor symptoms of PD is dementia (PDD). While PD subjects that develop dementia all have Lewy bodies, there is often co-pathology with tau and β-amyloid found at autopsy or by PET amyloid imaging; thus, subjects diagnosed with AD were also included in the study. The development of the category, mild cognitive impairment (MCI) in AD, and in PD, provides an opportunity to identify and examine a transitional state between normal aging and dementia; this is a patient population ideally suited for therapeutic intervention. Progress in the detection, validation, and standardization of molecular biomarkers from biofluids, such as extracellular RNAs (exRNAs), would be efficient and cost-effective aids in the assessment of disease progression, cognitive decline, and response to therapeutics. We have provided the raw fastq files for the sequencing data from each sample. We are also providing demographic information, as complete as we have for each person; including age, diagnosis, sex, and cognitive assessments.

  Study phs003300

• Treatment of genetic screening of hypertriglyceridemia type I, III, and V - HTG Amsterdam

  This is a cohort of patients with extreme hypertriglyceridemia. Patients have been screened for loss of function mutations in LPL, GPIHBP1, APOC2, APOA5 and LMF1.

  Study phs000511

• DAC for "Cancer-associated fibroblasts promote drug resistance in ALK-driven lung adenocarcinoma cells by upregulating lipid biosynthesis"

  DAC for the data of "Cancer-associated fibroblasts promote drug resistance in ALK-driven lung adenocarcinoma cells by upregulating lipid biosynthesis" with: • Holger Sültmann • h.sueltmann@dkfz.de • German Cancer Research Center (DKFZ) • Ann-Kathrin Daum • a.daum@dkfz.de • German Cancer Research Center (DKFZ)

  Dac EGAC50000000076

• Analysis_of_somatic_mutations_in_normal_blood__AML_and_MDS_samples

  Targeted pulldown of genes known to be recurrently mutated in AML & MDS from patient and normal samples using Agilent Sureselect and for some cases also using Illumina Truseq technology.

  Study EGAS00001000525