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• A Scalable, GMP-Compatible, Autologous Organotypic Cell Therapy for Dystrophic Epidermolysis Bullosa

  Gene editing in induced pluripotent stem (iPS) cells has been hailed for enabling new cell therapies for various monogenetic diseases including dystrophic epidermolysis bullosa (DEB). However, manufacturing, efficacy, and safety roadblocks have limited the development of genetically corrected, autologous iPS cell-based therapies. Dystrophic Epidermolysis Bullosa Cell Therapy (DEBCT), is a new generation, Good Manufacturing Practice-compatible (cGMP), reproducible, and scalable platform to produce autologous clinical-grade iPS cell-derived organotypic induced skin composite (iSC) grafts to treat incurable wounds of patients lacking type VII collagen (C7). DEBCT uses a single step, combined, high-efficiency reprogramming, and CRISPR-based genetic correction to generate genome scar-free, COL7A1 corrected clonal iPS cells from primary patient fibroblasts. Validated iPS cells are converted into epidermal, dermal, and melanocyte progenitors with a novel 2D organoid differentiation protocol, followed by CD49f enrichment and expansion to minimize maturation heterogeneity. iSC product characterization by single cell transcriptomics was followed by mouse xenografting for disease correcting activity at 1 month and toxicology analysis at 1-6 months. Culture-acquired mutations, potential CRISPR-off target effects, and cancer-driver variants were evaluated by targeted and whole genome sequencing. iPS cell-derived iSC grafts were reproducibly generated from four recessive DEB patients with different pathogenic mutations. Organotypic iSC grafts onto immune-compromised mice developed into stable stratified skin with functional C7 restoration. Single cell transcriptomic characterization of iSCs revealed prominent holoclone stem cell signatures in keratinocytes and the recently described Gibbin-dependent signature in dermal fibroblasts. The latter correlated with enhanced graftability. Multiple orthogonal sequencing and subsequent computational approaches identified random and non-oncogenic mutations introduced by the manufacturing process. Toxicology revealed no detectable tumors after 3-6 months in DEBCT-treated mice. In conclusion, DEBCT successfully overcomes previous roadblocks and establishes a robust, scalable, and safe cGMP manufacturing platform for the production of a CRISPR-corrected autologous organotypic skin graft to heal DEB patient wounds.

  Study phs003271

• Northwestern NUgene Project: Type 2 Diabetes

  The ability to correlate genetic variation with disease susceptibility and response to drug therapy depends on genotype or sequence analysis of large numbers of richly characterized DNA samples. Eight years agoWe are a part of NHGRI's electronic Medical Records and Genomics (eMERGE) Network, whose goal is to conduct genome-wide association studies in thousands of individuals using EMR-derived phenotypes and DNA from linked biorepositories. For eMERGE, Northwestern University (NU) is studying type 2 diabetes as a phenotype. In addition, in order to explore race differences in the prevalence of type 2 diabetes, NU collaborated with Vanderbilt University to study a mix of both Caucasian and African-Americans. Northwestern University: In 2002, Northwestern committed to the development of a DNA repository to serve as a platform for the identification and validation of genotype-phenotype associations that will impact healthcare. The NUgene Project is a repository with longitudinal medical information from participating patients at affiliated hospitals and outpatient clinics from the Northwestern University Medical Center. Participants' DNA samples are coupled with data from a questionnaire (2 versions were used, 1 before and 1 after February 2006, both are included) and continuously updated data from our Electronic Medical Record (EMR) representing actual clinical care events. Northwestern has a state-of-the art, comprehensive inpatient and outpatient EMR system of over 2 million patients. NUgene has broad access to participant data for all outpatient visits as well as inpatient data via a consolidated data warehouse. NUgene participants consent to distribution and use of their coded DNA samples and data for a broad range of genetic research by third-party investigators. Vanderbilt University: BioVU, Vanderbilt's DNA databank, is an enabling resource for exploration of the relationships among genetic variation, disease susceptibility, and variable drug responses, and represents a key first step in moving the emerging sciences of genomics and pharmacogenomics from research tools to clinical practice. BioVU acquires DNA from discarded blood samples collected from routine patient care. The biobank is linked to de-identified clinical data extracted from Vanderbilt's EMR, which forms the basis for phenotype definitions used in genotype-phenotype correlations.

  Study phs000237

• Surgical Treatment for Ischemic Heart Failure (STICH-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. ObjectiveTo compare medical therapy with coronary bypass surgery and/or surgical ventricular reconstruction for patients with congestive heart failure and coronary artery disease.BackgroundCoronary artery disease (CAD) is the most common cause of heart failure, which in turn is a major cause of death and disability globally. Evidence from previous clinical trials supports the use of coronary-artery bypass grafting (CABG) to relieve disabling symptoms of angina, particularly among high-risk subgroups with extensive CAD. However, the studies did not include patients with severe left ventricular dysfunction, and developments in medical therapy have since led to updated guidelines. In addition, the benefits of CABG in patients with ischemic cardiomyopathy had still not been clearly established at the time of this study. STICH sought to evaluate the role of CABG in the treatment of patients with CAD and left ventricular systolic dysfunction.Reduced left ventricular function may occur after myocardial infarction, often in conjunction with left ventricular remodeling, including left ventricular enlargement and changes in chamber geometry. Left ventricular remodeling is correlated with progression of heart failure and a poor prognosis. Therefore, a surgical approach to remodeling through left ventricular volume reduction could improve outcomes for patients with CAD and heart failure. Surgical ventricular reconstruction (SVR) has been shown to reduce the left ventricular volume, increase the ejection fraction, and improve ventricular function. There is also evidence that SVR performed with CABG may reduce the rate of hospitalization and improve ventricular function, as compared to CABG alone. As part of a second hypothesis, STICH additionally investigated whether SVR when added to CABG would improve outcomes in patients with heart failure and CAD.ParticipantsA total of 2,136 participants were enrolled in STICH. 1,212 were enrolled in the hypothesis 1 component of the trial, with 602 participants assigned to receive medical therapy alone, and 610 participants assigned to receive medical therapy plus CABG. 1,000 were enrolled in the hypothesis 2 component, with 499 participants assigned to receive medical therapy plus CABG, and 501 participants assigned to receive medical therapy plus CABG and SVR. 76 participants that were assigned to the CABG with medical therapy treatment were enrolled in both hypothesis components.DesignAfter initial determination of overall eligibility, participants were evaluated to determine which component of the STICH program was appropriate for them on the basis of suitable therapeutic options. All participants underwent cardiac imaging for assessment of left ventricular function and wall motion. Participants in the hypothesis 1 component were randomly assigned to receive either medical therapy alone or medical therapy plus CABG. Participants in the hypothesis 2 component were randomly assigned to receive either medical therapy plus CABG or medical therapy plus CABG and SVR.At baseline, demographic factors and clinical characteristics were assessed, including current medications and prior diagnostic and other cardiovascular procedures, and a physical examination was performed. Guideline-based recommendations for drug and device use were emphasized for all participants. All participants underwent follow-up evaluations at the time of discharge or at 30 days for participants still hospitalized, every 4 months for the first year, and every 6 months thereafter. The median length of follow-up was 56 months for hypothesis 1 and 48 months for hypothesis 2.For participants receiving CABG, arterial grafting for stenosis of the left anterior descending coronary artery was required for all participants without specific contraindications. The use of additional arterial conduits supplemented by vein grafts was recommended for revascularization of all major vessels with clinically significant stenoses. Concurrent mitral-valve surgery for regurgitation was performed at the discretion of the surgeon. For participants receiving SVR, the operation was most commonly performed during a single period of cardioplegic arrest after construction of bypass grafts. However, the procedure could also be performed with the heart beating in order to facilitate identification of the noncontractile zone of scarring. After an anterior left ventriculotomy was centered in the zone of anterior asynergy, a suture was placed in the interior of the ventricle to encircle the scar at the boundary between the akinetic and viable tissue. Visual inspection and palpation facilitated the judgment of whether a patch was needed to optimize the chamber size without deforming the left ventricle during closure of the ventriculotomy.The primary outcome for hypothesis 1 was the rate of death from any cause. The primary outcome for hypothesis two was a composite of death from any cause and hospitalization for cardiac causes.ConclusionsThere was no significant difference between medical therapy alone and medical therapy plus CABG for death from any cause, though participants that underwent CABG had lower rates of death from cardiovascular causes, death from any cause, or hospitalization for cardiovascular causes. Adding SVR to CABG reduced the left ventricular volume, as compared with CABG alone. However, this anatomical change was not associated with a greater improvement in symptoms or exercise tolerance, or with a reduction in the rate of death or hospitalization for cardiac causes.

  Study phs003493

• Heart Failure Network - Renal Optimization Strategies Evaluation in Acute Heart Failure and Reliable Evaluation of Dyspnea (HFN ROSE-BioLINCC)

  ObjectivesTo test the two independent hypotheses that when compared to placebo, addition of: (1) low dose dopamine; or (2) low dose nesiritide to diuretic therapy will enhance decongestion and preserve renal function in patients with acute heart failure and renal dysfunction.Background A primary treatment goal in acute heart failure is to achieve adequate decongestion while avoiding renal dysfunction and other side effects. Patients with acute heart failure and moderate or severe renal dysfunction are at risk for inadequate decongestion and worsening renal function - both of which are associated with worse outcomes. Renal adjuvant therapies that enhance decongestion and preserve renal function during treatment of acute heart failure are needed. Dopamine is an endogenous catecholamine which, at low doses, may selectively activate dopamine receptors and promote renal vasodilatation. Previous studies have suggested that the addition of low dose dopamine to diuretic therapy enhances decongestion and preserves renal function during diuretic therapy in acute heart failure; however, these studies were small with variable study designs and dopamine doses. B-type natriuretic peptide (BNP) is a cardiac peptide with vasodilating, renin and aldosterone inhibiting, natriuretic and diuretic properties. Nesiritide is human recombinant BNP approved for management of acute heart failure. The recommended dose lowers blood pressure and atrial pressures and produces modest improvement in dyspnea, but does not favorably impact clinical outcomes or renal function, potentially due to its hypotensive effects. Small studies using low dose nesiritide in acute heart failure and cardiac surgery patients have demonstrated favorable effects on urine output and renal function. Therefore, the Renal Optimization Strategies Evaluation (ROSE) trial was initiated to determine the benefits and safety of intravenous administration of low dose nesiritide or low dose dopamine in patients with congestive heart failure and kidney dysfunction. ParticipantsA total of 360 participants were enrolled. Design Participants were enrolled within 24 hours of hospital admission and randomized in a 1:1 ratio to the nesiritide or dopamine strategies. Participants randomized to the dopamine strategy were randomized in a double-blind 2:1 ratio to low dose dopamine (2 µg/kg/min for 72 hours infused via local guideline stipulated vascular access) or placebo. Participants randomized to the nesiritide strategy were randomized in a double-blind 2:1 ratio to low dose nesiritide (0.005 μg/kg/min for 72 hours infused via peripheral intravenous access without initial bolus) or placebo. All participants received open-label, intravenous loop diuretic treatment with a recommended total daily dose equal to 2.5x the total daily oral outpatient furosemide (or equivalent) dose at 7 days prior to admission up to a maximum of 600 mg/day. Participants naive to outpatient loop diuretics received 80 mg/day of intravenous furosemide. One-half of the total daily diuretic dose was administered as a bolus twice daily for at least 24 hours. Use of other medications and diuretic dosing after 24 hours were at the discretion of the clinician. All participants were placed on a 2000 mg sodium diet and 2000 cc fluid restriction. After the primary endpoint assessment at 72 hours, study drug was discontinued and subsequent treatment was at the clinician's discretion. The two co-primary endpoints were the 72-hour cumulative urinary volume as an index of decongestion efficacy and the change in cystatin-C from randomization to 72 hours as a measure of renal function preservation. Conclusions In participants with acute heart failure and renal dysfunction, neither low-dose dopamine nor low-dose nesiritide enhanced decongestion or improved renal function when added to diuretic therapy.

  Study phs003589

• BAM files from capture-based targeted sequencing of 12 agressive B-cell lymphoma tumour samples (IG-MCL-panel)

  This dataset contains BAM files from capture-based targeted sequencing of 12 agressive B-cell lymphoma tumour samples for cases 1 to 6 and 8 to 13. The sequencing panel used is a MCL-oriented panel containing 159 genes.

  Dataset EGAD50000000801

• ATAC Dataset for 19 T-ALL patient samples and 1 normal control sample

  19 ATAC-seq from T-ALL patient samples and one healthy normal control sample. Reads were aligned to HG38 reference

  Dataset EGAD50000000024

• EGAD00000000047

  Signal data for from 3 recurrent and 1 ovarian primary Granulosa Cell Tumour samples

  Dataset EGAD00000000047

• SG10K_Pilot Dataset: Whole genome sequencing data of 4810 individuals from Singapore

  Genomic data obtained from the joint processing and variant calling of 4,810 individuals from Singapore. VCF files are by Chromosome (chr. 1-22 plus X) for all 4,810 individuals. Self-reported ethnicity is found in the "Region" column of metadata file.

  Dataset EGAD00001005337

• SF11964 scRNA-Seq Low Grade Glioma IDHR132H mutant Male

  Single cell RNA-Seq Low Grade Astrocytoma IDHR132H mutant. Male, 64. Single Cell RNA seq from primary astrocytoma sample. NovaSeq6000 was used for RNA seq. The files uploaded are bam files created with grch38 reference through Cellranger count (10xGenomics.)

  Dataset EGAD00001005396

• SF10022 snRNA-Seq Primary High-grade Glioma

  SF10022 single nuclei RNA-Seq Primary High-grade glioma. gender Male Age 65. Single Nuclei RNA seq from high grade primary glioma sample. NovaSeq6000 was used for RNA seq. The files uploaded are bam files created with grch38 reference

  Dataset EGAD00001005409