3613 results for "*geneti*"

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• Somatic Mutations and Their Etiological Determinants for Breast Cancer in African American Women (B-CAUSE Study)

  The breast cancer health disparity between women of African ancestry (AA) and European ancestry (EA) remains a major public health challenge in the United States. AA women are afflicted by higher rate of triple-negative breast cancer (TNBC) and bear the highest mortality rate of all populations from the disease. Even within TNBC, some data suggest that AA women have poorer outcomes than EA women. Mounting evidence points to population differences in cancer biology, a fundamental question that remains unsettled. The disparity also manifests in representativeness in tumor sequencing projects, due to the low inclusion of AAs in genomic studies. A recent analysis of The Cancer Genome Atlas (TCGA) data revealed that the number of AA cases sequenced was sufficient only for studying frequently mutated genes (≥10%), and the power was worse for TNBC as a separate disease entity. As a result, the breast tumor mutational landscape elucidated to date is derived mostly from EA cases, and may not necessarily represent AA cancer genomes. Moreover, as discovery potential for new driver genes has come close to a plateau, cancer in AAs derived from distinct genetic and environmental contexts may provide a powerful venue for discovering mutations that are rare in EA cases. This is showcased in recent studies in colon and prostate cancer. Thus, we carried out a collaborative project, B-CAUSE, to characterize the mutational landscape of AA breast cancer genomes by pooling resources from five established studies, including the Women's Circle of Health Study (WCHS), the Black Women's Health Study (BWHS), the Southern Community Cohort Study (SCCS), the Nashville Breast Health Study (NBHS), and the Southern Tri-State Breast Health Study (STSBHS). This effort has created the largest AA-specific breast tumor mutation dataset to date in an efficient manner. The data deposited here are from the whole-exome sequencing (WES) of matched tumor-normal pairs of 462 TNBC in AA women from the B-CAUSE Study.

  Study phs003962

• 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

• A Depression and Opioid Pragmatic Trial in Pharmacogenetics (ADOPT PGx): Chronic Pain Trial

  This study was comprised of three separate pharmacogenetic trials grouped into a single protocol due to similarities in the intervention, the hypotheses, and the trial design. The three trials are the Acute Pain Trial, the Chronic Pain Trial (this study), and the Depression Trial. Participants could enroll in only one of the three trials. Trial-specific outcomes will be compared between participants in the intervention arm and control arms who have an actionable phenotype.Chronic Pain Trial: A prospective, multicenter, two arm randomized pragmatic trial. Participants meeting eligibility criteria were randomly assigned to either immediate pharmacogenetic testing and genotype-guided opioid therapy (Intervention arm) or standard care with 6-month delayed pharmacogenetic testing (Control arm). Actionable phenotypes are defined as CYP2D6 intermediate metabolizers (IMs) and poor metabolizers (PMs) (i.e. CYP2D6 activity score ≤ 0.75) for the chronic pain trial. Approximately 1050 participants seen in primary care or pain specialty clinics who are already prescribed or anticipated to be prescribed tramadol, codeine, or hydrocodone for pain control.

  Study phs004059

• Pomalidomide for the Treatment of Bleeding in HHT (PATH-HHT)

  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.Objectives: To determine efficacy (reduction in severity of epistaxis), tolerability, and improvement in quality of life of pomalidomide compared to placebo after 24 weeks of treatment.Background: This study addresses the efficacy of pomalidomide in the treatment of epistaxis in patients with Hereditary Hemorrhagic Telangiectasia (HHT) who have anemia and/or require blood transfusion or iron infusion for treatment of bleeding-induced anemia and iron deficiency. HHT (also known as Osler-Weber-Rendu disease) is an inherited bleeding disorder. Over 95% of patients develop recurrent epistaxis, which may be severe and result in chronic anemia, need for iron infusions and blood transfusions, substantial psychiatric comorbidity (including depression and post-traumatic stress disorder) and reduction in health-related quality of life (HRQoL). HHT is clinically diagnosed using the Curacao criteria, which consists of 1) spontaneous and recurrent epistaxis, 2) telangiectasias at characteristic sites, 3) visceral arteriovenous malformations (AVMs) or telangiectasias, and 4) a first degree relative with HHT (inheritance is usually autosomal dominant). Patients with three criteria are considered to have definite HHT, and those with 2 criteria probable HHT. HHT affects approximately 1 in 3,800 individuals. Significant manifestations of HHT often do not appear until the third or fourth decades, sometimes later.Participants: 144 patients from 11 clinical centers were enrolled.Design: This is a multi-center, double blind, randomized placebo-controlled trial that investigated the efficacy and safety of pomalidomide in patients with HHT and chronic epistaxis leading to iron-deficiency anemia or requiring intravenous iron infusions or blood transfusion.Screening evaluation included the Epistaxis Severity Score (ESS) with three-month recall, which reflected the patient's history of epistaxis and bleeding over the prior three months, as well as detailed review of iron infusion and red cell transfusion over the preceding six months. Eligible patients were provided a diary to record the duration of each epistaxis event that occurred during the 4 weeks prior to the baseline visit, and then returned for the baseline randomization visit, at which time patients underwent genetic testing, if this had not been previously performed, and completed an ESS with 4-week recall and quality of life assessments. Patients were randomized 2:1, stratified by study site, to either pomalidomide 4 mg/day or matching placebo during each of six 28 day cycles (24 weeks). Patients were seen every four weeks during treatment, and at a 4-week post-treatment follow-up visit to measure the ESS (with 4-week recall), laboratory assessments including iron stores and need for iron infusion, CBC, and metabolic profile. Patients were assessed for adverse events (AE) throughout the study. Treatment dosage could be reduced, or temporarily or permanently discontinued following AE-specific guidelines related to fatigue, cytopenias or other toxicities.Quality of life assessments were completed at baseline, and the 12- and 24-week visits, and the 4-week post-treatment follow-up visit using validated NIH instruments of 1) Neuro-QOL satisfaction with social roles and activities, 2) PROMIS emotional distress – depression, and 3) PROMIS fatigue, and the HHT-specific quality of life instrument developed specifically for this study. The effect of pomalidomide on duration of epistaxis was assessed via diary between weeks 8-12, 20-24 and the 4-week post-treatment period.Conclusions: Among patients with HHT, pomalidomide treatment resulted in a significant, clinically relevant reduction in epistaxis severity. No unexpected safety signals were identified (Al-Samkari et al., 2024; PMID: 39292928)

  Study phs003948

• Human Epilepsy Genetics: Mosaic Mutations in Focal Epilepsy

  This study investigates the role of somatic mosaic mutations in human focal epilepsies, including focal cortical dysplasia (FCD) and mesial temporal lobe epilepsy (mTLE). It leverages genomic and single-cell transcriptomic data from surgically resected brain tissue to identify pathogenic variants and characterize their effects on specific cell types and molecular pathways. The study employs methods such as deep whole-exome and targeted sequencing, single-nucleus RNA sequencing (snRNA-seq), and integrated genotype-transcriptome profiling (e.g., GO-TEN) to define the cellular architecture and functional consequences of mosaic mutations. Data generated under this project aim to elucidate mechanisms of epileptogenesis and support discovery of potential therapeutic targets.

  Study phs004124

• Single Cell Profiling of Transcriptional and Epigenetic Differences Between Virus and Severity in Infants Infected with SARS-CoV-2 and RSV

  This study compares the transcriptional and epigenetic immune responses to SARS-CoV-2 and RSV in infant PBMCs across different disease severities. Infants and young children hospitalized with SARS-CoV-2 (n=30) or RSV (n=19) were enrolled from February 2019 through January 2022. Blood samples were obtained within 24 hours for peripheral blood mononuclear cell isolation. Healthy controls (n=17) enrolled pre COVID-19 pandemic were also enrolled for baseline comparisons. Infants with COVID-19 were classified as subacute (n=9); moderate (n=12), or severe (n=9) based on level of clinical care, viral loads, and days post-exposure to COVID-19. Four of the five infants with severe COVID-19 were treated with dexamethasone and were reclassified as severe treated. Infants with RSV were classified as mild (n=5), moderate (n=7), or severe (n=7) based on an established clinical disease severity score designed for assessing severity in RSV. In total, 66 samples were included for scRNA-seq, and 51 samples were included for snATAC-seq. New data to be submitted from this study includes data for 27 scRNA-seq and 53 snATAC-seq. Note: Two additional samples (1 healthy control and 1 subacute COVID-19) were later determined to have signatures of viral infection (healthy control sample) or co-infection with another virus (subacute COVID-19 sample) during downstream analysis. These samples (adding up to the total of 68 scRNA-seq and 53 snATAC-seq) were included for reproducibility.

  Study phs003859

• Remodeling of the Immune System across Human Lifespan at Single Cell Resolution

  The human immune system undergoes dynamic remodeling from infancy through old age. We profiled PBMCs from 167 healthy individuals (ages 2 months to 105 years): infants (n=36), children (n=26), adolescents (n=20), young adults (n=24), middle aged (n=16), older adults (n=33) and oldest old (n=12) using scRNA seq and snATAC seq (n=23). MAIT and γδ T cells showed a “rise and fall” pattern, rising in childhood, peaking in young adulthood, and declining with age. Conventional CD8⁺ T cells were most profoundly altered with age, with decreasing naïve and increasing GZMK⁺ and TEMRA cells. The oldest old had increased TEMRA, adaptive NK, and KLRF1⁺ γδ T cells. Infants showed increased CD16⁺ monocytes and pDCs, constitutive interferon stimulated gene expression, and expanded SOX4⁺ naïve T cells. Inflammatory and stress response pathways increased with age, while interferon pathways declined. This map provides insights into human immune system dynamics across the lifespan, emphasizing unique features of the infant immune system. This study includes 95 samples generated in-house (this submission) and 72 samples obtained from four publicly available datasets, for a total of 167 samples. Participants were grouped into seven age categories: • Infants (2 months–2 years): n = 36 • Children (2–12 years): n = 26 • Adolescents (12–18 years): n = 20 • Young adults (18–40 years): n = 24 • Middle-aged adults (45–65 years): n = 16 • Older adults (65–85 years): n = 33 • Oldest old (85–105 years): n = 12 The public datasets are described below: • Deng et al. (GSE231906): n = 21 • Wang et al. (syn61609846): n = 45 • Wang et al. (GSE168732): n = 3 • Zhong et al. (GSE206295): n = 3 For epigenetic analyses, single nucleus ATAC sequencing (snATAC seq) data from 23 healthy PBMC donors were utilized, distributed across age groups as follows: • Infants and children: n = 9 • Adolescents: n = 3 • Young and middle aged adults: n = 6 • Older adults: n = 5 The raw data (fastq files) from participants HY13, HY18 and HY19 will not be included in the dataset per consent. HI17 and HI23 samples originate from the same infant collected at two time points (2 months for HI17 and 11 months for HI23).

  Study phs003259

• Fusion Transcription Factor Dosage Controls Cell State in Rhabdomyosarcoma

  In the fusion-positive subset of rhabdomyosarcoma, the PAX3::FOXO1 oncoprotein is the most common fusion driver. We previously established a human myoblast system for inducible expression of PAX3::FOXO1. In this myoblast system, MYCN is constitutively expressed. In this current study, we aim to modulate PAX3::FOXO1 protein expression to understand the epigenetic and phenotypic functions at different PAX3::FOXO1 levels. Dosage-specific gene expression profiles in the human myoblast system with varying PAX3::FOXO1 expression were assessed by RNA sequencing.

  Study phs004381

• Divergent Control of Epithelial Homeostasis, Regeneration, and Inflammation by NEDD8 and SUMO2

  This study includes de-identified primary human keratinocytes derived from discarded neonatal foreskin collected under an IRB-approved biospecimen protocol. The submitted data are from in vitro assays in primary keratinocytes used to characterize how NEDD8 and SUMO2 related pathways regulate epithelial progenitor maintenance and differentiation. Sequencing based assays used in these primary cells include transcriptomic and functional genomic profiling of genetic and pharmacologic perturbations and associated limited sample metadata. Across these assays, loss of NEDD8 signaling promoted differentiation associated programs, whereas loss of SUMO2 machinery impaired differentiation associated programs. This identified opposite roles for these ubiquitin-like pathways in human keratinocyte state control. Data available through dbGaP will consist of de-identified human sequencing data and accompanying study metadata from these keratinocyte experiments.

  Study phs004614

• Prevention and Early Treatment of Acute Lung Injury Network - Vitamin D to Improve Outcomes by Leveraging Early Treatment (PETAL VIOLET-BioLINCC)

  Data Access NOTE: Please refer to the "Authorized Access" section below regarding accessing data through the BioData Catalyst ecosystem. The data from this accession is not available for download through dbGaP. Biospecimens: Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from PETAL VIOLET include Plasma and Whole Blood. Please note that use of biospecimens in genetic research is subject to a tiered consent. Specimens may not be used to produce commercial products.Objectives: To evaluate the effect of short-term vitamin D supplementation on mortality among critically ill patients with a vitamin D deficiency.Background: Observational data indicate that vitamin D deficiency is common among critically ill patients and constitutes a potentially modifiable risk factor associated with longer lengths of stay in the hospital and intensive care unit (ICU), lung and other organ injury, prolonged mechanical ventilation, and death. In a previous phase 2 trial, vitamin D supplementation administered to vitamin D-deficient, critically ill patients was associated with lower observed mortality than placebo at 28 days and at 6 months. Because of the need for a larger, phase 3 trial, the PETAL-VIOLET study was initiated to determine if early administration of high-dose vitamin D3 would reduce all-cause mortality among critically ill patients with a vitamin D deficiency.Participants: 1360 patients underwent randomization, 690 were assigned to the vitamin D group and 668 were assigned to the placebo group. Of the 1078 patients confirmed to have a vitamin D deficiency by liquid chromatography-tandem mass spectrometry (LC-MS-MS), 538 had been assigned to the vitamin D group and 540 had been assigned to the placebo group.Design: PETAL-VIOLET was a multicenter, double-blind, placebo-controlled, phase 3 trial. Patients were enrolled within 12 hours after the clinician's decision to admit the patient to the ICU from the emergency department, hospital ward, operating room, or outside facility. Patients were tested for vitamin D deficiency, with a threshold of plasma 25-hydroxyvitamin D level of less than 20 ng per milliliter. Patients were randomly assigned in a 1:1 ratio, stratified according to site, to receive either a single enteral (administered orally or through a nasogastric or orogastric tube) dose of 540,000 IU of vitamin D3 or matched placebo, in liquid form, administered within 2 hours after randomization.Conclusions: After the first interim analysis, the data and safety monitoring board recommended that the trial be stopped for futility.A single 540,000 IU enteral dose of vitamin D3 administered early during critical illness rapidly corrected vitamin D deficiency but did not provide an advantage over placebo with respect to mortality or other clinically important end points.

  Study phs003879