3613 results for "*geneti*"

in 54.02 milliseconds.

• Cognitively Affected DMD Patients have Unique Methylation Signatures Compared to Cognitively Normal DMD Patients

  The overarching goal of this project was to identify changes in methylation patterns in Duchenne muscular dystrophy (DMD) patients with discordant symptoms using whole genome bisulfite sequencing (WGBS) from genomic DNA isolated from whole serum. DMD siblings (biological brothers) had the same genetic mutation in the dystrophin gene but with discordance in symptoms such as ambulation, cardiopulmonary function, and cognition. Trios (DMD sibling brothers and biological mother or father) and quartets (DMD sibling brothers and biological mother and father) were recruited for this study for intra- and inter-familial comparisons of the methylation of gene bodies.

  Study phs003118

• MP2PRT: PI3K Pathway Activation and Its Associated Genomic Profile as Predictive Biomarkers of HPV-Related Oropharyngeal Cancer: Evaluation of NRG HN002 and RTOG 1016

  The Molecular Profiling to Predict Response to Treatment (MP2PRT) program is part of the NCI Cancer Moonshot Initiative. The aim of this program is the retrospective characterization and analysis of biospecimens collected from completed NCI-sponsored trials of the National Clinical Trials Network. This study, titled “PI3K Pathway Activation and Its Associated Genomic Profile as Predictive Biomarkers of HPV-Related Oropharyngeal Cancer: Evaluation of NRG-HN002 and RTOG 1016”, is one of the selected studies under this program. For this study, molecular characterization (i.e., WES, Total RNAseq, and multiplex immunofluorescence staining) was performed on formalin-fixed paraffin embedded tumor tissue and matching germline previously collected from patients with HPV-related oropharyngeal cancer. This project will investigate genomic alterations within the PI3K pathway (PIK3CA and PTEN). It is hypothesized that an improved understanding of this pathway in a specific genetic context may lead to the development of novel therapies to guide future clinical trials and improve the clinical outcomes of patients with HPV-positive oropharyngeal cancer.

  Study phs003089

• Analysis of Epigenomes and Genome Topology in Colorectal Cancer

  When diagnosing cancer, pathologists use nuclear morphology as a hallmark of tumor cells, but the topological changes linked to alterations in the shape of the nucleus were poorly understood. To uncover the molecular changes that occur in the 3D structure of cancer genomes, we integrated topological maps for colon tumors and normal colon tissues with epigenetic, transcriptional, and imaging data. We characterized tumor-associated changes in chromatin loops, topologically associated domains (TADs), and large-scale compartments. We found that chromatin loop rewiring contributes to oncogenic gene expression programs. Whereas TAD structures are largely stable, the spatial partitioning of the open and closed genome compartments is compromised in tumors and is accompanied by hypomethylation and histone mark rearrangements. We also identified a compartment that is reorganized in tumors and is at the interface between the canonical A and B compartments. Similar changes were evident in non-malignant cells that had accumulated excessive cellular divisions. Our analyses suggest that these compartment changes repress stemness and invasion programs while inducing immunity genes, and they may therefore restrain malignant progression.

  Study phs002288

• Retrovirus Epidemiology Donor Study-II (REDS II) Molecular Surveillance (MS) - (REDS_II_MS_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.Protocol Synopsis: We propose to conduct a genetic analysis of incident and prevalent strains of HIV, HCV and HBV by testing blood specimens from HIV, HCV or HBV positive blood donors who give blood at REDS-II, UBS, BCP, NYBC and ARC blood centers between 2006 and 2008. The frequency of the different genetic lineages of these viruses will be evaluated and compared between incident (recently acquired) and prevalent (more remotely acquired) infections. We will also evaluate if genotypic distributions vary by demographic characteristics and by geographical area. Informative viral genetic regions will be PCR amplified, sequenced and phylogenetically analyzed to determine genotypes and subtypes. Anti-viral drug and antibody neutralization resistance mutations will also be recorded. This study will provide an oversight of the genetic diversity of blood borne agents detected in the US using current NAT, antigen and serological assays. Using published data, this analysis of viruses in blood donors will allow us to also determine whether this population is infected with the same strains of viruses as seen in more at-risk populations. Genetic characterization of viruses in NAT-yield and recent seroconverting donations, which represent incident cases, will allow for characterization of circulating strains of viruses thus enabling early detection of rare variants and longitudinal tracking of changes in genotype frequency of actively transmitted strains. Because genetic variants of HIV, HCV and HBV appear to differ in properties such as pathogenicity, anti-viral therapy response and antibody neutralization properties, the genetic characterization of incident strains will also guide future anti-viral and vaccine research in the US.Objectives The objective of the study was to conduct a genetic analysis of incident and prevalent strains of HIV, HCV and HBV by testing blood specimens from HIV, HCV or HBV positive blood donors who gave blood at REDS-II centers, as well as at UBS, NYBC and ARC blood centers between 2006 and 2009. Background Genetic variations of human immunodeficiency virus (HIV), hepatitis C virus (HCV), and hepatitis B virus (HBV) can affect diagnostic assays and therapeutic interventions. Recent changes in prevalence of subtypes/genotypes and drug/immune-escape variants were characterized by comparing recently infected vs. more remotely infected blood donors.ParticipantsThis study included qualifying donations from 1 January 2006 through 31 December 31 2009 from 3 Retrovirus Epidemiology Donor Study-II (REDS-II) blood centers (Blood Centers of the Pacific, Blood Center of Wisconsin, and Hoxworth Blood Center/University of Cincinnati), all American Red Cross Blood Services regions, United Blood Services regions and the New York Blood Center. Together, these centers account for approximately 70% of the US blood supply.DesignInfected donors were identified among approximately 34 million US blood donations, 2006–2009 based on screening and confirmatory tests for HIV and HCV nucleic acid testing, HIV and HCV antibody, HBsAg, and anti-HBV core antibody; incident infections were defined as having no or low antiviral antibody titers. Viral genomes were partially sequenced.ConclusionsViral genetic variant distribution in blood donors was similar to that seen in high-risk US populations. Blood-borne viruses detected through large-scale routine screening of blood donors can complement molecular surveillance studies of highly exposed populations. (Delwart et. al. 2012)

  Study phs004524

• Prematurity-Related Ventilatory Control: Role in Respiratory Outcomes (Pre-Vent-BioLINCC)

  ObjectivesTo develop a predictive model of short-term respiratory outcomes in extremely preterm infants, based on quantitative analysis of neonatal ICU cardiorespiratory monitoring data.BackgroundPreterm birth is a major cause of infant mortality and morbidity worldwide and a leading contributor to disability. Abnormal control of breathing is common in preterm infants and usually manifests as apnea, intermittent hypoxemia, bradycardia, and periodic breathing. Extremely preterm infants may also have impaired gas exchange caused by respiratory distress syndrome and subsequent bronchopulmonary dysplasia. The combination of apnea and lung disease often leads to more prolonged episodes of intermittent hypoxia. Such chronic intermittent hypoxia is associated with worse short-term outcomes (e.g., increased respiratory support, retinopathy of prematurity) and neurodevelopmental impairment that are difficult to predict in the neonatal ICU (NICU). The contribution of abnormal control of breathing to respiratory outcomes has not been determined. The Pre-Vent study was initiated to analyze cardiorespiratory continuous waveform monitoring data to delineate mechanisms of immature ventilatory control in preterm infants and identify predictive markers.ParticipantsInfants less than 29 weeks gestational age with continuously archived cardiorespiratory monitoring data were included. 717 total infants were evaluated.DesignPre-Vent was an observational multicenter prospective cohort study. Clinical data collected included respiratory support, medications, and co-morbidity data. Physiologic data consisted of variables extracted from cardiorespiratory monitoring data and quantified by count of events per day and duration per event. The extracted variables were apnea (≥20 seconds), periodic breathing (wavelet transform using a five-breath template), intermittent hypoxia events with oxygen saturation Infants discharged prior to 40 weeks post-menstrual age or inpatient infants at 40 weeks post-menstrual age had a favorable outcome if they were not on respiratory support or respiratory medications. Infants discharged prior to 40 weeks post-menstrual age or inpatient infants at 40 weeks post-menstrual age had an unfavorable outcome if they were on respiratory medications and/or respiratory support, or deceased. ConclusionsThe major findings of this study were that mathematical models based on cardiorespiratory bedside monitoring can identify alterations in physiologic measures that are independently associated with unfavorable respiratory outcomes in extremely preterm infants. Both physiologic and clinical variables contributed to good prediction models, with the contribution by physiologic variables increasing with postnatal age (Ambalavanan N, Weese-Mayer DE, Hibbs AM, et al. Am J Respir Crit Care Med. 2023;208(1):79-97.), (Weese-Mayer DE, Di Fiore JM, Lake DE, et al. Pediatr Res. 2024;95(4):1060-1069). 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. Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from Pre-Vent include DNA. Please note that use of biospecimens in genetic research is subject to a tiered consent.

  Study phs004826

• Kidney Precision Medicine Project (KPMP)

  The Kidney Precision Medicine Project (KPMP) is a prospective cohort study, whose goal is to use deep molecular phenotypes of kidney biopsies, along with longitudinally collected clinical phenotypic data, in order to develop new disease ontologies, classification systems, and treatments for acute kidney injury (AKI) and chronic kidney disease (CKD). Since its inception, the KPMP has sought out and included substantive patient-representative feedback regarding disease experience, lack of innovation in new kidney disease therapies and patient tolerance for risk levels in balance with potential benefits both to the individual and society. As established in 2017, the objectives of the Kidney Precision Medicine Project (KPMP) are: • Diverse longitudinal cohort. Recruit adults from varied age, sex, racial, ethnic, socioeconomic, and geographic backgrounds with AKI and CKD to undergo protocol research biopsies linked to longitudinal clinical data and biosamples. • Public resource. Create a publicly available data hub with de-identified clinical, physiologic, imaging, cellular, and molecular data using FAIR principles (findable, accessible, interoperable, and reusable). • Kidney tissue atlas. Create a collection of maps to locate and classify different cell types and interstitial components accounting for health, disease, age, sex, race, ethnicity, socioeconomic, and geographic backgrounds. The atlas will help define disease subgroups and identify critical cells, interstitial components, pathways, and targets for novel therapies. • State/transition markers. Identify cellular and molecular markers that classify cells as healthy, injured, activated, or undergoing recovery via adaptive or maladaptive repair. • Clinical subgroups. Use all available data to define disease subgroups to allow for clinical stratification into distinct endophenotypes. • Molecular pathways. Identify and understand healthy and disease pathways that are activated in a cell type in a subgroup of people. • Biomarkers. Discover sets of subgroup and pathway biomarkers. Molecular and imaging data derived from kidney tissue will be integrated with clinico-pathologic and genetic information, as well as other data derived from analyses of fluid biospecimens, including peripheral blood, urine, and stool. Using advanced analytics to integrate the data, KPMP will aim to define kidney disease subgroups in molecular terms by identifying critical cells, pathways and targets for novel therapies. Patients with AKI or CKD will be recruited from clinical care encounters (e.g., clinic visits for CKD patients, hospitalization or emergency room visits for AKI patients) and from electronic resources (e.g., existing registries, electronic health records). All study procedures are designed to optimize participant safety and will be ethically conducted, ensuring subjects fully understand the scope of the study and any possible risks. For each participant, kidney tissue will be obtained for molecular phenotyping and clinical diagnosis. The diagnostic interpretation will be returned to the participant's primary caregiver to inform clinical care, but no treatment interventions will be prescribed by the KPMP. In addition to kidney biopsy, the study will involve collection of baseline (time of biopsy) and longitudinal biospecimens (including urine, plasma, serum, DNA and stool) and demographic, clinical, and laboratory data. Participants will be followed through scheduled in-person and remote (telephone) study visits, as well as through periodic review of electronic health records.Limited phenotype data and whole genome sequences will be made available in dbGaP. The KPMP will retain the more comprehensive data described above. Investigators may contact the KPMP for access to these data.

  Study phs004574

• International Cancer Proteogenome Consortium (ICPC): Proteogenomics of Oral Squamous Cell Carcinoma in Taiwan

  Oral cavity squamous cell carcinoma (OSCC) is the major subtype (~90%) of oral cancer, which is leading cancer with high mortality worldwide. The environmental risk factors associated with OSCC are quite different in Taiwan as compared to other populations. In most non-Taiwanese populations, OSCC is often associated with tobacco chewing, cigarette smoking, alcohol drinking, or human papillomavirus (HPV) infection. In Taiwan, in contrast, the OSCC occurs mainly in males aged 30 years or older who have habitual betel nut chewing, cigarette smoking, and alcohol drinking. To uncover molecular mechanisms and identify new therapeutic strategies of oral squamous cell carcinoma, this study recruited 112 treatment-naïve OSCC patients and generated multi-omics data, including WES, RNA-Seq, TMT-labeled proteomes, and phosphoproteomes from paired normal/tumor tissues. We have investigated our multi-omics data, covering molecular characterizations such as mutation signatures, impacts of mutations on RNA/protein/phosphoprotein, RNA-protein correlation, somatic copy number alteration, and the relationship with RNA & protein, proteome, and phosphoproteome analysis (T vs NAT), novel peptides (somatic variants, neoantigens, CT antigens, T cell receptors, etc.), as well as molecular subtyping (& pathway analysis). Notably, we have discovered a higher frequency of APOBEC3B deletion polymorphism in the Taiwanese population, and APOBEC3A is a potential prognostic biomarker. Our proteogenomic data enable us to further stratify patients into four groups based on APOBE3A expression level, which is found inversely correlated with EGFR expression. Therefore, the patients with high EGFR and low APOBEC3A expression may benefit from anti-EGFR therapy, while those with low EGFR and high APOBEC3A expression may benefit from immunotherapy. To clarify if there is an interaction between genetic polymorphisms and betel nut chewing habit in Taiwanese OSCC, we plan to concurrently evaluate the effect of habitual betel nut chewing on the gene mutation pattern, the dysregulated protein/phosphoproteins as novel biomarkers and/or therapeutic targets, and the molecular subtyping of patients for effective treatments. 

  Study phs002580

• Genetic Factors Associated with Anthracycline-Induced Cardiomyopathy (COG-ALTE03N1)

  We investigated the genetic mechanisms underlying anthracycline-induced cardiomyopathy, a serious long-term complication among childhood cancer survivors. We focused on the role of DNA damage response and repair (DDR) genes, which had not been previously studied in this context. A gene-based and pathway-based approach was applied to assess both the main effects and gene-by-anthracycline interaction effects of DDR genes on cardiomyopathy risk. The analysis was conducted using a matched case-control design within the COG-ALTE03N1 study, including 113 cases and 226 controls, all of whom were non-Hispanic White childhood cancer survivors exposed to anthracyclines. For each case, we randomly selected 1-3 childhood cancer survivors with no cardiomyopathy, matched on primary cancer diagnosis, year of diagnosis (±10y), and race/ethnicity. The selected controls had to have a longer duration of follow-up compared with time from cancer diagnosis to cardiomyopathy for the corresponding case. Participants provided blood or saliva for germline DNA isolation and genotyping. Genotyping was performed using Illumina HumanOmniExpress-12 v1.0 (709,358 SNPs) and IlluminaOmni5Exome-4 v1.3 arrays (4,293,368 SNPs), with merging of genotype data from the two arrays (683,781 overlapped SNPs) and quality control (QC) using PLINK. Of the 220 genes in the MD Anderson DDR gene website, 187 genes with 2,220 single nucleotide polymorphisms [SNPs] identified on our array data were included in the analyses. A total of 2,170 SNPs were retained in the final gene-based and pathway-based analysis in 339 anthracycline-exposed non-Hispanic White (NHW) patients (113 cases; 226 controls). Key findings included significant associations for FANCC and XRCC5 with cardiomyopathy risk (main effect), and a significant gene-environment interaction involving MGMT. The study also confirmed the involvement of DDR-related biological pathways through both genetic association and interaction analyses.Data Available Through dbGaP: • Genotype data (GWAS) for all study participants • Phenotype data: age at primary cancer diagnosis, sex, race/ethnicity, case-control status This dataset supports further research into genetic susceptibility to chemotherapy-induced adverse outcomes and enables cross-cohort comparisons in cardio-oncology.

  Study phs003792

• The Role of E2F4 in Controlling Resistance to Irinotecan (CPT-11) in Human Colon Cancer

  This study reports the results of RNA sequencing (RNA-seq) experiments performed on three isogenic clones of the human HT29 colon cancer cell line, genetically engineered to achieve the selective inactivation of the adenovirus early 2 (E2) gene transcription factor 4 (E2F4) protein, a key functional component of the multimeric transcriptional repression complex known as the dimerization partner (DP), retinoblastoma-like (RB-like), E2F and multi-vulva class B (MuvB) complex (DREAM). In previous studies, we identified E2F4 as a key regulator of colorectal cancer (CRC) resistance to irinotecan (CPT-11), a cytotoxic agent that stands at the backbone of multiple chemotherapy regimens for the treatment of metastatic CRCs. The molecular mechanisms linking E2F4 to irinotecan resistance, however, remain poorly understood. The present study was designed to identify which genes are under the transcriptional control of E2F4, either at baseline or following exposure to SN38 (i.e., the active metabolite of irinotecan, generated in vivo by biotransformation in the liver) in order to clarify the role played by E2F4 in shaping colon cancer resistance to chemotherapy. The cell line used for this study (HT29) is aneuploid and contains three copies of the E2F4 gene, because of a trisomy of chromosome 16, where the E2F4 gene is located (Kawai et al., Genes, Chromosomes & Cancer, 34:1-8, 2002; PMID: 11921276). HT29 cells were infected with lentivirus vectors encoding for CRISPR/Cas9 constructs designed to selectively inactivate the E2F4 gene, using three distinct guide-RNAs (gRNAs), each targeting a different sequence within the proximal exons of the E2F4 gene (exon 1, exon 2). Lentivirus-infected cells were sub-cloned by single-cell fluorescence-activated cell sorting (FACS), based on the differential expression of a fluorescent reporter (EGFP) expressed in tandem with the gRNAs. Isogenic clones (EGFP+) were then screened to identify those with a tri-allelic knock-out, as revealed by both genetic sequencing of the E2F4 gene (revealing the presence of three distinct frameshift mutations) and Western blot (revealing complete loss of E2F4 protein expression). The study includes twelve (n=12) RNA-seq experiments, representative of 3 experimental replicates (i.e., three distinct isogenic clones of the HT29 cell line, each displaying complete loss of E2F4 expression) and 3 negative controls (i.e., three independent preparations of the parent HT29 cell line, infected with a lentivirus vector encoding for a non-targeting gRNA) exposed to 2 distinct in vitro cell culture conditions: a) treatment with SN38 resuspended in dimethyl sulfoxide (DMSO); or b) treatment with DMSO alone (negative control). The in vitro treatment regimen used for SN38 (32 nM, 24 hours) was designed so that the exposure to SN38 experienced in vitro by HT29 cells would mirror the exposure to SN38 experienced in vivo by malignant tissues, as measured, for example, in metastatic CRC patients receiving a standard dose of irinotecan (180 mg/m2) administered by intravenous infusion over 90 minutes (Deyme et al., Cancer Chemotherapy and Pharmacology, 88:247-258, 2021; PMID: 33912999).

  Study phs003560

• Developing Allelic Imbalance Analysis from Single-Nucleus RNA-Seq Data

  Single-cell RNA-seq (scRNA-seq) is emerging as a powerful tool for understanding gene function across diverse cells. Recently, this has included the use of allele-specific expression (ASE) analysis to better understand how variation in the human genome affects RNA expression at the single-cell level. We reasoned that, because intronic reads are more prevalent in single-nucleus RNA-Seq (snRNA-Seq) and introns are under lower purifying selection, and are thus enriched for genetic variants, that snRNA-seq should facilitate single-cell analysis of ASE. Here we demonstrate how experimental and computational choices can improve the results of allelic imbalance analysis. We explore how experimental choices, such as RNA source, read length, sequencing depth, genotyping, etc., impact the power of ASE-based methods. We developed a new suite of computational tools to process and analyze scRNA-seq and snRNA-seq for ASE. As hypothesized, we extracted more ASE information from reads in intronic regions than those in exonic regions and show how read length can be set to increase power. Additionally, hybrid selection improved our power to detect allelic imbalance in genes of interest. We also explored methods to recover allele-specific isoform expression levels from both long- and short-read snRNA-seq. Overall, we provide an end-to-end experimental and computational approach for future studies.

  Study phs003749