14509 results for "PLOS+ONE+Pennsylvania+German+ACS+language+code+pdc+open+access+study"

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• Genetic Basis of Breast Cancer Resistance in BRCA1 Mutation Carrier

  Our study addressed a specific question in NCI RFA-CA-12-022: "What underlying causal events - e.g., genetic, epigenetic, biologic, behavioral, or environmental - allow certain individuals to survive beyond the expected limits of otherwise highly lethal cancers?". A germline mutation in BRCA1 (BRCA1+) is the most penetrant genetic predisposition for breast cancer. Nevertheless, a portion of BRCA1+ carriers does not develop breast cancer in their lifetime, suggesting that the genetic predisposition can be antagonized by resistant factors. BRCA1+ was inherited from an ancestor of the carrier family thousand years ago. We hypothesize that evolution could select certain genetic components to suppress oncogenesis caused by the predisposition. We compared germline variants in all genes in 27 pairs of breast cancer-unaffected and -affected BRCA1+ carriers, each pair inherited the same BRCA1+. We identified 12 deleterious variants enriched in breast cancer-unaffected carriers, all are common variants. A variant rs3735400 is located in ANLN, a cytokinesis-essential gene. Overexpression of variant-containing ANLN and suppressed expression of endogenous ANLN decrease ANLN nuclear localization and delay cell growth. Our findings suggest that common variants can be selected to resist oncogenesis imposed by BRCA1+.

  Study phs001243

• Whole Exome and Transcriptome Sequencing in Sporadic ALS

  Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a fatal and devastating neurodegenerative disorder that causes the progressive death of upper and lower motor neurons. Although many efforts have been done to elucidate molecular factors involved in the onset and progression of the disorder, the causes of ALS are yet unknown and undefined. Transcriptome studies, based mostly on microarrays, have revealed multiple perturbations of the motor neuron function, supporting the current idea that several cellular events contribute to the pathobiology of the disease, including mitochondrial dysfunction, enhanced apoptosis, glutamate-mediated excitotoxicity, free radical injury, protein misfolding, abnormal calcium metabolism and altered axonal transport. In the present study, we have deeply sequenced the whole transcriptome of ventral horns of the human lumbar spinal cord from matched control and ALS post-mortem donors. Whole exome sequencing from the same donors has also been performed to exclude known genetic variants associated to the familiar form of ALS. In addition, to characterize the ALS transcriptome we have sequenced the RNA fraction at low molecular weight in the same tissues and individuals. Genomic and transcriptomic reads have been generated using the Illumina HiSeq2000 sequencer.

  Study phs000747

• Next Generation Mendelian Genetics: Neonatal Diabetes

  The NHGRI Next Generation Mendelian Genetics project uses exome resequencing to identify variants in unsolved Mendelian diseases. Neonatal diabetes mellitus (ND) is a rare form of monogenic diabetes (90,000-260,000 live births) that is diagnosed in the first 6 months of life. The disease has been classified as transient or permanent and although it can be inherited, more frequently is sporadic as a result of 'de novo' mutations. Defects in 12 genes have been found as responsible for the disease (defects in the paternally imprinted chromosomal region 6q24, IPF1, SLCA2A, INS, EIF2AK3, GCK, FOXP3, GLIS3, PTF1A, HNF1Beta, KCNJ11 and ABCC8). The two subunits of the ATP-sensitive K channel (ABCC8 and KCNJ11) and the insulin gene (INS), account for almost half of the cases and similar to CHI, the other half, remains genetically unexplained. We became part of this study when we submitted 4 DNA samples for exome sequencing, from patients with NDM of Caucasian ancestry, which had no mutations identified in ABCC8 or KCNJ1, with the goal to identify new mutations in known genes or new mutations or genetic variants in new genes.

  Study phs000542

• Characterizing TP53 and PPM1D Mutations as Resistance Drivers to Radiation Therapy in Diffuse Intrinsic Pontine Gliomas

  Pediatric high-grade gliomas (pHGGs), encompassing diffuse midline gliomas (DMGs) and hemispheric tumors, represent the most common cause of cancer-related deaths in children age 0-14 years. Over the last decade, several landmark papers have revealed recurrent single nucleotide variants (SNVs) in the core histones H3.3 and H3.1, co-occurring with alterations in the TP53 signaling pathway and receptor tyrosine kinases (RTKs). However, the contribution of structural variants (SVs) to gliomagenesis has not been systematically explored. We performed a comprehensive analysis of whole genome sequencing (WGS) data on pediatric high-grade gliomas (pHGGs) from 179 children, including 61 hemispheric tumors and 118 diffuse midline gliomas, or DMGs, of which 61 are novel to this study. Among the DMGs, 84 (71%) were from pre-treatment biopsies including 33 obtained from the first multi-institutional North American clinical trial to incorporate diagnostic biopsies. This represents the largest cohort of pretreatment DMGs with whole genome sequencing to date. This large cohort of whole genome sequences provides an unparalleled opportunity to assess significantly recurrent structural variants in pHGG and their associations with driver SNVs and SCNAs. 

  Study phs002380

• Genomic Data Archive From the Network for Pancreatic Organ Donors With Diabetes

  The Network for Pancreatic Organ Donors with Diabetes (nPOD) is the largest biorepository of human pancreata from organ donors with type 1 diabetes (T1D), maturity-onset diabetes of the young (MODY), cystic fibrosis-related diabetes (CFRD), type 2 diabetes (T2D), gestational diabetes, and islet autoantibody positive (AAb+)/pre-T1D. The mission of the nPOD is to distribute biospecimens and associated de-identified data/metadata to an international researcher network, and to promote the development of new treatments for these diabetes conditions. Here, we describe the release of high-parameter genotyping data for the nPOD cohort. Specifically, 372 subjects were genotyped using a customized precision medicine single nucleotide polymorphism (SNP) microarray (UFDIchip). These data were technically validated using published algorithms to evaluate donor relatedness, ancestry, imputed HLA, and T1D genetic risk score. Additionally, 207 subjects were queried for rare known and novel coding region variants via whole exome sequencing (WES). These data are now publicly available, enabling genotype-selected sample requests and the study of novel genotype : phenotype associations, ultimately to explain diabetes heterogeneity and inform precision medicine strategies to interrupt diabetes pathogenesis.

  Study phs002861

• Youth Drug Abuse, ADHD and Related Disorders

  There are two major aims with this study. 1. To describe the developmental trajectory of (a) a community-based sample of youth with a childhood diagnosis of ADHD that has been prospectively followed from childhood into adulthood (approximately a 17-year span), and (b) a clinical sample of youth that received drug abuse treatment during adolescence (variable time span). 2. To examine the association of phenotypes of drug involvement severity and risk alleles that prior research has suggested to be associated with drug abuse and externalizing disorders. The sample (N=607) consists of three groups based on youth status: Treatment, High Risk, and Control. These groups are defined as follows: Treatment - attended treatment or a brief intervention for a substance use disorder during adolescence (n=402); High Risk - elevated scores on standardized measures of disruptive behaviors during childhood based on teacher and parent reports (n=142); Control - normative scores during childhood on standardized measures of disruptive behaviors based on teacher and parent reports, and absent of any DSM-based behavioral/mental disorder when assessed during childhood based on parent report (n=66). Among the 610 participants who provided DNA, 607 are usable samples.

  Study phs001734

• Genetics of Cutaneous T-Cell Lymphoma

  Mycosis fungoides (MF) is a common extranodal T-cell lymphoma primarily arising in the skin. In early disease stages, MF presents as skin patches and plaques that in some cases may progress to tumor and disperse to lymph nodes and other internal organs. The 10-year overall survival is 50% in advanced stages. Early diagnosis is difficult as the histology overlaps with features of inflammatory skin diseases. Even when the diagnosis is established, there are no prognostic markers that predict whether the disease will be aggressive or indolent. Lastly, there are no curative treatments and MF will invariably relapse, even after aggressive chemotherapy. The disease is a diagnostic, prognostic and therapeutic challenge. The main objective of this study is to address the question of tumor heterogeneity in MF. To date, MF is considered to be monoclonal, derived from a transformed, mature memory T-cell. However, clinical observations and preliminary data suggest that MF comprises multiple subclones, which may be of importance for understanding disease evolution and resistance to therapy. We plan to address this objective using Whole Exome Sequencing (WES) of MF tissue prepared by laser microdissection (LMD).

  Study phs001877

• Impact of Race and Genetic Factors on Beta Blocker Effectiveness in Heart Failure

  Heart Failure (HF) continues to be an enormous public health problem, despite the many advances in its pharmacotherapy over the past 25 years. The availability of multiple therapeutic options for HF requires individualization of therapy. However, there are currently insufficient tools to guide the optimal selection of therapy. The expansion of human genomic information has led to exciting new opportunities to improve the selection of drug therapy. In order to evaluate whether genetic variation impacts outcomes and drug response in heart failure, we performed a cohort study of patients with heart failure. Our overall plan was to recruit patients who have heart failure and receive treatment through HAP-HFMG. This allowed us to collect clinical outcomes, and quantify medication adherence via electronic pharmacy claims data. We collected whole blood samples for genetic analysis. We then tested whether genetic variants can predict patient outcomes (survival) in the context of their medical therapy (drug exposure). The primary medications of interest were beta blockers. Outcomes were modeled overall, accounting for the amount of exposure to the agent, and adjusting for baseline characteristics.

  Study phs001501

• Extracorporeal Life Support Survival in a Pediatric Hematopoietic Cellular Transplant Recipient with Presumed Graft Versus Host Disease-Related Fulminant Myocarditis

  We report the case of a 15-year-old female with hypodiploid pre-B acute lymphoblastic leukemia status post allogeneic hematopoietic stem cell transplantation (HCT) from a matched unrelated male donor who presented on transplant day +75 with cardiac arrest due to ventricular fibrillation associated with fulminant myocarditis. Using conventional diagnostics, an exhaustive search for microbial pathogens in the heart biopsy as well as nasopharynx, blood, urine, and endotracheal aspirate was performed but did not uncover a candidate pathogen. The family consented to a research study for the use of unbiased next-generation genomic sequencing for pathogen identification in the myocardial biopsy. DNA sequencing was performed on 1.5 x 108 sequencing pairs and no microbial pathogens were identified. Interestingly, a significant component of Y-chromosomal human DNA was identified, suggesting infiltration of at least 10 donor leukocytes per host cell. This finding is grossly consistent with the lymphocyte:myocyte ratio in the biopsy according to visual inspection at 40x magnification. This case merits discussion due to (1) her survival after 17 days of veno-arterial extracorporeal life support (ECLS) and (2) the possibility of cardiotropic graft versus host disease (GVHD).

  Study phs001336

• Epigenetic Biomarkers of Aging

  The aim of the study was to discover new epigenetic biomarkers of aging. We used a genome-wide screen for genetic loci showing consistent changes of DNA methylation with progressive aging. Blood DNA samples from 19 apparently healthy individuals aged 22-80 years obtained from the NINDS repositories were analyzed for DNA methylation using Reduced Representation Bisulfite Sequencing. We followed the New England Biolabs (NEB) protocol for methylated adaptors as described previously. Briefly, 1 microgram of genomic DNA was spiked with 100 picograms of lambda phage DNA as the unmethylated standard and digested with MspI endonuclease at C’CGG sites. Ends of restriction fragments were filled in, 3’-dA tailed and methylated adaptors were ligated to the ends of restriction fragments. Bisulfite treatment using the Epitect kit (Qiagen) followed. Bisulfite-converted libraries were amplified using EpiMark Taq DNA polymerase (NEB) and primers with dual barcode indices. The libraries were pooled and sequenced on Illumina HiSeqX instrument using paired end reads of 150 bases. We used Bismark v0.23.1 to align the sequences to hg19 human genome assembly. We used methylKit v1.22.0 to analyze differential methylation in individuals of different ages.

  Study phs003046