14507 results for "PLOS+ONE+Pennsylvania+German+ACS+language+code+pdc+open+access+study"

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• The Role of Germline Mutation and Parental Age in Autism Spectrum Disorders

  <p>We will apply whole genome sequencing of trio families to determine how patterns of germline mutation throughout the genome determine risk for Autism Spectrum Disorder (ASD). We will investigate the nature intrinsic hypermutability and the extrinsic forces, such as paternal age, that influence rates of germline mutation. We will accomplish these goals through the following specific aims: Specific Aim 1 will characterize germline de novo mutations (DNMs) by whole genome sequencing in families. These studies will identify and validate ~8,000 de novo point mutations and structural variants in trios and controls to determine the parent of origin of DNMs. Specific Aim 2 will identify hot spots for germline mutation based on the regional density of DNMs in the genome, and determine the effects of DNA sequence features on rates of mutation. We will determine the association of mutation hotspots with ASD in the discovery sample and in genomic datasets from an independent sample of 2700 cases and 2700 controls. Specific Aim 3 will characterize the effects of extrinsic factors, including parental age and environment, on genome-wide rates of mutation. We will quantify the effect of paternal age on pathogenic and neutral alleles in sperm and investigate whether some DNMs confer a germline selective advantage. The findings of this study will provide fundamental insights into the genetic basis of autism risk and the genetic mechanism of the observed parental age effects in ASD. We will identify genes that confer significant risk for autism, and we will determine how intrinsic properties of the genome interact with extrinsic forces to determining risk for disease in offspring.

  Study phs001164

• Discovery and Characterization of Genetic Risk Loci in Sjogren's Syndrome

  The Sjögren's Genetics Network (SGENE) is an international collaboration focused on identifying and understanding the genetic variations that influence Sjögren’s pathology. Collectively, SGENE collaborators from 26 different sites (5 in the United States; 21 in foreign countries) have recruited a large cohort of geographically diverse participants of European ancestry. Recruitment, sample collection, and genotyping were performed at unique SGENE sites in compliance with local institutional review board approval. High-density SNP genotyping data were collated by the Oklahoma Medical Research Foundation (OMRF) and used to perform a GWAS of Sjögren's of European ancestry. Participants underwent extensive medical assessment for Sjögren's Syndrome using internationally accepted American-European Consensus Group (AECG) classification criteria or the American College of Rheumatology/European League Against Rheumatism classification criteria. Data quality control, GWAS imputation using the Haplotype Reference Consortium, panel version 1.1, and dbGaP preparation/posting were performed at the OMRF. To facilitate research focused on understanding the genetics of Sjögren's syndrome, the Genomic Summary Results from this GWAS are being made available herein using a total of n=3232 Sjögren's cases and n=17,481 controls. A total of n=8962 controls were obtained from our SGENE collaborators or from our previous study (Lessard, et al. Nature Genetics 2013. PMID: 24097067). To achieve adequate case-to-control ratios for the GWAS analyses, population-based control GWAS data were also obtained from dbGaP (phs000428.v2.p2; phs000672.v1.p1; phs000196.v3.p1; phs000187.v1.p1). In accordance with IRB approval, subject consents, and data sharing restrictions, we are also making available the individual-level genotyping data for a subset of Sjögren's cases (n=1,199) that were genotyped at the OMRF.

  Study phs002723

• NINDS Deep Sequencing for the Detection of Viral Sequences in Primary Progressive Multiple Sclerosis Brains

  Deep sequencing allows for a rapid, accurate characterization of microbial DNA and RNA sequences in many types of samples. Deep sequencing (also called next generation sequencing or NGS) is being developed to assist with the diagnosis of a wide variety of infectious diseases. In this study, seven frozen brain samples (n = 7) from deceased subjects with recent encephalitis were investigated. RNA from each sample was extracted, randomly reverse transcribed, and sequenced. The sequence analysis was performed in a blinded fashion and confirmed with pathogen-specific PCR. This analysis successfully identified measles virus sequences in two brain samples and herpes simplex virus type-1 sequences in three brain samples. No pathogen was identified in the other two brain specimens. These results were concordant with pathogen-specific PCR and partially concordant with prior neuropathological examinations, demonstrating that deep sequencing can accurately identify viral infections in frozen brain tissue (Chan et al., 2014). Data from the primary progressive multiple sclerosis (PPMS) brain specimens (n = 14) and Normal Control brain specimens (n = 14) are also submitted here. All the subjects studied here (encephalitis, PPMS, and controls) were selected from existing collections at the Rocky Mountain and UCLA brain banks. These selections were performed by the directors at the two centers (Dr. Corboy at RM and Nagra at UCLA) based on clinic information provided at the time of collection. All the specimens are from deidentified deceased individuals. The submitting investigators have no identifying information on any of these subjects. To avoid confusion, the dbGaP Subject IDs are identical to the brain bank identifying numbers.

  Study phs000715

• Binding of Epstein Barr Virus EBNA2 Unifies Multiple Sclerosis Genetic Mechanisms

  This study is focused on multiple sclerosis (MS). MS is likely caused by a combination of genetic and environmental factors; however, the mechanisms contributing to these factors remain poorly understood. Epstein-Barr virus (EBV) in particular is a well-established environmental risk factor for MS. We have created a computational algorithm that systematically searches for common molecular mechanisms that might be impacted at multiple MS-associated loci. Using this algorithm, we have discovered that over 40% of MS-associated loci contain MS genetic variants that fall within regions of the human genome occupied by the EBV-encoded EBNA2 protein. The same MS-associated variants also impact gene expression levels of MS-associated genes in EBV-infected B cell lines. Our hypothesis is that allele-dependent binding of EBNA2 and its co-factors explains the allele-dependent risk at many MS genetic loci. Importantly, this hypothesis links the genetic associations of MS to the known molecular roles played by EBV and Notch signaling in disease processes.Subjects with and without MS were recruited into an Institutional Review Board (IRB)-approved protocol through the Cincinnati Autoimmune Registry and Repository. From each subject, DNA from peripheral blood was isolated for whole genome sequencing (WGS). These data will be used to identify genotype-dependent transcriptional regulation in cells assessed from patients and controls. This WGS data was deposited before the full integration of sequence data with other functional genomic data types.From each subject, 90 mL of blood is drawn for isolation of peripheral blood mononuclear cells from which primary B and T cells will be isolated. For each B cell isolation, an EBV-transformed B cell line will be derived.

  Study phs003240

• Genomic Studies in Charcot-Marie-Tooth Disease

  The various forms of Charcot-Marie-Tooth disease (CMT) comprise a genetically heterogeneous set of peripheral neuropathies. Currently, >90 different CMT genes have been identified; yet, for the axonal CMT2 subtype these genes explain only 30-40% of the genetic effect. In particular, the application of exome sequencing has led to an unprecedented pace in identifying about half of those genes in the past five years. We have been at the forefront of this development with 22+ published new gene identifications in the past seven years. This success was only possible through broad national and international collaborations, data sharing, and the development of advanced analysis tools and methods. We also learned that despite an accumulation of exome sequencing data, over 50% of axonal CMT patients remain undiagnosed, suggesting even more genes are involved; additionally, our preliminary data also support the existence of non-coding variations as Mendelian allele contributors. In this study, we will continue our highly impactful work in CMT family recruitment, exome sequencing and traditional gene identification. In addition, we will expand the genetic studies to whole genome sequencing with a focus on families already explored unsuccessfully in whole exome studies. We further plan to perform the first large rare variant burden analysis in the rare disorder CMT2. This is only possible through the exceptional clinical resources we have built over the past decade. Finally, with many CMT genes available, we will perform statistical network analyses on a CMT-ome to identify gene modules and pathways that will be the starting point of polypharmacology, and provide insight into pathophysiology of peripheral nerve degeneration. All data will be available in real-time to an existing network of CMT investigators worldwide, and deposited in dbGaP annually.

  Study phs003389

• Genetic Neuroscience: How Human Genes and Alleles Shape Neuronal Phenotypes

  The goal of this collaborative, interdisciplinary project is to develop powerful, generalizable approaches for discovering how risk variants for psychiatric disorders shape neurobiological processes at multiple levels of analysis, and to identify the processes whose dysregulation underlies disease.Induced pluripotent stem cells (iPSCs) were used towards the development of these new experimental and inferential systems bridging gaps between human genetics and experimental biology. The largest publicly available collection of iPSCs (2607 lines) has been generated from 2184 donors by the California Institute for Regenerative Medicine (CIRM). To expand our donor collection, an additional 44 iPSC donors from the McLean_Levy cohort were identified. We wish to share the available SNP data for 2167 CIRM lines and whole genome sequence data generated at the Broad Institute for 473 of the CIRM and 44 McLean_Levy iPSC donors. These data can be used to identify (for experiments) lines with specific genotypes of interest and lines from donors with high or low polygenic risk scores for phenotypes of interest. The data can also be used to identify acquired mutations in the iPSC lines. The CIRM iPSC lines are available through Fujifilm Cellular Dynamics iPSC Repository (https://www.fujifilmcdi.com/cirm-ipsc-products/). The McLean_Levy lines are available through the NIMH Repository & Genomics Resource (https://www.nimhgenetics.org/).Additional project data registered with the study includes data from an iPSC line derived from an SMA patient (n=1), as well as single-cell RNA sequence data and supplemental processed genomic datasets in support of project publications.Molecular DatasetsSingle-cell RNA-seq: 10X Genomics, Illumina NovaSeqSupplemental "cell village" pooled genomic sequence data: Illumina NextSeqWhole Genome Genotyping: Infinium Global Screening Array-24 Kit, Illumina HumanCore chipWhole Genome Sequencing: Illumina NovaSeq

  Study phs002032

• Aberrant Activation of Wound Healing Programs within the Metastatic Niche Facilitates Lung Colonization by Osteosarcoma Cells

  Lung metastasis is responsible for nearly all deaths caused by osteosarcoma, the most common pediatric bone tumor. How malignant bone cells coerce the lung microenvironment to support metastatic growth is unclear. This study delineates how osteosarcoma cells educate the lung microenvironment during metastatic progression.Using single-cell transcriptomics (scRNA-seq), we characterized genome– and tissue-wide molecular changes induced within lung tissues by disseminated osteosarcoma cells in both immunocompetent murine models of metastasis and patient samples. We confirmed transcriptomic findings at the protein level and determined spatial relationships with multi-parameter immunofluorescence. We evaluated the ability of nintedanib to impair metastatic colonization and prevent osteosarcoma-induced education of the lung microenvironment in both immunocompetent murine osteosarcoma and immunodeficient human xenograft models.Osteosarcoma cells induced acute alveolar epithelial injury upon lung dissemination. scRNA-seq demonstrated that the surrounding lung stroma adopts a chronic, non-resolving wound-healing phenotype similar to that seen in other models of lung injury. Accordingly, metastasis-associated lung demonstrated marked fibrosis, likely due to the accumulation of pathogenic, pro-fibrotic, partially-differentiated epithelial intermediates. Inhibition of fibrotic pathways with nintedanib prevented metastatic progression in multiple murine and human xenograft models. Our work demonstrates that osteosarcoma cells co-opt fibrosis to promote metastatic outgrowth. When harmonized with data from adult epithelial cancers, our results support a generalized model wherein aberrant mesenchymal-epithelial interactions are critical for promoting lung metastasis. Adult epithelial carcinomas induce fibrotic pathways in normal lung fibroblasts, whereas osteosarcoma, a pediatric mesenchymal tumor, exhibits fibrotic reprogramming in response to the aberrant wound-healing behaviors of an otherwise normal lung epithelium, which are induced by tumor cell interactions.

  Study phs003569

• Whole Exome Sequencing of Head and Neck Patients-Derived Tumor Organoids and Formalin Fixed Paraffin Embedded Tumor Tissue

  In this study, tissue specimens were procured from head and neck squamous cell carcinoma (HNSCC) patients undergoing routine diagnostic procedures as part of their standard of care. For surgical cases, only excess tissue remaining after allocation for essential pathological diagnosis was utilized for research purposes. We aimed to validate the genomic fidelity of patient-derived organoids (PDOs) compared to their originating tumors. Whole exome sequencing was performed on four paired sets of PDOs and matched surgical specimens preserved as formalin-fixed paraffin-embedded (FFPE) samples. The objective was to demonstrate that the in vitro PDO models maintain the genomic profile of the patient-specific tumors, thus supporting their potential application in identifying efficacious personalized treatment regimens. Comparative analyses of single nucleotide variants (SNVs) and copy number variants (CNVs) between matched PDO and FFPE pairs were conducted to assess global genomic similarity and shared HNSCC-relevant variants. The results indicated that the PDOs closely recapitulated the mutational landscape of the resected tumors from which they were derived. This finding supports the validity of the employed in vitro culture conditions for potential use in precision medicine approaches for HNSCC. The data submitted to dbGaP comprise eight whole exome sequencing profiles of matched pairs of HNSCC FFPE and PDO samples from four subjects. Novogene (Novogene Co., Ltd, CA, USA) generated these profiles from 1.0μg genomic DNA per sample, using the Agilent SureSelect Human All Exon kit (Agilent Technologies, CA, USA). Deposited files include raw BAM files of reads aligned to human genome Hg19 using BWA (v.0.7.8-r455), sorted with Samtools (v1.0), and filtered for duplicate reads using Picard (v1.111). Additionally, we've deposited VCF files of SNV variant calls from GATK (v3.8).

  Study phs003755

• Effects of Metformin on Transcriptomic and Metabolomic Profiles in Breast Cancer Survivors Enrolled in the Randomized Placebo-Controlled MetBreCS Trial

  Metformin reduces the incidence of breast cancer in patients with obesity and type 2 diabetes. However, our knowledge of the effects of metformin on breast cancer recurrence is limited. Within the randomized double-blind placebo-controlled phase II trial MetBreCS, we examined changes in breast tissue from breast cancer survivors with BMI >25 kg/m2 after treatment with metformin. To identify metformin-regulated signaling pathways, we integrated the transcriptomic, metabolomic and steroid hormone profiles using bivariate and functional analyses. We identified MS4A1, HBA2, MT-RNR1 and MT-RNR2 expression to be differentially expressed in breast tissues from metformin-treated women. We also found metformin-associated down-regulation of EGFL6 and FDCSP in postmenopausal women. The integration of transcriptomic and metabolomic profiles revealed down-regulation of immune response genes associated with reduced levels of arginine and citrulline in the metformin-treated group. The integration of transcriptomic and steroid hormone profiles showed an enrichment of steroid hormone biosynthesis and metabolism pathways with highly negatively correlated CYP11A1 and CYP1B1 expression in breast tissue from postmenopausal metformin-treated women. Our results indicate that breast cancer survivors treated with metformin have specific changes in breast tissue gene expression that may prevent the development of new tumors. Within the randomized double-blind placebo-controlled phase II trial MetBreCS, we examined changes in breast tissue from breast cancer survivors with BMI >25 kg/m2 after treatment with metformin using bulk RNAseq (total mRNA sequencing), that is deposited in Federated EGA. The steroid hormones, and metabolomics and the insulin sensitivity serum biomarker data underlying this article may be shared upon reasonable request to the PI of the MetBreCS study (Dr. Bernardo Bonanni), following approval by the Data and Safety Monitoring Board at IEO, Milan.

  Study EGAS50000000874

• Efficacy and Immune Effects of Anakinra Prophylaxis for Neurologic Toxicity and Cytokine Release Syndrome in Patients with Lymphoma Receiving Axicabtagene Ciloleucel

  Chimeric antigen receptor T cells have transformed the treatment of multiple hematologic malignancies, but are limited in application due to treatment-related toxicities. Cytokine release syndrome (CRS) and neurotoxicity (NT) are the primary toxicities associated with these therapies and are thought to be mediated by broad immune activation due to robust T-cell expansion. Current treatment of these toxicities utilize anti-IL-6 directed therapy and/or systemic glucocorticoids to mitigate the consequences of this complex inflammatory cascade. We sought to use anakinra, an IL-1R antagonist, as a prophylactic strategy to prevent clinically meaningful CRS/NT, defined as grade 2 or higher toxicity necessitating clinical intervention. Although our study, in line with others, demonstrated that IL-1R antagonism is insufficient to prevent such toxicities entirely, we were able to gain insight into the molecular immune signaling associated with breakthrough CRS & NT in the presence of anakinra prophylaxis using our scRNA dataset of patients treated with and without IL-1R antagonism. We demonstrate that IL-4 and IL-10 anti-inflammatory pathways in infused CAR-T products of both anakinra and non-anakinra cohorts were negatively associated with grade 2+ toxicities. We also found that expression of IFN-gamma pathways and ligand-receptor activities, as well as cytokine levels of IFN-gamma and CXCL10 in CD14+ monocytes, were significantly enriched in patients with breakthrough toxicity in the anakinra cohort. This correlated with an increase in IFN-gamma in the peripheral blood of patients with breakthrough toxicities, among other cytokines. These data identify IFN-gamma as a potential key mechanism in the development of CAR-T cell-associated toxcities and suggest that this pathway is also targetable and not inhibited by anakinra alone.

  Study phs003655