13393 results for ""pdc"+"heritage+language"+census+study"

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• Defining Cutaneous Gene Expression Signatures in Juvenile Dermatomyositis

  Skin inflammation in juvenile dermatomyositis (JDM) can signal disease onset or flare up and prevent complete disease remission. Our objective was to evaluate JDM cutaneous expression signatures through tape stripping in both lesional and non-lesional skin and as compared to paired blood. A total of 28 JDM and 20 control (CTL) patients participated in the study. All patients had tape strip sampling of non-lesional (NL) skin at enrollment visit. Within our JDM cohort, paired lesional (L) skin was additionally sampled if rash was present. 16/28 of JDM patients had at least one additional skin sample associated with a follow-up (FU) visit (total number of follow-up samples included = 26 NL and 4 L). We identified a common innate immune signature in both lesional and non-lesional JDM skin. Using unsupervised hierarchical clustering of skin expression data, we distinguished a JDM molecular subgroup characterized by a mitochondrial dysfunction signature. In comparison to blood expression data, we determined that skin may more effectively highlight the JDM subgroup characterized by a mitochondrial dysfunction expression signature. Data available include bulk RNA-sequencing data from tape strips and blood of the JDM and control patients from this study.

  Study phs003884

• Kids First: Pediatric Research Project on the Genomic Analysis of Congenital Diaphragmatic Hernia

  The Gabriella Miller Kids First Pediatric Research Program (Kids First) is a trans-NIH effort initiated in response to the 2014 Gabriella Miller Kids First Research Act and supported by the NIH Common Fund. This program focuses on gene discovery in pediatric cancers and structural birth defects and the development of the Gabriella Miller Kids First Pediatric Data Resource (Kids First Data Resource). Both, childhood cancers and structural birth defects are critical and costly conditions associated with substantial morbidity and mortality. Elucidating the underlying genetic etiology of these diseases has the potential to profoundly improve preventative measures, diagnostics, and therapeutic interventions. WGS and phenotypic data from this study are accessible through dbGaP and kidsfirstdrc.org, where other Kids First datasets can also be accessed. In collaboration with the University of Utah, DNA from four families were selected for high-depth WGS (60X) including diaphragm and skin tissue to identify mosaicism. In collaboration with the Broad Institute, DNA from four families underwent linked long read sequencing using 10X Genomics technology. Probands with congenital diaphragmatic hernia/defects and both biological parents enrolled as part of the DHREAMS study.

  Study phs001110

• Whole Genome Sequencing for Metastatic Mutational Burden in Extraskeletal Myxoid Chondrosarcoma

  Extraskeletal myxoid chondrosarcoma (EMC) is an ultra-rare cancer. Though it has a favorable prognosis and an indolent course, it has high rates of local recurrence and metastasis to the lungs. EMC is most often characterized by a translocation involving the NR4A3 gene most often fusing with EWSR1, leading to constitutive expression of NR4A3, the biological significance of which is unknown. Our study presents a case of EMC with case-matched lung and advanced pelvic metastases. We conducted Whole Genome Sequencing to examine differences in the mutational landscape at two different stages of metastasis. This is the first study to our knowledge to analyze mega-base scale structural variants (SVs) in EMC. Our data validates copy number variants (CNVs) found in previous studies. While the primary tumor and lung metastasis had similar somatic variations and CNVs, the pelvic metastasis had more SVs with especially increased mutational burden of SVs in chromosome 2. This suggests that different molecular drivers appear in more advanced, relapsing EMC compared with the primary tumor and early lung metastasis. The sequencing data is available through dbGaP.

  Study phs003305

• CSER: Exome Sequencing in Diverse Populations in Colorado and Oregon/CHARM Cancer Health Assessments Reaching Many

  The CHARM (Cancer Health Assessment Reaching Many) study, part of the Clinical Sequencing Evidence-Generating Research (CS.ER2) effort, aimed to assess the utility of clinical exome sequencing and how it affects care in diverse populations. The study population included adults at risk for hereditary cancer syndromes. The primary objective was the implementation of a hereditary cancer risk assessment program in healthy 18-49 year-olds in primary care settings within a vertically integrated health delivery system (Kaiser Permanente) and a federal qualified health center (Denver Health). The investigators aimed to assess clinical exome sequencing implementation and interpretation, as well as tailored interactions for low health literacy including a contextualized consent process, and a modified approach to results disclosure and genetic counseling. The investigators were also assessing the clinical utility (healthcare utilization and adherence to recommended care) and personal utility of primary and additional results from clinical exome sequencing, and evaluate the ethical and policy implications of considering personal utility of genomic information decisions for health care coverage.Sequencing and analysis for CHARM was conducted at the Northwest Clinical Genomics Laboratory, University of Washington, Seattle (https://nwgc.gs.washington.edu/).

  Study phs002111

• Development of cell lines and mouse models of bone and soft tissue sarcoma to establish novel treatment

  Malignant giant-cell tumors are extremely rare bone sarcomas that transform from conventional giant-cell tumors during long periods of treatment. We have applied the culture methods and succeeded in establishing patient-derived organoids (PDO) of rare sarcomas. This study aimed to investigate the genomic characteristics of our established novel organoids from human malignant giant-cell tumors. The developed tumors with xenograft were genomically analyzed to compare their characteristics with those of the original tumors. Genetic changes over time throughout treatment were analyzed, and the genomic status of the established organoid was confirmed. Next generation sequencing revealed that the established organoids lacked the H3-3A G34W mutation. The xenografted organoids of the malignant giant-cell tumor had phenotypes genetically similar to those of the original tumor. The established organoids were confirmed to be derived from human malignant giant-cell tumors. In summary, the present study demonstrated a novel organoid model of a malignant giant-cell tumor that was genetically confirmed to be a malignant transformed tumor. Our organoid model could be used to elucidate the molecular pathogenesis of a malignant giant-cell tumor and develop novel treatment modalities.

  Study JGAS000618

• Single-cell multidimensional profiling of tumor cell heterogeneity in supratentorial ependymomas

  Supratentorial ependymomas (ST-EPNs) are aggressive and treatment-resistant pediatric brain tumors that form along the human cortex, with suspected origin from radial glia cells. Although histologically similar, ST-EPNs are molecularly classified into six distinct subgroups, many of them remaining understudied. Here, we integrated molecular cell states and spatial architecture to resolve the cellular origins and aberrant differentiation trajectories of ST-EPNs at single-cell resolution. We show that, while all ST-EPNs display a unified origin from neuroepithelial cells, different subgroups harbor highly diverse cell states and differentiation potential associated with neural or ependymal differentiation. Spatial mapping uncovered a higher-order structural tumor organization driven by presence of the mesenchymal state, and refines classical histological features based on detailed molecular resolution. By benchmarking a morpho-molecular cell-state classification system in different disease models and human tumors, we identified four cellular subtypes defined by the architecture of neurite-like extensions that mediate either self-renewal or fast, saltatory invasive phenotypes reminiscent of neurons during neurodevelopment. Collectively, our study provides a comprehensive framework for the study of ST-EPN cellular states, and reveals biologically relevant tumor compartmentalization with potential clinical implication.

  Study EGAS50000001513

• Response to tumor-infiltrating lymphocyte adoptive therapy is associated with preexisting CD8+ T-myeloid cell networks in melanoma

  Adoptive cell therapy (ACT) using ex vivo–expanded tumor-infiltrating lymphocytes (TILs) can eliminate or shrink metastatic melanoma, but its long-term efficacy remains limited to a fraction of patients. Using longitudinal samples from 13 patients with metastatic melanoma treated with TIL-ACT in a phase 1 clinical study, we interrogated cellular states within the tumor microenvironment (TME) and their interactions. We performed bulk and single-cell RNA sequencing, whole-exome sequencing, and spatial proteomic analyses in pre- and post-ACT tumor tissues, finding that ACT responders exhibited higher basal tumor cell–intrinsic immunogenicity and mutational burden. Compared with nonresponders, CD8+ TILs exhibited increased cytotoxicity, exhaustion, and costimulation, whereas myeloid cells had increased type I interferon signaling in responders. Cell-cell interaction prediction analyses corroborated by spatial neighborhood analyses revealed that responders had rich baseline intratumoral and stromal tumor–reactive T cell networks with activated myeloid populations. Successful TIL-ACT therapy further reprogrammed the myeloid compartment and increased TIL-myeloid networks. Our systematic target discovery study identifies potential T-myeloid cell network–based biomarkers that could improve patient selection and guide the design of ACT clinical trials.

  Study EGAS50000001217

• Pipeline Olympics: Continuous benchmarking of computational workflows for DNA methylation sequencing data

  DNA methylation is a widely studied epigenetic mark and a powerful biomarker of cell type, age, environmental exposure, and disease. Genome-wide DNA methylation profiling is usually performed using whole-genome sequencing following selective conversion of unmethylated cytosines into thymines via bisulfite treatment or enzymatic methods. Numerous software tools facilitate processing of raw sequencing data for DNA methylation profiling, but a comprehensive benchmarking has been lacking. In this study, we systematically compared methods and tools for processing DNA methylation sequencing data. We established a dedicated benchmarking dataset comprising genome-wide DNA methylation profiling data for four reference samples using five experimental protocols each. The results of data processing were compared to highly quantitative locus-specific DNA methylation measurements available for 46 genomic loci. Based on this gold-standard reference dataset, we identified workflows that consistently demonstrated high performance. We present our results in an interactive application that provides a “living benchmark” ready for continuous updating as new workflows are proposed and require benchmarking against existing methods. In summary, our study provides guidance for any laboratory studying DNA methylation on a genome-wide scale.

  Study EGAS50000000541

• An_exome_sequencing_study_of_the_HIV_elite_long_term_non_progressors_and_rapid_progressors__CASCADE_cohorts_

  Background: A rare subgroup of HIV infected individuals naturally controls infection withouttreatment. These ?elite controllers? constitute an important model for the natural control ofHIV infection. Indeed, the study of these individuals may provide insights into strategies forthe development of HIV vaccines. Although several HLA and chemokine alleles are knownto be over-represented in elite controllers, only a small portion of HIV phenotypic variation isexplained by known genetic variants. The elite controller phenotype is rare and distinct,representing the extreme of an infectious disease trait. As such, this phenotype may be partlyexplained by variation in host immune control, which may be characterized by differences inrare functional genetic variants. Genomic regions underlying elite control can be potentiallyidentified by comparing the presence or frequency of variants in this group to thatrepresenting the opposite extreme. In this context, ?rapid progressors? is a group defined byits rapid immunological and clinical disease progression.Aim: To extend an existing study, in order to identify DNA sequence variants involved in thecontrol of HIV infection with greater statistical resolution. Specifically, we aim to sequence upto 200 exomes from multiple cohort studies within the EuroCoord CASCADE collaboration (acollaboration of 25 HIV seroconversion cohort studies across Europe).

  Study EGAS00001000522

• Whole-genome sequencing of two probands with hereditary spastic paraplegia reveals novel splice-donor region mutation and known pathogenic mutation in SPG11

  Hereditary spastic paraplegias (SPG) are a group of heterogeneous neurodegenerative disorders, which are often presented with overlapping phenotypes such as progressive paraparesis and spasticity. To assist the diagnosis of SPG subtypes, next-generation sequencing is often used to provide supporting evidence. In this study, we report the case of two probands from the same family with SPG symptoms, including bilateral lower limbs weakness, unsteady gait, cognitive decline, dysarthria and slurring of speech since age of 14. Subsequent whole-genome sequencing revealed that the patients are compound heterozygous for mutations in SPG11 gene, including the paternally inherited c.6856C>T (p.Arg2286*) mutation and the novel maternally inherited c.2316+5G>A splice donor region mutation. Mutations in SPG11 are the common cause of autosomal recessive Spastic Paraplegia type 11. According to the ClinVar database, there are already 101 reported pathogenic mutations in SPG11 that are associated with SPG. To our knowledge, this is the first report of SPG11 mutations in our local population. Novel splice mutation identified in this study would enrich the catalog of SPG11 mutations, potentially leading to better genetic diagnosis of SPG.

  Study EGAS00001001849