12501 results for ""non-traditional+communal+storytelling+approach"+novel+segment+noted+in+critical+commentary"

in 20.43 milliseconds.

• National Institute of Neurological Disorders and Stroke (NINDS) Parkinson's Disease

  This study utilized the well characterized collection of North American Caucasians with Parkinson's disease, and neurologically normal controls from the sample population which are banked in the National Institute of Neurological Disorders and Stroke (NINDS Repository) collection. Two sub-studies are included, in sub-study NINDS-Genome-Wide Genotyping in Parkinson's Disease, genome-wide, single nucleotide polymorphism (SNP) genotyping of these publicly available samples was originally done in 267 Parkinson's disease patients and 270 controls, and this has been extended to include genome wide genotyping in 939 Parkinson's disease cases and 802 controls; in sub-study NINDS-Exome Sequencing in Parkinson's Disease, genome wide exome DNA sequencing was done in 618 Parkinson's disease samples deposited in Coriell NINDS repository. The DNA comes from a mixture of blood, and from cell lines (lymphoblast cell lines) derived from blood. The GWAS data and exome sequencing data was generated and provided by the laboratory of Neurogenetics lead by Dr. Andrew Singleton, NIA, and Dr. John Hardy, a former chief at NIA, NIH. The NINDS Parkinson's Disease Cohort study is utilized in the following dbGaP individual studies. To view genotypes, whole exome sequencing, and derived variables collected in these individual studies, please click on the following individual studies below or in the "Sub-studies" box located on the right hand side of this top-level study page phs001172 NINDS Parkinson's Disease Cohort study. phs000089 PD GWAS phs001103 PD Exome

  Study phs001172

• Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis

  Monozygotic (MZ) twins have been widely employed for dissection of the relative contributions of genetics and environment in disease. In multiple sclerosis (MS), an autoimmune demyelinating disease that commonly causes neurodegeneration and disability in young adults, disease discordance in MZ twins has been interpreted to indicate environmental importance in pathogenesis. However, genetic and epigenetic differences between MZ twins have been described, challenging the accepted experimental paradigm in disambiguating effects of nature and nurture. Here, we report the genome sequences of one MS-discordant MZ twin pair and messenger RNA (mRNA) transcriptome and epigenome sequences of CD4+ lymphocytes from three MS-discordant, MZ twin pairs. No reproducible differences were detected between co-twins among ~3.6 million single nucleotide polymorphisms (SNPs) or ~0.2 million insertion-deletion polymorphisms (indels). Nor were any reproducible differences observed between siblings of the three twin pairs in HLA haplotypes, confirmed MS-susceptibility SNPs, copy number variations, mRNA and genomic SNP and indel genotypes, or expression of ~19,000 genes in CD4+ T cells. Only two to 176 differences in methylation of ~2 million CpG sites were detected between siblings of the three twin pairs, in contrast to ~800 differences in methylation between T cells of unrelated individuals and several thousand differences between tissues or normal and cancerous tissues. In the first systematic effort to estimate sequence variation among MZ co-twins, we did not find evidence for genetic, epigenetic or transcriptome differences that explained disease discordance. These are the first female, twin and autoimmune disease genome sequences reported.

  Study phs000239

• C3 SNPs and outcome after lung transplantation

  Background: Development of chronic rejection is still a severe problem and causes high mortality rates after lung transplantation (LTx). Complement activation is important in the development of acute rejection (AR) and bronchiolitis obliterans syndrome, with C3 as a key complement factor. Methods: Since a single nucleotide polymorphism (SNP) in the C3 gene (rs2230199) is associated with long-term outcome after solid organ transplantation, we investigated this SNP in relation to LTx. In addition, we looked at local production of C3 by analyzing bronchoalveolar lavage fluid (BALF) of LTx patients using isoelectric focusing (IEF). Results: We demonstrated the presence of C3 in BALF and showed that this is produced by the donor lung based on the genotype of SNP rs2230199. We also analyzed donor and patient SNP configurations and observed a significant association between the SNP configuration in patients and episodes of AR during 4-years follow-up. Survival analysis showed a lower AR-free survival in homozygous C3 slow patients (p=0.005). Furthermore, we found a significant association between the SNP configuration in donors and BOS development. Patients receiving a graft from a donor with at least one C3 fast variant for rs2230199 had an inferior BOS-free survival (p=0.044). Conclusions: In conclusion, our data indicate local C3 production by donor lung cells. In addition, a single C3 SNP present in recipients affects short-term outcome after LTx, while this SNP in donors has an opposite effect on long-term outcome after LTx. These results could contribute to an improved risk stratification after transplantation.

  Study EGAS00001003843

• Transcriptional profiling of ovarian tumours and cell lines

  Purpose: Endogenous retroviruses (ERVs) play a role in a variety of biological processes, including embryogenesis and cancer. DNA methyltransferase inhibitors (DNMTi)-induced ERV expression triggers interferon responses in ovarian cancer cells via the viral sensing machinery. Baseline expression of ERVs also occurs in cancer cells, though this process is poorly understood and previously unexplored in epithelial ovarian cancer (EOC). Here, the prognostic and immunomodulatory consequences of baseline ERV expression was assessed in EOC. Experimental Design: ERV expression was assessed using EOC transcriptional data from TCGA and from an independent cohort (HH), as well as from untreated or DNMTi-treated EOC cell lines. LASSO logistic regression defined an ERV expression score to predict patient prognosis. Immunohistochemistry (IHC) was conducted on the HH cohort. Combination of DNMTi treatment with γδ T cells was tested in vitro, using EOC cell lines and patient-derived tumor cells. Results: ERV expression was found to define clinically relevant subsets of EOC patients. An ERV prognostic score was successfully generated in TCGA and validated in the independent cohort. In EOC patients from this cohort, a high ERV score was associated with better survival (log-rank p=0.0009) and correlated with infiltration of CD8+PD1+ T cells (r=0.46, p=0.0001). In vitro, baseline ERV expression dictates the level of ERV induction in response to DNMTi. Manipulation of ERV expression by DNMTi resulted in improved EOC cell killing by cytotoxic immune cells. Conclusions: These findings uncover the potential for baseline ERV expression to robustly inform EOC patient prognosis, influence tumor immune infiltration and affect anti-tumor immunity.

  Study EGAS00001004814

• Whole Exome Sequencing of Calcitonin Producing Pancreatic Neuroendocrine Neoplasms (CT-pNENs) Indicates a Unique Molecular Signature

  Calcitonin-producing pancreatic neuroendocrine neoplasms (CT-pNENs), which can mimic clinical and laboratory features of medullary thyroid carcinoma, are an extremely rare clinical entity with approximately 60 cases reported worldwide. The molecular profile of CT-pNENs is not yet known. Whole-exome sequencing (WES) was performed on tumor and corresponding serum samples of five patients with increased calcitonin serum levels and histologically proven calcitonin-positive CT-pNENs. cBioPortal analysis and gene enrichment analysis with DAVID were performed to validate candidate genes. Immunohistochemistry was used to detect protein expression of MUC4 and MUC16 in CT-pNEN specimens. Common somatic mutations of pNENs like MEN1, ATRX and PIK3CA were identified in cases of CT-pNENs. New somatic SNVs in ATP4A, HES4, and CAV3 have not yet been described in CT-pNENs. Pathogenic germline mutations in FGFR4 and DPYD were found in three of five cases. Mutations of CALCA (calcitonin) and the corresponding receptor CALCAR were found in all five tumor samples, but none of them resulted in clinical or protein sequelae. All five tumor cases showed single nucleotide variations (SNVs) in MUC4, and four cases showed SNVs in MUC16, both of which were membrane-bound mucins. Immunohistochemistry showed protein expression of MUC4 and MUC16 in one case each, and the liver metastasis of a third case was double positive for MUC4 and MUC16. The homologous recombination deficiency (HRD) score of all tumors was low.CT-pNENs have a unique molecular signature compared to other pNEN subtypes, specifically involving the FGFR4, DPYD, MUC4, MUC16 and the KRT family genes. However, these WES data from only five cases must be interpreted with caution because causal interpretation of the mutational landscape in CT-pNENs is difficult. Further research is needed to explain differences in pathogenesis compared with other pNENs. In particular, multi-omics data such as RNASeq, methylation, and whole genome sequencing could be informative.

  Study phs003060

• Alcohol Dependence: Sequencing from Multiplex Families

  Two multiplex for alcohol dependence family studies were initiated based on the gender of a pair of probands. Ascertainment of a pair of AD probands was used to increase the density of alcohol dependence within the family. Identification of male (Cognitive and Personality Factors in Relatives of Alcoholics Family Study) and female (Biological Risk Factors in Female Alcoholics Family Study) alcohol dependent probands was accomplished by identifying an alcohol dependent proband while in treatment in a substance abuse treatment facility in Pittsburgh and surrounding communities who provided contact information for a sibling whom he/she thought might be interested in participating. The studies had identical ascertainment requirements. DNA was banked for all willing participants.

  Study phs001775

• Genetic landscape of non-Down syndrome acute megkaryoblastic leukemia

  To define the mutation spectrum in non-Down syndrome acute megkaryoblastic leukemia (non-DS-AMKL), we performed transcriptome sequencing on diagnostic blasts from 14 pediatric patients and validated our findings in a recurrency/validation cohort consisting of 34 pediatric and 28 adult AMKL leukemia samples. Our analysis identified a cryptic chromosome 16 inversion [inv(16)(p13.3q24.3)] in 27% of pediatric cases, which encodes a CBFA2T3-GLIS2 fusion protein. Expression of CBFA2T3-GLIS2 in Drosophila and murine hematopoietic cells induced bone morphogenic protein (BMP) signaling, and resulted in a marked increase in the self-renewal capacity of hematopoietic progenitors. These data suggest that expression of CBFA2T3-GLIS2 directly contributes to leukemogenesis.

  Study EGAS00001000379

• Samples from the Greek island of Crete, MANOLIS cohort

  Genome-wide association studies of complex traits have been successful in identifying common variant associations, but a substantial heritability gap remains. The field of complex trait genetics is shifting towards the study of low frequency and rare variants, which are hypothesised to have larger effects. The study of these variants can be empowered by focusing on isolated populations, in which rare variants may have increased in frequency and linkage disequilibrium tends to be extended. This work focuses on isolated populations from Greece. Sequencing is very efficient in isolated populations, because variants found in a few samples will be shared by others in extended haplotype contexts, supporting accurate imputation.

  Study EGAS00001000067

• Collaborative Cohort of Cohorts for COVID-19 Research (C4R): Coronary Artery Risk Development in Young Adults Study (CARDIA)

  Cohort Description The Coronary Artery Risk Development in Young Adults (CARDIA) study is a study examining the development and determinants of clinical and subclinical cardiovascular disease and their risk factors. It began in 1985-6 with a group of 5115 black and white men and women aged 18-30 years. The participants were selected so that there would be approximately the same number of people in subgroups of race, gender, education (high school or less and more than high school), and age (18-24 and 25-30 years) in each of 4 centers: Birmingham, AL; Chicago, IL; Minneapolis, MN; and Oakland, CA. These same participants were asked to participate in follow-up examinations during 1987-1988 (Year 2), 1990-1991 (Year 5), 1992-1993 (Year 7), 1995-1996 (Year 10), 2000-2001 (Year 15), 2005-2006 (Year 20), 2010-2011 (Year 25), 2015-2016 (Year 30), and 2021-2022 (Year 35). Data Being Submitted Wave 1 questionnaire data includes 397 variables for up to 2434 CARDIA participants in C4RWave 2 questionnaire data includes 448 variables for up to 1901 CARDIA participants in C4RDried Blood Spot/Serosurvey data includes 7 variables for up to 1332 CARDIA participants in C4RDerived data includes 43 variables for up to 2723 CARDIA participants in C4RPhenotype data includes 113 variables for up to 2723 CARDIA participants in C4R

  Study phs003045

• Chromothripsis in human breast cancer (HIPO K26K/H017/A017)

  Chromothripsis is a form of genome instability, by which a presumably single catastrophic event generates extensive genomic rearrangements of one or a few chromosome(s). Widely assumed to be an early event in tumor development, this phenomenon plays a prominent role in tumor onset. We analyzed chromothripsis in 252 human breast cancers from two patient cohorts (149 metastatic breast cancers, 63 untreated primary tumors, 29 local relapses, 11 longitudinal pairs) using whole-genome and whole-exome sequencing. We showed that chromothripsis affects a substantial proportion of human breast cancers, with a prevalence over 60% in a cohort of metastatic cases and 25% in a cohort comprising predominantly luminal breast cancers (cohorts from HIPO K26K and H017 and A017). In the vast majority of cases, multiple chromosomes per tumor are affected, with most chromothriptic events on chromosomes 11 and 17 including, among other significantly altered drivers, CCND1, ERBB2, CDK12 and BRCA1. Importantly, chromothripsis generates recurrent fusions that drive tumor development. Chromothripsis-related rearrangements are linked with univocal mutational signatures, with clusters of point mutations due to kataegis in close proximity to the genomic breakpoints, and with the activation of specific signaling pathways. Analysis of the temporal order of events in tumors with and without chromothripsis as well as longitudinal analysis of chromothriptic patterns in tumor pairs revealed important insights on the role of chromothriptic chromosomes in tumor evolution.

  Study EGAS00001004662