19073 results for "Buy fc coins Buyfc26coins.com is EA Sports official for FC 26 coins They are the best FC seller..nEoY"

in 31.76 milliseconds.

• Foetal_phylogeny_8pcw___WGS_of_LCM_tissues

  This study relates to the overall project of constructing the phylogeny of foetal haematopoiesis. This is an additional project relating to pre-existing work in projects 2043, 2169, 2243 and 2244. This project is to perform WGS (to around 40X) of polyclonal LCM tissues from the 8pcw foetus that have previously undergone library prep and targeted sequencing only. This work is to address reviewers comments for the publication of this work.

  Study EGAS00001004674

• Tubulointerstitial fibrosis is the histological hallmark of chronic kidney disease (CKD). Hypoxia and inflammation (i.e., interleukin (IL)-1β signalling) are independent mediators of tubulointerstitial fibrosis. However, the physiological response of human kidney tubular cells to IL-1β/IL-1RI signalling under the hypoxic conditions of CKD is poorly understood and remains a clinical imperative for therapeutic targeting. This study reports that hypoxia and IL-1β act in synergy to trigger cell cycle arrest/cellular senescence of ex vivo patient-derived primary proximal tubular epithelial cells (PTECs).

  Hypoxia and interleukin (IL)-1β are independent mediators of tubulointerstitial fibrosis, the histological hallmark of chronic kidney disease (CKD). Here, we examine how hypoxia and IL-1β act in synergy to augment maladaptive proximal tubular epithelial cell (PTEC) repair in human CKD. Ex vivo patient-derived PTECs were cultured under normoxic (21% O2) or hypoxic (1% O2) conditions in the absence or presence of IL-1β and examined for maladaptive repair signatures. Hypoxic PTECs incubated with IL-1β displayed a discrete transcriptomic profile distinct from PTECs cultured under hypoxia alone, IL-1β alone or under normoxia. Hypoxia+IL-1β-treated PTECs had 692 ‘unique’ differentially expressed genes (DEGs) compared to normoxic PTECs, with ‘cell cycle’ the most significantly enriched KEGG pathway based on ‘unique’ down-regulated DEGs (including CCNA2, CCNB1 and CCNB2). Hypoxia+IL-1β-treated PTECs displayed signatures of cellular senescence, with reduced proliferation, G2/M cell cycle arrest, elevated senescence-associated β-galactosidase (SA-β-gal) activity and increased production of pro-inflammatory/fibrotic senescence-associated secretory phenotype (SASP) factors compared to normoxic conditions. Treatment of Hypoxia+IL-1β-treated PTECs with either a senolytic drug combination, quercetin+dasatinib, or a type I IL-1 receptor (IL-1RI) neutralizing antibody attenuated senescent cell burden. Our data identify a mechanism whereby hypoxia in combination with IL-1β/IL-1RI signalling trigger PTEC senescence, providing novel therapeutic and diagnostic check-points for restoring tubular regeneration in human CKD.

  Study EGAS00001007904

• The subclonal architecture of metastatic breast cancer: Results from a prospective community-based rapid autopsy program 'CASCADE'

  Background: Understanding the cancer genome is seen as a key step in improving outcomes for cancer patients. Genomic assays are emerging as a possible avenue to personalised medicine in breast cancer. The majority of work in this area has targeted primary tumours however, and very few studies have performed comprehensive profiling of advanced disease. Evolution of the cancer genome during the natural history of breast cancer is largely unknown, as is the profile of disease at death. We sought to study in detail these aspects of advanced breast cancers that have resulted in lethal disease. Methods and Findings: Three patients with ER-positive, HER2-negative breast cancer and one patient with triple negative breast cancer underwent rapid autopsy as part of an institutional prospective community-based rapid autopsy program. Cases represented a range of management problems in breast cancer, including late relapse after early stage disease; de novo metastatic disease; discordant disease response and disease refractory to treatment. Between 5 and 12 metastatic sites were collected at autopsy together with available primary tumours and longitudinal metastatic biopsies taken during life. Samples underwent paired tumour-normal whole exome sequencing and single nucleotide polymorphism arrays. Subclonal architectures were inferred by jointly analysing all samples from each patient. Mutations were validated using high depth amplicon sequencing.Between cases, there were significant differences in mutational burden, driver mutations, mutational processes and copy number variation. Within each case, we found dramatic heterogeneity in subclonal structure from primary to metastatic disease and between metastatic sites, such that no single lesion captured the breadth of disease. Metastatic cross seeding was found in each case and treatment drove subclonal diversification. Subclones displayed parallel evolution of treatment resistance in some cases, and apparent augmentation of key oncogenic drivers as an alternative resistance mechanism. We also observed the key role of mutational processes in subclonal evolution.Limitations of this study include the potential for bias introduced by joint analysis of formalin fixed archival specimens with fresh specimens, and the difficulties in resolving subclones with whole exome sequencing. Other alterations that could define subclones such as structural variants or epigenetic modifications were not assessed. Conclusions: This study highlights the variety of mechanisms that shape the genome of metastatic breast cancer, and the value of studying advanced disease in detail. Treatment drives significant genomic heterogeneity in breast cancers which has implications for disease monitoring and treatment selection in the personalised medicine paradigm.

  Study EGAS00001002153

• STAMPEED: Northern Finland Birth Cohort 1966 (NFBC1966)

  The Northern Finland Birth Cohorts program (NFBC) was initiated in the 1960s in the two northernmost provinces of Finland to study risk factors involved in pre-term birth and intrauterine growth retardation, and the consequences of these early adverse events on subsequent morbidity and mortality. The uniqueness of NBFCs is that the data of the cohorts were obtained from early fetal life (including maternal health during pregnancy) to adulthood. The NFBC1966 includes 12,058 live births to mothers in the two northern-most provinces of Finland. Two decades later, a second cohort of 9432 births was obtained (NFBC1986). In NFBC1966 pregnancies were followed prospectively from the first antenatal contact (10-16th week). After birth, the offspring were examined and then again underwent clinical evaluation at ages 1y, 7y, 14-16y and 31y. At each visit, a wide range of phenotypic, lifestyle and demographic data were gathered by questionnaires and clinical examinations. For the most part, NFBC1986 has undergone similar evaluations to NFBC1966. Linkage to national registries includes hospitalization, deaths, education, medication, pensions, and provides up-to-date demographic and clinical information for members of both cohorts. DNA samples were obtained from 5,923 subjects from NFBC1966 and 6688 subjects from NFBC1986. Data coverage, 96% of all births in 1966 and 99% in 1986, is highly representative for the whole population. The NFBC program comprises more than 20 different projects coordinated by the Center of Lifecourse Disease studies in Northern Finland (COLD) at Oulu University. The prospective data collected from the NFBCs form a unique resource, allowing the study of disease emergence, and of the importance of genetic, biological, social and behavioral risk factors. The genome-wide association (GWA) study sponsored through the STAMPEED program of NHLBI employed genomic DNA samples previously collected by the NFBC1966 study and stored in the DNA repository of the National Institute for Health and Welfare, Finland. This NHLBI sponsored RO1 project aimed to identify genetic variants contributing to metabolic and cardiovascular diseases (CVD). In addition to de-identified genome wide genotypic data, a selected list of phenotypic data related to CVD including weight, height, BMI, HDL, LDL, total cholesterol, triglyceride, glucose, insulin and fasting status, are also available in dbGaP. A summary of the GWAS for the NFBC1966 cardiovascular risk traits can be found in Sabatti et al., Nature Genetics 41: 35-46, 2009, PMID: 19060910. The version 2 release of this study contains sequence data from seventeen loci associated with levels of triglyceride, HDL-C, LDL-C, total cholesterol, fasting plasma glucose, and fasting plasma insulin (Kathiresan et al. 2008, Willer et al. 2008, Sabatti et al. 2009, Dupuis et al. 2010, Teslovich et al. 2010). At each locus, protein-coding regions and 5' and 3' untranslated regions of genes nearest to single nucleotide polymorphisms showing genome-wide significant association with metabolic syndrome-related traits, were sequenced. Targeted Illumina sequencing of 78 genes (~270kb) using 150bp probes was performed on 4943 subjects of the Northern Finland Birth Cohort 1966 (NFBC1966). Whole exome sequencing on the Illumina platform was carried out on 586 of those participants. The sequencing study is part of a larger project that is funded by the National Human Genome Research Institute's Allelic Spectrum in Common Disease Initiative, and comprises sequence data from more than 7000 individuals in two Finnish cohorts: NFBC1966 and the Finland-United States Investigation of NIDDM Genetics (FUSION) study.

  Study phs000276

• Low T cell diversity is associated with poor outcome in bladder cancer - Single cell RNAseq and TCRseq data

  T cells are crucial effector cells in the endogenous defense against cancer, yet the clinical impact of their quantity, diversity, and dynamics remains underexplored. In this study we performed single cell RNAseq paired with single cell TCR-seq on tumor and blood samples from 4 patients (n samples = 8). The goal was to investigate T cell subtypes of expanded and non-expanded T cell clones in blood and in tumors.

  Study EGAS50000000938

• scRNA transcriptome and TCR sequencing data modeling treatment responses in eight renal cell carcinoma patient

  Single cell RNA sequencing and coupled TCR sequencing data generated following immunological treatments in patient-derived ex vivo tumor models. Dataset consist of 46 sequencing samples originating from eight individual patient-derived ex vivo models. Single cell RNA and TCR sequencing data is generated using 10X Genomics platform with 5´ sequencing. The submission contains 46 Fastq files where each patient-derived ex vivo model and it's transcriptomic response to specified treatment is a unique sequencing run. TCR sequencing runs are submitted as one file per individual model, gathering all the treatment conditions.

  Dataset EGAD50000001934

• A spatial human thymus cell atlas mapped to a continuous tissue axis

  T cells develop from circulating precursor cells, which enter the thymus and migrate through specialised sub-compartments that support their maturation and selection. In humans, this process starts in early fetal development and is highly active until thymic involution in adolescence. To map the micro-anatomical underpinnings of this process in pre- and early postnatal stages, we established a novel quantitative morphological framework for the thymus, the Cortico-Medullary Axis, and used it to perform a spatially resolved analysis. By applying this framework to a curated multimodal single-cell atlas, spatial transcriptomics, and high-resolution multiplex imaging data, we demonstrate establishment of the lobular cytokine network, canonical thymocyte trajectories and thymic epithelial cell distributions within the first trimester of fetal development. We pinpoint tissue niches of thymic epithelial cell progenitors and distinct subtypes associated with Hassall’s corpuscles and uncover divergence in the timing of medullary entry between CD4 vs. CD8 T cell lineages. These findings provide a basis for a detailed understanding of T lymphocyte development and are complemented with a holistic toolkit for cross-platform imaging data analysis, annotation, and Organ Axis construction (TissueTag), which can be applied to any tissue.

  Dataset EGAD00001015384

• Genetic Analysis of the Chiari I Malformation

  This study used whole exome sequencing (WES) on families affected with Chiari I Malformation (CM1). Individuals were recruited from the Republic of Tartarstan in the Russian Federation, where CM1 has a high prevalence (approximately 413 out of 100,000). At least one-third of these affected individuals have an affected relative. In collaboration with Dr. Enver Bogdanov of Kazan State Medical University, seven extended families affected with CM1 were identified. Eligible participants for this study were required to 1) have CM1 and a family member with syringomyelia or CM1, or 2) be a family member of a patient with CM1 and have at least two immediate family members diagnosed with CM1. Adults and minors were eligible for this study and recruitment was through self and physician referral. Patients were excluded if they had a contraindication to MRI scanning, were unable to understand the risks of testing, were under one year of age, or could not undergo MRI scanning without sedation. Study participants underwent SPGR (Spoiled Gradient Recalled) and T1-weighted MR-imaging of the brain and cervical spinal cord to assess the volume of the posterior fossa, as well as the presence of CM1. Individuals were defined as having CM1 if the inferior aspect of the cerebellar tonsils were lying ≥=2 mm caudal to the foramen magnum. Individuals were defined as having a small posterior fossa volume if the ratio of the posterior fossa volume to the supratentorial volume was < 0.15. Sixty-two patients (both cases and controls) from the seven extended families had DNA extracted from blood lymphocytes contained in 10 milliliters of stored blood. Whole exome sequencing (WES) was performed by the National Intramural Sequencing Center (NISC). These genotype data, as well as the case-control phenotype data on CM1 diagnosis and small posterior fossa diagnosis, were made available to dbGaP.

  Study phs001795

• 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

• Genome-Wide Association Study of Anorexia Nervosa (Price Foundation, Klarman Family Foundation, Center for Applied Genomics at the Children's Hospital of Philadelphia, Scripps Translational Sciences Institute Clinical Translational Science Award)

  Twin studies are consistent with substantial heritability in anorexia nervosa (AN), although detecting and confirming individual risk alleles has been difficult, due to small effects of single alleles and limited samples in prior studies. Methods: 1105 AN DNA samples obtained in a multisite study and 3733 pediatric patients of normal body weight were genotyped using the Illumina 610Q chip at The Center for Applied Genomics at The Children's Hospital of Philadelphia. Cases and controls were of European ancestry. Single nucleotide polymorphism (SNP) genotypes were subjected to quality control procedures, including elimination of SNPs with: call rates < 95%, minor allele frequency < 5%, and if Hardy-Weinberg equilibrium testing yielded p < 0.0001. Samples were removed if not of European ancestry or if showing cryptic relatedness. Eight AN DNA samples were deleted for low call rate, and 51 AN samples were deleted for cryptic relatedness. The statistical program, PLINK, was used to calculate a P value for each SNP passing quality control using the Cochran-Armitage trend test. The PennCNV program was used to define copy number variation (CNV). Results: We performed a genome-wide association study (GWAS) using with 1033 AN cases and 3733 controls (genomic inflation factor = 1.08). There were 11 SNPs with P<1X10-5 [(rsID, chromosome location, nearest gene, distance to nearest gene (base-pair), P value) rs6959888, 7q21.13, ZNF804B, 0, 1.63E-06; rs17725255, 20p11.23, CSRP2BP, 39396, 1.72E-06; rs10494067, 1p13.3, NTNG1, 0, 5.83E-06; rs2383378, 14q12, AKAP6, 0, 6.41E-06; rs410644, 5q14.1, SSBP2, 40462, 6.74E-06; rs4479806, 5p14.1, CDH9, 156926, 7.79E-06; rs957788, 13q33.3, FAM155A, 0, 8.11E-06; rs830998, 2q31.1, LRP2, 0, 8.68E-06; rs6782029, 3p25.3, VGLL4, 0, 9.04E-06; rs512089, 9p21.3, ELAVL2, 47984, 9.85E-06; rs3808986, 11q24.3, APLP2, 29217, 9.92E-6]. CNV analyses were performed on 1015 AN cases and 3532 controls. Overall frequencies of common or rare CNVs were similar between cases and controls. Specific rare and large (>500 kb, <1%) CNVs of interest included deletion of a large (~1.4Mbp) region of chr13q12 found in 2 AN samples and at a 10 fold lower frequency in a large sample (72,918) of subjects containing the genes SGCG, SACS, TNFRSF19, MIPEP, PCOTH, C1QTNF9B, SPATA13, MIR2276, and C1QTNF9, and an overlapping deletion and a duplication observed in 3 AN samples overlapping the CNTN6 and CNTN4 genes. Partially overlapping ~ 30 kb duplications were seen in 12 AN cases and in 1 control at the CDC5L gene on chromosome 6. Partially overlapping deletion of the 3' half of the PSTPIP1 gene was seen in 5 AN cases and no controls. Finally, a ~ 60 kb deletion of the PLEC1 gene was observed in 5 AN cases and in none of 3532 controls. Discussion: This is the first GWAS of AN. These preliminary results are consistent with absence of a major gene effect in AN. These results are consistent with genetic risk conveyed by multiple common alleles of small effect, as well as some uncommon CNVs of potentially larger effect. None of the implicated genes has a clear role in eating behavior. It must be emphasized that these results are preliminary and an additional ~ 400 AN cases will be analyzed as time and resources permit. These results require confirmation through study of independent populations of AN women.

  Study phs000679

• Treatment stratification and biomarker validation using patient-derived head and neck cancer organoids

  Background Organoids are three-dimensional structures that can be grown from patient-derived material including carcinomas. These in vitro models can be cryopreserved to generate “living” biobanks that reflect patient heterogeneity. Head and neck cancer (HNC) is a collective term used for tumors arising in the head and neck area, including squamous cell carcinomas (HNSCC) and adenocarcinoma of the salivary gland. Methods to culture patient-derived HNC organoids have previously been described. Methods Organoids were derived from resection or biopsy material of patients included between 2016 and 2022. Organoids were characterised with immunohistochemistry and whole exome sequencing (WES) and exposed to chemo-, radio- and targeted-therapies. CRISPR/Cas9-based gene editing was applied to validate proposed biomarkers. Results We have extended our previously published organoid biobank to a total of 110 organoid models, some of which were characterised by histology and WES. Organoids recapitulated both single nucleotide variants and copy number alterations as found in patient HNSCC samples. Organoid and patient response to radiotherapy (RT; primary (n=6) and adjuvant (n=15)) could be compared in 21 HNC cases. In the adjuvant RT group, organoids derived from patients that relapsed were more resistant to RT in vitro, showing potential for guiding treatment options in this subset of patients. Conclusion Taken together, these results indicate illustrate the potential of organoids as a diagnostic tool in personalised medicine for HNC and indicate the potential of this technology for biomarker discovery and validation within the context of relevant patient heterogeneity.

  Study EGAS00001007076

• Preservation of stemness in high-grade serous ovarian cancer organoids requires low Wnt environment

  High-grade serous ovarian cancer (HGSOC) likely originates from the fallopian tube (FT) epithelium, but advanced stages are mostly found outside the FT. We used ex-vivo cultures of HGSOC and knock-out of tumor suppressors in FT organoids to study changes in epithelial cells and niche requirements for normal and transformed FT cells. We found that transformed cells require BMP signaling and are growth arrested in Wnt rich medium.

  Study EGAS00001003821

• Whole-exome sequencing of ovarian clear cell carcinoma in clinical outliers

  Whole-exome sequencing dataset for the Australian Ovarian Cancer Study (AOCS) and The Jikei University School of Medicine (JIKEI) ovarian clear cell carcinoma (OCCC) clinical outliers project, representing 10 donors. Although OCCC are commonly resistant to platinum based chemotherapy, good clinical outcomes are observed in a subset of patients. Exome sequencing was performed in 10 patients who had either unusually long survival (N=5) or had a very short time to progression (N=5).

  Study EGAS00001004248

• BCR Signaling in human BM PC

  The functions of bone marrow plasma cells (BMPC) beyond antibody production are not fully elucidated and distinct subsets of BMPC suggest potential different functions. Phenotypic differences were identified for human BMPC depending on CD19 expression. Since CD19 is a co-stimulatory molecule of the B-cell-receptor (BCR), and IgA+ and IgM+ BMPC express the BCR on their surface, we here studied whether CD19 expression affects cellular responses, such as BCR signaling and the expression of checkpoint molecules. We analyzed 132 BM samples from individuals undergoing routine total hip arthroplasty. We found that both CD19+ and CD19- BMPC expressed BCR signaling molecules. Notably, the BCR-associated kinase spleen tyrosine kinase (SYK) including pSYK was higher expressed in CD19+BMPC compared to CD19- BMPC. BCR stimulation also resulted in increased kinase phosphorylation downstream of the BCR while expression of CD19 remained stable afterwards. Interestingly, the BCR response was restricted to IgA+ BMPC independently of CD19 expression. With regard to the expression of checkpoint molecules, CD19- BMPC expressed higher levels of co-inhibitory molecule programmed cell death protein-1 (PD-1) than CD19+ BMPC. IgA+ BMPC characteristically upregulated PD-1 upon BCR stimulation in contrast to other PC subsets and inhibition of the kinase SYK abrogated PD-1 upregulation. In contrast, expression of PD-1 ligand, B and T lymphocyte attenuator (BTLA) and CD28 did not change upon BCR activation of IgA+ BMPC. Here, we identify a distinct functiotype of IgA+ BMPC that is independent of the phenotypic heterogeneity of the subsets according to their CD19 expression. The data suggest that IgA+ BMPC underlie different regulatory principles and/or exert distinct regulatory functions.

  Study EGAS00001004948

• SCANDARE HNSCC DNA targeted panel sequencing

  SCANDARE (NCT03017573) is a multicentric biobanking study, enrolling adult patients with newly diagnosed head and neck squamous cell carcinoma (HNSCC), triple negative breast cancer (TNBC), ovarian and cervical cancer. Tumor tissue and blood samples are collected at several time points during patient's journey, including at diagnosis, post-neoadjuvant chemotherapy in case of neoadjuvant treatment, at surgery, at recurrence and at disease progression following treatment initiated at recurrence. Since its launch in 2017 at Institut Curie, SCANDARE has enabled the longitudinal collection and preservation of samples for in-depth analyses. Here, we describe molecular alterations in 232 FFPE samples at baseline from 83 HNSCC patients using DNA targeted panel sequencing, with FASTQ files deposited in the dataset.

  Dataset EGAD50000001654

• SCANDARE ovarian WES data

  SCANDARE (NCT03017573) is a multicentric biobanking study, enrolling adult patients with newly diagnosed head and neck squamous cell carcinoma (HNSCC), triple negative breast cancer (TNBC), ovarian and cervical cancer. Tumor tissue and blood samples are collected at several time points during patient's journey, including at diagnosis, post-neoadjuvant chemotherapy in case of neoadjuvant treatment, at surgery, at recurrence and at disease progression following treatment initiated at recurrence. Since its launch in 2017 at Institut Curie, SCANDARE has enabled the longitudinal collection and preservation of samples for in-depth analyses. Here, we describe molecular alterations in 91 frozen samples (n = 53 at baseline, n = 31 Post-NAC, n= 7 Recurrence, and n = 62 germline DNA) from 64 ovarian cancer patients using WES technology, with FASTQ files deposited in the dataset.

  Dataset EGAD50000001658

• SCANDARE TNBC transcriptomics data

  SCANDARE (NCT03017573) is a multicentric biobanking study, enrolling adult patients with newly diagnosed head and neck squamous cell carcinoma (HNSCC), triple negative breast cancer (TNBC), ovarian and cervical cancer. Tumor tissue and blood samples are collected at several time points during patient's journey, including at diagnosis, post-neoadjuvant chemotherapy in case of neoadjuvant treatment, at surgery, at recurrence and at disease progression following treatment initiated at recurrence. Since its launch in 2017 at Institut Curie, SCANDARE has enabled the longitudinal collection and preservation of samples for in-depth analyses. Here, we describe molecular alterations in 124 frozen samples (n=84 at baseline and n=40 paired at post-NAC surgery) from 91 TNBC patients using total RNAseq technology, with FASTQ files deposited in the dataset.

  Dataset EGAD50000001416

• Open_Targets_020_Epigenomes_of_Cell_Lines

  There is currently a drive to establish cell based assay systems of greater human biological and disease relevance through the use of well characterised transformed cell lines, primary cells and complex cellular models (e.g. co-culture, 3D models). However, although the field is gaining valuable experience in running more non-standard & complex cell assays for target validation and compound pharmacology studies, there is the lack of a systematic approach to determine if this expansion in cell assay models is reflected in increased human biological and disease relevance. The increasing wealth of publically available transcriptomic, and epigenome (ENCODE and Epigenome Roadmap) data represents an ideal reference mechanism for determining the relationship between cell types used for target & compound studies to primary human cells and tissues from both healthy volunteers & patients. The CTTV020 epigenomes of cell line project aims to generate epigenetic and transcriptomic profiles of cell lines and compare these with existing and newly generated reference data sets from human tissue and cell types. The aim is to identify assay systems which will provide greater confidence in translating target biology and compound pharmacology to patients. Multiple cell types commonly used within research have been grouped according to biology. Examples include erythroid, lung epithelial, hepatocyte cell types and immortalised models of monocyte / macrophage biology. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001003138

• Genomics of Brain Metastases

  Brain metastases are the most frequently occurring intracranial tumors in adults. Median survival after the diagnosis of a brain metastasis is in the order of a few months. Despite its large burden of disease and devastating clinical sequelae, we continue to have a limited understanding of the molecular mechanisms driving brain metastasis. We subjected 86 trios consisting of primary tumor, brain metastasis, and matched normal tissue to whole exome sequencing (WES). To analyze the data, we developed novel computational tools to perform an integrative analysis of somatic single nucleotide variants (SSNVs) and somatic copy-number alterations (SCNAs). This analysis allowed us to estimate the clonal architecture of the primary and metastatic samples of each patient, and to reconstruct a phylogenetic tree relating all of the subclones.

  Study phs000730

• Genomics of Glomerular Disorders

  The purpose of the "Genomics of Glomerular Disorders" study is to identify genetic contributions to primary glomerulopathies. This repository includes a total of N = 4,238 patients with a kidney biopsy diagnosis of a primary glomerular disorder across the following categories: focal segmental glomerulosclerosis (FSGS, N = 583), Henoch-Schönlein purpura nephritis (HSPN, N = 403), IgA nephropathy (IgAN, N = 1,555), membranous nephropathy (MN, N = 1,003), and minimal change disease (MCD, N = 694). The dataset includes a total of 2,290 patients recruited into the Cure Glomerulonephropathy (CureGN) study and another 1,948 patients from the Columbia University CKD Biobank (i.e., non-CureGN patients). The sample sizes by phenotype are counted based on enrollment diagnoses. The repository includes 3,958 WGS samples and 2,129 RNA-seq samples.

  Study phs002480

• Integrated Genomic Analysis of Chronic Lymphocytic Leukaemia

  Chronic lymphocytic leukaemia (CLL) is a frequent and heterogeneous disease whose genetic alterations determining the clinicobiological behaviour are not fully understood. Here, we describe a comprehensive evaluation of the genomic landscape of 452 CLLs and 54 monoclonal B-lymphocytosis (MBL), a precursor disorder. This study provides an integrated portrait of the genomic landscape of CLL, identifies new recurrent mutations acting as drivers of the disease, and suggests clinical interventions which may improve the management of patients with this neoplasia. The data here included was described in the ICGC-CLL manuscript published by Puente et al (Nature 2015). Note that complementary RNA-seq data generated within the IGCG-CLL can be found in EGAS00001000374.

  Study EGAS00001001306

• miRNA expression data from primary tumors, metastasis and matched normals.

  MicroRNAs (miRs) have been recognized as promising biomarkers. It is unknown to what extent tumor-derived miRs are differentially expressed between primary colorectal cancers (pCRCs) and metastatic lesions, and to what extent the expression profiles of tumor tissue differ from the surrounding normal tissue. Next-generation sequencing (NGS) of 220 fresh-frozen samples, including paired primary and metastatic tumor tissue and non-tumorous tissue from 38 patients, revealed expression of 2245 known unique mature miRs and 515 novel candidate miRs. Unsupervised clustering of miR expression profiles of pCRC tissue with paired metastases did not separate the two entities, whereas unsupervised clustering of miR expression profiles of pCRC with normal colorectal mucosa demonstrated complete separation of the tumor samples from their paired normal mucosa. Two hundred and twenty-two miRs differentiated both pCRC and metastases from normal tissue samples (false discovery rate (FDR) <0.05). The highest expressed tumor-specific miRs were miR-21 and miR-92a, both previously described to be involved in CRC with potential as circulating biomarker for early detection. Only eight miRs, 0.5% of the analysed miR transcriptome, were differentially expressed between pCRC and the corresponding metastases (FDR <0.1), consisting of five known miRs (miR-320b, miR-320d, miR-3117, miR-1246 and miR-663b) and three novel candidate miRs (chr 1-2552-5p, chr 8-20656-5p and chr 10-25333-3p). These results indicate that previously unrecognized candidate miRs expressed in advanced CRC were identified using NGS. In addition, miR expression profiles of pCRC and metastatic lesions are highly comparable and may be of similar predictive value for prognosis or response to treatment in patients with advanced CRC.

  Dataset EGAD00001001644

• NHLBI TOPMed: HyperGEN - Genetics of Left Ventricular (LV) Hypertrophy

  The Hypertension Genetic Epidemiology Network Study (HyperGEN) - Genetics of Left Ventricular (LV) Hypertrophy is a familial study aimed to understand genetic risk factors for LV hypertrophy by conducting genetic studies of continuous traits from echocardiography exams. The originating HyperGEN study aimed to understand genetic risk factors for hypertension. Data from detailed clinical exams as well as genotyping data for linkage studies, candidate gene studies and GWAS have been collected and is shared between HyperGEN and the ancillary HyperGEN - Genetics of LV Hypertrophy study.

  Study phs001293

• Effects of interferon-gamma treatment on human small intestinal organoids generated from healthy donors

  The intestine is vulnerable to interferon-gamma as intestinal epithelial stem cells undergo cell death when exposed to interferon-gamma. Here, we developed a novel human intestinal organoid-based 3D model system to study the effects of interferon-gamma-induced intestinal epithelial damage at the RNA level. We treated organoids with 10 ng/mL for either 6 or 18h. Knowledge generated with this dataset is relevant for a variaty of intestinal pathologies with an immune component, for instance graft-versus-host disease.

  Study EGAS50000000083

• National Institute of General Medical Sciences (NIGMS) Human Genetic Cell Repository Human Variation Panels including 100 African-Americans (HD100AA), 100 Caucasians (HD100CAU), 100 Han People of Los Angeles (HD100CHI) and 100 Mexican American Community of Los Angeles (HD100MEX)

  The Human Genetic Cell Repository is sponsored by the National Institute of General Medical Sciences (NIGMS) with the mission of supplying scientists with the materials for accelerating disease gene discovery and functional studies. The resources available include highly-characterized, contaminant-free cell cultures and high quality, well-characterized DNA samples derived from these cultures, both subjected to rigorous quality control. The Repository was established in 1972 at Coriell and contains more than 9,500 cell lines, primarily fibroblasts and transformed lymphoblasts. The Repository has a major emphasis on inherited diseases and chromosomally aberrant cell lines. In addition, it contains a large collection dedicated to understanding human variation that includes samples from populations around the world, the CEPH collection, the Polymorphism Discovery Resource, Human Variation and many apparently healthy controls. The Human Variation collection provides cell lines and DNA samples from a variety of populations. The panels of African-Americans (HD100AA) and Caucasians (100CAU) used for this study are comprised of samples present in the Repository that were originally collected over the years from apparently healthy people to be used as "controls", for example, unaffected family members of persons with identified mono-genetic diseases. The samples for the Han people of Los Angeles (HD100CHI) and the Mexican American Community of Los Angeles (HD100MEX), however, were collected relatively recently from volunteers, identified as member of these communities, specifically for use in these panels. The Coriell Genotyping and Microarray Center in conjunction with the NIGMS repository used the Affymetrix Genome-Wide Human SNP 6.0 platform to genotype 400 samples from the NIGMS human variation panels. The populations genotyped included Americans of African, Caucasian, Mexican, and Han Chinese ancestry. The Affymetrix SNP 6.0 array detects approximately 940,000 SNPs and provides copy number information for more than 900,000 additional locations across the genome.

  Study phs000211

• Orphan_Tumour_Study_NB

  The aim of this study is to investigate the transcriptional landscape of human cancer. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001003445

• Gtag&T single-cell genome and transcriptome data

  This submission contains single-cell genome and transcriptome data that is used for the following manuscript: https://doi.org/10.1101/2023.01.13.521174. All Illumina data deposited here is retrieved from HCC38(BL) cell lines and a melanoma PDX model as described in the paper.

  Study EGAS00001007043

• Population Architecture using Genomics and Epidemiology (PAGE): Causal Variants Across the Life Course (CALiCo): Atherosclerosis Risk in Communities (ARIC)

  CALiCo ARIC The Atherosclerosis Risk in Communities Study (ARIC), sponsored by the National Heart, Lung and Blood Institute (NHLBI), is a prospective epidemiologic study conducted in four U.S. communities. ARIC is designed to investigate the etiology and natural history of atherosclerosis, the etiology of clinical atherosclerotic diseases, and variation in cardiovascular risk factors, medical care and disease by race, gender, location, and date. ARIC includes a Cohort Component and a Community Surveillance Component. Cohort enrollment began in 1987. Each ARIC field center randomly selected and recruited a sample of approximately 4,000 individuals aged 45-64 from a defined population in their community. A total of 15,792 participants received an extensive examination, including medical, social, and demographic data. These participants were reexamined every three years with the first screen (baseline) occurring in 1987-89, the second in 1990-92, the third in 1993-95, and the fourth and last exam wastook place in 1996-98. Follow-up occurs yearly byA fifth cohort examination is underway (2011-2013). Yearly telephone tointerviews maintain contact with participants and to assess health status of the cohort. In the Community Surveillance Component, currently ongoing, these four communities are investigated to determine the community-wide occurrence of hospitalized myocardial infarction and coronary heart disease deaths in men and women aged 35-84 years. Hospitalized stroke is investigated in cohort participants only. The study conducts community surveillance of inpatient heart failure (ages 55 years and older) and cohort surveillance outpatient heart failure events beginning in 2005.

  Study phs000223

• Kids First: Genetics of Kidney and Urinary Tract Malformations

  Congenital defects of the kidney and urinary tract are a common cause of kidney failure in children and adults and elucidation of the genetics of these disorders will provide new opportunities for diagnosis, risk stratification and prevention of complications.

  Study phs002162

• GWAS data (Illumina 2.5 M SNPs) in Cuban cohorts of dengue disease

  We will have 274 individuals typed for the Illumina Human Omni 2.5 chip. The individuals are from two locations in Cuba (Havana and Guantanamo) and from four phenotype classes (asymptomatic, control dengue fever and dengue hemorrhagic fever).

  Study EGAS00001002276

• Anaplastic Thyroid Cancer somatic variants (MuTect)

  Sequence was aligned to the GRCH38 reference genome. Aligned sequence was analyzed with GATK/MuTect, to generate somatic variant calls across the SureSelect All Exon V5+UTR target region. Somatic variant calls are in VCF format. In total there are 166 tumour samples, 94 of which have a matched normal. Somatic variants for tumours without a matched normal, were called against a panel of normals. Details for the mutect call can be found in the vcf header.

  Dataset EGAD00001004129

• Suspected Lynch syndrome dataset

  This dataset comprises a genomic and a phenotypic excel sheet displaying 137 cases classified as suspected Lynch syndrome. Included are genotypic data such as tumour mutational burden, tumour mutational signatures and germline/somatic variant calls for each colorectal, endometrial or sebaceous skin tumour screened. Genomic data is derived from targeted multigene panel sequencing including ~300 hereditary cancer genes.

  Dataset EGAD50000000031

• Neuroblastoma Smart-Seq2 Single Nuclei Sequencing Data

  Heterogeneity of tumors, including the presence of resistant clones, represents a great challenge for high-risk neuroblastoma (NB). Currently, there are no treatments that address cancer heterogeneity. Classification of bulk tumors and corresponding predictions are poor and too general. Understanding heterogeneity will provide critical insight for the development of targeted therapeutic strategies. In this study, we collected 10 human neuroblastoma tumor samples and performed whole-transcriptome profiling at single-nucleus resolution using SMART-Seq2 technology. This approach enables comprehensive characterization of transcriptional diversity within individual tumors, allowing us to identify distinct cellular subpopulations.

  Study EGAS50000001103

• Sequencing data from a highly cost-effective cell-free DNA methylome test

  Plasma cell-free DNA (cfDNA), originating from multiple organs, holds significant potential for non-invasive diagnostics and prognostics. Current cfDNA methylation assays primarily focus on single clinical indications by targeting specific genomic loci. In contrast, comprehensive profiling of cfDNA methylome can enable simultaneous detection of multiple diseases by capturing organ-specific methylation signatures, thereby offering a holistic view of health, when disease etiology is unclear or when conventional biochemical diagnostics are unavailable. However, deep sequencing required for sensitive detection of methylation abnormalities remains prohibitively expensive, limiting widespread clinical use. To overcome this barrier, we developed MethylScan, a highly cost-effective approach for cfDNA methylome sequencing. We demonstrated its broad clinical utility in a cohort of 1,061 individuals across diverse applications, including multi-cancer detection in general population, liver cancer surveillance in high-risk individuals, liver disease classification, identification of organ abnormalities, and race prediction from cfDNA.

  Study EGAS00001008125

• Fixation effects on variant-calling in a clinical resequencing panel

  Formalin fixation is the standard method for preservation of tissue for diagnostic purposes, including pathological review and molecular assays. However, this method is known to cause artifacts that can affect the accuracy of molecular genetic tests. We assessed the applicability of alternative fixatives to determine whether these perform significantly better on next-generation sequencing assays, and whether adequate morphology is retained for primary diagnosis, in a prospective study using a clinical-grade laboratory-developed targeted resequencing assay. We examined and quantified several parameters relating to sequencing quality and variant-calling from tumor and normal colon epithelial tissues. We identify one alterative fixative, Sakura Universal Molecular Fixative that suppresses many formalin-related artifacts while retaining adequate morphology for pathological review.

  Study EGAS00001003507

• WGS analysis of Japanese liver cancer

  Liver cancer is prevalent worldwide, mainly associated with virus infection, and its underlying etiology and genomic structure are heterogeneous. Here we provide a whole-genome landscape of somatic alterations in 300 Japanese liver cancers. Our comprehensive analysis elucidated point mutations in non-coding regions, structural variants (SVs), and virus integrations, in addition to coding mutations, and demonstrated new mutational signatures related with liver carcinogenesis, novel recurrently mutated coding and non-coding regions such as lincRNA NEAT1/MALAT1, promoters, CTCF binding sites, and regulatory regions. SV analysis found a significant association with replication timing, and revealed that known cancer genes (CDKN2A, CCND1, APC, and TERT) and new cancer genes (ASH1L, NCOR1, MACROD2) were recurrently affected by SVs, leading to altered expression of nearby genes. These results emphasize the value of whole genome sequencing analysis to discover cancer driver mutations and to understand comprehensive molecular profiles of liver cancer, especially for SVs and non-coding mutations.

  Study JGAS000151

• A tumor-associated photoreceptor signature unifies distinct central nervous system malignancies

  Pineoblastoma is a clinically aggressive childhood brain tumor composed of distinct molecular subgroups with divergent driver genes, demographics, and clinical outcomes. To identify developmental origins and mechanisms governing disease pathogenesis, we derive single-cell transcriptomes from pineal parenchymal tumors, aligning malignant cells with our atlas of pineal gland development to retrace cellular origins. Integrative computational analyses maps pineoblastoma origins to transient cycling pinealocyte progenitors during development. Lineage-specific perturbation of suspected drivers in the early pineal gland yields preclinical models representative of consensus molecular subgroups. Multi-omic characterization of patient tumors and these models uncovers a tumor-associated photoreceptor signature common to pineoblastoma, retinoblastoma, and Group 3 medulloblastoma. Transcriptional activity of this signature within respective cellular origins establishes a developmental basis for molecular similarities between entities. Photoreceptor signature constituents are selective dependencies across these anatomically distinct central nervous system malignancies, motivating future studies evaluating developmentally encoded programs of malignancy as potential therapeutic liabilities.

  Study EGAS50000001457

• HuBMAP: A Spatially Resolved Molecular Atlas of Human Endothelium

  The human circulatory system plays a vital role in the proper functioning of every organ in the human body. Because vascular related diseases, such as atherosclerosis, do not occur homogeneously throughout the vascular tree, differences in the endothelium of various organs must exist. There is even evidence of heterogeneity of adjacent endothelial cells. We are studying normal endothelium throughout the body and across individuals of different ages to characterize these differences. The first step will be to procure normal tissue samples from a wide range of organs. From disaggregated samples of these tissues, we will perform single cell combinatorial indexing (sci-) to generate chromatin accessibility (sci-ATAC-seq) and transcriptome (sci-RNA-seq) data from millions of single cells across hundreds of samples.  Molecular heterogeneity might correlate with multiple facets of the anatomical distribution of endothelium, including vascular vs. lymphatic, arteries vs. veins, capillaries vs. larger vessels, differences between organs, organ zonation, cell-to-cell differences, etc. Based on heterogeneous markers defined from deep profiling of disaggregated cells, we will employ seqFISH to spatially relate the distinct endothelial subpopulations arising from the single nuclei data to histologic preparations. For example, this will allow us to identify subpopulations with particular markers as arterial, capillary, venous, or lymphatic. The end product will include multiparameter images in which the complete gene expression and chromatin accessibility profile can be interactively visualized for every cell.

  Study phs002267

• WGS of T-cell and NK-cell lymphoma for ICGC (NKTL-SG)

  Lymphomas are malignancies originating from the lymphatic system and there is a worldwide significant increase in incidences of this cancer. Lymphomas can be further classified into 2 categories namely Hodgkin’s (HL), and Non-Hodgkin’s lymphoma (NHL). The latter can be divided further into B, T and NK cell NHL. Peripheral T-cell lymphoma (PTCL) and Natural Killer/ T-cell lymphoma (NKTL) arise from mature T lymphocytes and NK cells. The more common subtypes include NKTL, PTCL not-otherwise-specified (PTCL-NOS), systemic anaplastic large cell lymphoma (ALCL), follicular PTCL (F-PTCL), angioimmunoblastic T-cell lymphoma (AITL) and enteropathy-associated T-cell lymphoma (EATL). Whole genome analyses on T-cell and NK-cell lymphoma samples from various countries to gain a better understanding of the pathogenesis and biology of these tumors. The comprehensive profiling and comparison among patients from various countries with different etiopathogenesis will hopefully facilitate the elucidation of key pathways and underlying molecular mechanisms driving these cancers, opening up novel therapeutic strategies in the future.

  Study EGAS00001002398

• CINECA synthetic data.Please note: This study contains synthetic data (with cohort “participants” / ”subjects” marked with FAKE) has no identifiable data and cannot be used to make any inference about cohort data or results.

  Please note: This study contains synthetic data (with cohort “participants” / ”subjects” marked with FAKE) has no identifiable data and cannot be used to make any inference about cohort data or results. The purpose of this dataset is to aid development of technical implementations for cohort data discovery, harmonization, access, and federated analysis. In support of FAIRness in data sharing, this dataset is made freely available under the Creative Commons Licence (CC-BY). Please ensure this preamble is included with this dataset and that the CINECA project (funding: EC H2020 grant 825775) is acknowledged. For any questions please contact isuru@ebi.ac.uk or cthomas@ebi.ac.uk

  Study EGAS00001002472

• Warm_Autopsy_Single_Cell_X10

  Study of cell lineage and embryogenesis using biopsy samples from sites across the whole body (post mortem). Sample donors are recruited sensitively through the Phoenix study and consent to samples being taken after their death for both the Phoenix study and this WTSI study.

  Study EGAS00001001698

• The Genomics of Pilocytic Astrocytoma Formation in Neurofibromatosis Type 1

  Neurofibromatosis type 1 (NF1) inherited cancer predisposition syndrome is one of the most common autosomal dominant tumor predisposition syndromes in which affected individuals develop brain tumors. These low-grade glial neoplasms (pilocytic astrocytomas) typically arise in children younger than 7 years of age and are hypothesized to result from a combination of germline and acquired somatic NF1 tumor suppressor gene mutations. In this study, whole genome sequence analysis was performed on three NF1-associated pilocytic astrocytoma tumors (NF1-PA) and matched normal blood samples to establish the genomic landscape of NF1-PA. These data support the existence of multiple distinct mechanisms (mutation, LOH, and methylation) underlying somatic NF1 inactivation in NF1-PA tumors.

  Study phs000563

• iNeuron_RNAseq

  Characterisation of a timecourse of differentiation of induced cortical excitatory neurons generated by overexpression of the Ngn2 transcription factor transgenically in BOB iPSCs. The aim is to understand the differentiation trajectory undergone in this process, and characterise the transcriptome in these cells for further disease modelling. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001004238

• Genomic profiling of Acute Lymphoblastic Leukemia in Ataxia Telangiectasia patients reveals tight link between ATM mutations and chromothripsis

  Recent developments in sequencing technologies led to the discovery of a novel form of genomic instability, termed chromothripsis. This catastrophic genomic event, involved in tumorigenesis, is characterized by tens to hundreds of simultaneously acquired locally clustered rearrangements on one chromosome. We hypothesized that leukemias developing in individuals with Ataxia Telangiectasia, who are born with two mutated copies of the ATM gene, an essential guardian of genome stability, would show a higher prevalence of chromothripsis due to the associated defect in DNA double-strand break repair. Using whole-genome sequencing, fluorescence in situ hybridization and RNA sequencing, we characterized the genomic landscape of Acute Lymphoblastic Leukemia (ALL) arising in patients with Ataxia Telangiectasia. We detected a high frequency of chromothriptic events in these tumors, specifically on acrocentric chromosomes, as compared to tumors from individuals with other types of DNA repair syndromes (27 cases total, 10 with Ataxia Telangiectasia). Our data suggest that the genomic landscape of Ataxia Telangiectasia ALL is clearly distinct from that of sporadic ALL. Mechanistically, short telomeres and compromised DNA damage response in cells of Ataxia Telangiectasia patients may be linked with frequent chromothripsis. Furthermore, we show that ATM loss is associated with increased chromothripsis prevalence in additional tumor entities.

  Study EGAS00001002270

• Single-cell level characterization of B cell depletion and repopulation following rituximab in systemic lupus erythematosus

  Rituximab, a CD20+ B cell depletion therapy, is frequently used in the treatment of systemic lupus erythematosus (SLE). However, variability in patient response highlights the need for a deeper understanding of the underlying immune cell dynamics of B cell depletion and repopulation. In this study, we conducted longitudinal single-cell profiling of nine SLE patients treated with rituximab from pretreatment to up to 15 months post-treatment. These were compared to eight healthy controls. We profiled PBMCs via 10X Genomics single-cell RNA, surface protein (CITE-seq), B cell receptor (BCR), and T cell receptor (TCR) sequencing and sequenced bulk BCR repertoires in parallel. For single cell sequencing, 10 pools were created with an equal number of cells from 4 samples each. Samples collected at different timepoints from the same patient were distributed across different pools to allow demultiplexing of individuals using genotypes captured from the scRNA-seq data. Libraries were pooled using a ratio of GEX:CITE:TCR:BCR=9:2:1:1 and were sequenced across two lanes of the NovaSeq 6000. For bulk BCR sequencing, individual samples were demultiplexed using primer barcodes and paired-end BCR amplicon reads were merged prior to submission; data are provided as unmapped single-end reads.

  Dataset EGAD00001015817

• Next generation sequencing on cardiac samples in Hungarian patients of dilated cardiomyopathy

  Heterozygous (HET) truncating mutations in the TTN gene (TTNtv) encoding the giant titin protein are the most common genetic cause of dilated cardiomyopathy (DCM). We investigated 127 clinically identified DCM human cardiac samples with targeted sequencing using the TruSight Cardio panel on an Illumina MiSeq system with a special focus on TTNtvs. This dataset belongs to the publication of Kellermayer, D et al. Truncated titin is integrated into the human dilated cardiomyopathic sarcomere

  Dataset EGAD50000000066

• Whole exome sequencing in patients with ALS and concomitant FTD lacking the C9orf72 repeat expansion

  Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are part of a clinical, pathological and genetic continuum. The purpose of the present study was to assess the mutation burden that is present in ALS and/or FTD known disease-causing genes in 54 patients (16 with available postmortem neuropathological diagnosis) with concurrent ALS and FTD (ALS/FTD) not-carrying the C9orf72 hexanucleotide repeat expansion, the most important genetic cause in both diseases.

  Dataset EGAD00001003409

• Single-nucleus transcriptomic profiling of aging Down Syndrome brains

  Down syndrome (DS) – trisomy of human chromosome 21 (HSA21) – is characterized by lifelong cognitive impairments and development of neuropathological hallmarks of Alzheimer’s disease (AD). The cellular and molecular modifications responsible for these effects are not understood. Here we performed single-nucleus RNA-sequencing (snRNA-seq) employing both short (Illumina) and long-read (Pacific Biosciences) sequencing technologies on a total of 29 DS and non-DS control prefrontal cortex samples. In DS, the ratio of inhibitory-to-excitatory neurons was significantly increased, which was not observed in previous reports examining sporadic AD. DS microglial transcriptomes displayed AD-related aging and activation signatures in advance of AD neuropathology, with increased microglial expression of C1q complement genes (associated with dendritic pruning) and the HSA21 transcription factor gene RUNX1. Long-read sequencing detected vast RNA isoform diversity within and amongst specific cell types including numerous novel sequences that differed between DS and normal brains. Notably, over 8,000 genes produced RNAs containing intra-exonic junctions (IEJs), including APP that had previously been associated with somatic gene recombination. These and related results illuminate large-scale cellular and transcriptomic alterations as novel features of the aging DS brain.

  Study EGAS00001005691

• National Eye Institute (NEI) Primary Open-Angle African American Glaucoma Genetics (POAAGG) Study

  The purpose of the POAAGG study is to investigate the genetic architecture of primary open-angle glaucoma (POAG) in African Americans. This population is up to eight times more likely to develop glaucoma than non-Hispanic whites, yet no large-scale genetics studies have specifically addressed this ethnic group. The POAAGG study aims to enroll 7765 patients, consisting of a discovery cohort of 5500 subjects (2000 cases and 3500 controls) and a validation cohort of 2265 subjects (1000 cases and 1265 controls). The study population consists of self-identified blacks (African Americans, African descent, or African Caribbean), 35 years or older, identified from the Philadelphia region. Subjects are recruited from the Scheie Eye Institute and its research sites in Philadelphia, PA, as well as from the Penn Medicine Biobank. Fellowship-trained glaucoma specialists classify each subject as a case, control, or glaucoma suspect based on specified criteria. As of 02/01/2017, a total of 8187 subjects have been recruited to the POAAGG study, including 2522 cases, 4545 controls, and 1120 suspects. A comprehensive genetic analysis of POAG, including a genome-wide association analysis, is currently underway. The GWAS was conducted on the Illumina Infinium Multi Ethnic Genotyping Array (MEGA), which contained custom content tailored to POAG and African Americans. A comprehensive genetic analysis of quantitative traits associated with POAG is also in progress. Over 90% of cases have full phenotypic information, including intraocular pressure, cup-to-disc ratio, central corneal thickness, retinal nerve fiber layer thickness, visual acuity, and visual fields.

  Study phs001312

• Novel compound heterozygous mutations in UHRF1 are associated with atypical immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome with distinctive genome-wide DNA hypomethylation

  Our study goal is to reveal underlying molecular pathogenesis of Immunodeficiency, Centromeric instability, and Facial anomalies (ICF) syndrome, which is characterized by hypomethylation of centromeric/pericentromeric repeats.

  Study JGAS000559