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• Genomic Analyses of Germline and Somatic Variation in High-Grade Serous Ovarian Cancer

  The goal of this study was to identify and characterize germline and somatic genetic variation in women with high grade serous ovarian cancers treated at a single cancer center and their associations with relapse-free and overall survival. We conducted paired tumor/normal targeted next-generation sequencing of 577 genes in pathways of DNA repair, response to DNA damage, cell-cycle regulation, programmed cell death, MAPK, and P13K/AKT/MTOR signaling in 114 tumors from 71 women. In addition, we investigated single copy number alterations (SCNAs) and loss of heterozygosity in a subset of 61 tumors. We validated our results with data from ovarian tumors in TCGA. Our results were similar to other studies of high-grade serous carcinomas. As an example, we found that approximately one third of the tumors harbored loss of function variants in homologous recombination genes and that >90% had TP53 somatic mutations. Through GISTIC analysis of the OncoScan data on tumor DNA from 61 cases, we identified several regions of high copy number alterations including including NOTCH3 and PIK3R2 that were significantly associated with an increase in cancer recurrence and a reduction in overall survival. We identified few changes in mutation profiles where we had multiple tissues, either from multiple surgeries or from the primary site to metastatic sites within the same surgery. However, we did not investigate copy number alterations in multiple tissues from the same individuals, and so it may be that copy number alterations are more important. Data available through dbGAP will be the BAM files and the phenotypic data on the tumor samples, the age, race, ethnicity of the participants and their outcomes, and the Oncoscan OSCHP files.

  Study phs003198

• National Cancer Institute Clinical and Laboratory Analysis of Familial Cancer

  The purpose of this study is to continue the analysis begun on 09C0079 which was focused on identification of the genetic mutation associated with a new gastric polyposis syndrome, Gastric Adenocarcinoma and Proximal Polyposis of the Stomach (GAPPS). GAPPS, first described in 2012, is an autosomal dominant gastric polyposis syndrome that confers a substantial risk for gastric adenocarcinoma. The GAPPS phenotype consists of a carpeting of greater than 100 fundic gland polyps (FGPs) in the oxyntic mucosa of the gastric body and fundus, with antral sparing with some FGPs displaying high-grade dysplasia. This is in contrast to sporadic FGPs that are benign, most often are not associated with high-grade dysplasia though low-grade dysplasia has been reported, and are fewer in number. Gastric FGPs have been found to be associated with Familial Adenomatous Polyposis (FAP) and attenuated FAP, which is an autosomal dominant condition associated with germ line mutations in APC which confers a phenotype consisting of multiple (>100) adenomatous polyps in the colon and rectum developing after the first decade of life. FGPs are reported to occur in 12-84% of patients with FAP, whereas sporadic FGPs are identified in ~5% of patients undergoing upper gastrointestinal endoscopy. Gastric adenocarcinoma arising from FGPs in individuals with FAP have been reported. Other manifestations of FAP and AFAP include polyps in the upper gastrointestinal tract, congenital hypertrophy of retinal pigment epithelium, osteomas and epidermoid cysts, supernumerary teeth, desmoid formation, and other malignancies such as thyroid, small bowel cancer, hepatoblastoma, and medulloblastoma. Thus far there are no reports in GAPPS of polyposis arising in the esophagus, gastric antrum, pylorus, small intestine, or colon.

  Study phs001935

• A Population Genomics Study Using a Disease-Targeted Cell model: Integration of

  The common genetic variants associated with complex traits typically lie in non-coding DNA and may alter gene regulation in a cell type-specific manner. Consequently, the choice of tissue or cell model in the dissection of disease associations is important. We carried out an expression quantitative trait loci (eQTL) study of primary human osteoblasts (HOb) derived from 95 unrelated donors of Swedish origin, each represented by two independently derived primary lines to provide biological replication. We combined our data with publicly available information from a genome-wide association study (GWAS) of bone mineral density (BMD). The top 2000 BMD-associated SNPs were tested for cis-association of gene expression in HObs and in lymphoblastoid cell lines (LCLs) using publicly available data and showed that HObs have a significantly greater enrichment (threefold) of converging cis-eQTLs as compared to LCLs. The top 10 BMD loci with SNPs showing strong cis-effects on gene expression in HObs were selected for further validation using a staged design in two cohorts of Caucasian male subjects. All 10 variants were tested in the Swedish MrOS Cohort (n = 3014), providing evidence for two novel BMD loci (SRR and MSH3). These variants were then tested in the Rotterdam Study (n = 2090), yielding converging evidence for BMD association at the 17p13.3 SRR locus. The cis-regulatory effect was further fine-mapped to the proximal promoter of the SRR gene (rs3744270). Our results suggest that primary cells relevant to disease phenotypes complement traditional approaches for prioritization and validation of GWAS hits for follow-up studies. Reprinted from Grundberg E, Kwan T, Ge B et al., Genome Res Nov 2009, with permission from Genome Research, Cold Spring Harbor Press, PMID:19654370.

  Study phs000225

• Rare Diseases Clinical Research Network (RDCRN) Vasculitis Clinical Research Consortium (VCRC) Longitudinal Protocol for Takayasu's Arteritis

  The development and validation of accurate biological markers and predictors of disease activity and outcome for Takayasu's arteritis, a form of idiopathic vasculitis, would have a major positive impact on the clinical care of patients with this rare disease, be an important advance in the design of clinical trials and feasibility of new drug development, and provide important insight into the pathogenesis of this condition. Current measures of disease activity, including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), while helpful in selected settings, are mostly considered highly flawed and markers whose poor correlation with disease flares makes them inadequate to help guide therapy. Similarly, ESR and CRP are clearly unhelpful as diagnostic tests for vasculitis. The current state of clinical investigation for vasculitis relies heavily upon determination of disease status solely by clinical presentation and investigator opinion. Thus, discovery and validation of more precise markers that quantifiably measure activity, predict disease course, and correlate with an important biological process, would be of great importance. Knowledge to be gained from this study could potentially be highly important. Discovery of effective biomarkers of vasculitis and assessment of long term disease course and complications by the collection of clinical and diagnostic imaging studies proposed could lead to better care and less toxic treatment regimens. Furthermore, insight into the pathophysiology of vasculitis could be gained and this might lead to better treatments and improved outcomes in terms of reduction of vascular and treatment related complications. Ideally, excellent biomarkers reflect a sophisticated understanding of the pathophysiology of a disease.

  Study phs000589

• Exome Sequencing for Diseases of the Immune System: X-linked Immunodeficiency with Magnesium Defect, EBV Infection, and Neoplasia (XMEN)

  The etiologies of primary immunodeficiencies often yield novel insights about the immune system. Although a genetic etiology has been suspected for patients with abnormally low CD4+ T cells in the absence of HIV infection or any known causes of lymphopenia, no genetic mutation has been described to date for any case of primary CD4 lymphopenia. In this study, we characterized a non-consanguineous family with two non-HIV infected boys exhibiting an inverted CD4 to CD8 T cell ratio and a history of recurrent chronic viral infections since birth. Consistent with a decreased thymic output of CD4+ T cells, the percentage of CD31+ cells in the CD4+ naive population of these patients was decreased. In addition, the activation of T cells was significantly impaired in the patient upon TCR stimulation. Given the mother's T cells show completely skewed X chromosome inactivation, we suspected that the nature of this disease is X-linked. We performed X-chromosome exon-capture targeted single-end Solexa sequencing on two brothers and the mother and found a 10 base pair deletion at an intron-exon junction of Magnesium Transporter 1 (MAGT1), a Mg2+ specific transporter. We confirmed that this deletion leads to altered splicing, frameshift, early termination of the mRNA, and deficient protein expression in the lymphocytes of the two patients. Moreover, knockdown of this transporter in T cells isolated from healthy donors can recapitulate the observed T cell activation defect while its ectopic expression in the patients' lymphocytes can restore T cell stimulation. Our discovery highlights the significance of this transporter to T cell function.

  Study phs000365

• 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

• Genetic Aberrations and Subclonal Structure Impact Chronic Lymphocytic Leukemia

  Large-scale whole-exome sequencing (WES) of primary tumor samples enables the unbiased discovery of recurrent putative driver events and patterns of clonal evolution. We report the identification of 44 recurrently mutated genes and 11 recurrent CNVs through the WES of 538 chronic lymphocytic leukemia (CLL) and matched germline DNAs. These include previously unrecognized cancer drivers (e.g., RPS15, IKZF3), and collectively identify nuclear export, MYC activity and MAPK signaling as central pathways affected by somatic mutation in CLL. A clonality analysis of this large dataset further enabled the reconstruction of temporal relationships between these driver events. Several drivers were associated with shorter progression-free survival (PFS) in 280 samples that were collected prior to uniform treatment with front line chemo-immunotherapy, with mature follow up of greater than 10 years. Direct comparison between matched pretreatment and relapse CLL from 59 samples demonstrated marked clonal evolution occurring in more than 95% of these patients. Distinct patterns of clonal evolution in relationship to specific gene alteration were observed, suggesting a hierarchy of fitness amongst mutations. Thus, large WES datasets of clinically informative samples enable the discovery of novel driver genes as well as the network of relationships between the drivers and their impact on disease relapse and clinical outcome.Additionally, we performed RNA-seq for 268 CLL samples (including 26 follow-up samples) and used them to identify expression subtypes of CLL. RRBS for 30 of these samples was also generated. In an integrative analysis of genetic, transcriptomic, and epigenetic data, incorporating known and newly identified subtypes of CLL, we built new models to improve patient prognostication.

  Study phs000922

• Center for Inherited Disease Research (CIDR)-National Institute on Aging (NIA) Whole Exome Analysis of Ehlers-Danlos Syndrome

  The Ehlers-Danlos syndromes (EDS) are a family of hereditary disorders of connective tissue characterized by joint hypermobility and skin involvement with soft, translucent, stretchy skin, and atrophic scarring. To date, over 12 different types of EDS are known, and the genes causing almost all of them have been found. However, the gene(s) underlying the most common of Ehlers-Danlos syndrome, known as the hypermobile type, remain elusive. The hypermobile type of Ehlers-Danlos syndrome is associated with multiple co-morbidities, including dysautonomia, chronic musculoskeletal pain, gastrointestinal dysmotility, mast cell activation and multiple neurologic complications. Affected persons often suffer from chronic fatigue and may be chronically disabled. While the precise frequency of the condition is not known, it may be as common as between 1/500 and 1/1000 persons. There is a significant overlap with the phenotype of fibromyalgia, and multiple persons diagnosed with fibromyalgia may well have the hypermobile type of Ehlers-Danlos syndrome. The phenotype of hypermobile EDS segregates as a single dominant trait with complete penetrance, variable expressivity, and a markedly evolving phenotype over time. Identification of the genetic cause of this hereditary disorder has the potential to inform rational therapy for this disabling condition. It is hoped that the insight into the pathogenesis of the hypermobile type of EDS will lead to a similar breakthrough in therapy for this disorder. Toward this end, whole exome sequencing (WES) of DNA from a total of 167 patients will be performed at the Center for Inherited Disease Research (CIDR) to identify genes underlying the hypermobile type of Ehlers-Danlos syndrome and those with EDS of an uncharacterized type.

  Study phs001779

• Newborn Screening Translational Research Network (NBSTRN): Newborn Sequencing in Genomic Medicine and Public Health (NSIGHT2)

  Large-scale studies of whole genome sequencing (WGS) in neonates have largely been neglected. Thus, the clinical and social implications of this absence are largely unknown. The proposed study aims to increase scientific knowledge for acutely ill neonates. This population may stand to benefit largely from WGS given the severity of illness. The proposed clinical study is a prospective, randomized, partially-blinded study that has both quantitative and qualitative assessments of the risks and benefits of the use of STATseq, a 2-day genome test, in acutely ill neonates at Children's Mercy Hospital. Study participants include neonates, their parents, and clinicians caring for them. The overall aims will provide a nuanced understanding of the role of rapid diagnostic WGS for acutely ill neonates, including relative diagnostic sensitivity and change in management both for broad NICU populations and subpopulations, accuracy, reproducibility, and relative value of proband WGS and familial triads. The technological aims include improving diagnostic sensitivity without sacrificing the rapid turnaround time. The clinical aims include looking at increased diagnostic yield, shorter time to diagnosis and clinician perception of management changes that result from implementation of STAT-seq. Finally, the study will investigate the perceived value of STAT-seq in parents and clinicians using structural equation modeling. The studies also are designed for long-term continuation of assessment of the enrollees (beyond the current funding period) and in additional sample types (via a biorepository). Long-term continuation studies will test effects on long-term morbidity, mortality, quality of life and cost of care. We hope that the study results will be sufficient to provide an evidence base for physician adoption and provider reimbursement of WGS in Level 3 and 4 NICUs.

  Study phs002094

• Chromatin Landscape of BET Inhibitor-Treated CD8+ T-cells from Chronic Lymphocytic Leukemia Patients

  The pan-BET (bromodomain and extra-terminal) inhibitor, OPN-51107 (OPN5) was found to alleviate features of T-cell exhaustion in models of chronic lymphocytic leukemia (CLL). To evaluate if OPN5 treatment could relieve fixed chromatin states associated with terminal T-cell dysfunction, ATAC-sequencing was performed on CLL patient T-cells. Peripheral blood mononuclear cells (PBMCs) from 4 treatment-naïve CLL patients were treated ex vivo with 0.5 μM OPN5 or equivalent vehicle (DMSO) in the presence of T-cell activating stimuli (10 μg/mL anti-CD3 and 5 μg/mL anti-CD28) for 16 hours. Live CD8+ T-cells were then isolated via fluorescence-activated cell sorting, and approximately 100,000 viable CD8+ T-cells were subjected to ATAC-sequencing. Libraries were prepared using the Active Motif ATAC-seq kit and underwent paired-end sequencing (2 x 50 bp, 100 cycles) on an Illumina NovaSeq 6000 SP sequencer. Analysis of this data revealed that OPN5 treatment induces a unique chromatin landscape in CLL patient T-cells that is less like that of terminally exhausted T-cells and more like that of effector and memory T-cells. In particular, OPN5 treatment reduced chromatin accessibility at promoter regions of terminal exhaustion-associated genes (e.g., CD101, CCR5, LAG3, BATF3) and increased chromatin accessibility at promoter regions of genes associated with progenitor T-cell function (e.g., TCF7, IL2, CXCR5, IFNG). Individual raw sequencing (fastq) files and processed bigwig files (aligned to the hg38 human reference genome), as well as bigwig files for grouped OPN5- and vehicle-treated samples (aggregate of all 4 patient samples per treatment group) are available via authorized access request through dbGaP.

  Study phs003613