19114 results for "Buy fc coins Buyfc26coins.com is EA Sports official for FC 26 coins They are the best FC seller..nEoY"

in 17.76 milliseconds.

• DNA methylomes of monozygotic twins clinically discordant for multiple sclerosis

  Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Although genetic susceptibility is important, a modest concordance rate for MS in monozygotic (MZ) twins suggests that interaction with other risk factors is required to develop clinical symptoms. In this study, we examined whether DNA methylation differences contribute to the discordant clinical manifestation of MS in MZ twins, and studied the impact of MS treatments on the DNA methylome. Genome-wide DNA methylation profiles of peripheral blood mononuclear cells (PBMCs) of 45 MZ twins clinically discordant for MS were generated using the Illumina HumanMethylationEPIC array. Repetitive element methylation and selected differentially methylated positions (DMPs) were validated using targeted deep bisulfite sequencing (TDBS). In addition, we performed whole genome bisulfite sequencing (WGBS) to profile CD4+ memory T-cells of a subset of four MS discordant MZ twins. Our results show that interferon treatment causes robust DNA methylation changes and several epigenetic biomarkers for interferon treatment response were identified. However, overall the PBMC-based methylomes of the MS discordant MZ twins were highly similar, since large systematic methylation differences (>5%) were absent in the data. This suggests that previously reported large methylation changes are probably caused by genetic rather than epigenetic differences. In addition, our data does not support the hypothesis that the observed maternal parent-of-origin effect in MS is due to genomic imprinting errors, and no evidence was found that copy number variations explain the discordant phenotype in these MZ twins. Although not genome-wide significant, a couple of DMPs associated with the MS phenotype were identified and successfully technically replicated using TDBS, including a differentially methylated region (DMR) in the promoter of the transmembrane protein encoding gene TMEM232. Another MS-associated DMP, located in an enhancer in the gene body of the transcription factor ZBTB16, was also associated with medium-term glucocorticoid treatment history. WGBS analysis confirmed this DMP as a promising epigenetic biomarker for glucocorticoid treatment. In conclusion, this epigenome-wide association study (EWAS) in genetically identical twins identified a DMR in the TMEM232 promoter as a candidate loci associated with the clinical manifestation of MS. In addition, epigenetic biomarkers for MS treatments were identified, revealing that not only short-term, but also medium-term treatment effects are detectable in immune cells, which should be taken into account in future EWAS designs.

  Study EGAS00001003147

• Germline elongator mutations in sonic hedgehog medulloblastoma

  Cancer genomics has illuminated a wide spectrum of genes and core molecular processes contributing to human malignancy. Still, the genetic and molecular basis of many cancers remains only partially explained. Genetic predisposition accounts for 5-10% of cancer diagnoses and genetic events cooperating with known somatic driver events are poorly understood. Analyzing established cancer predisposition genes in medulloblastoma (MB), a malignant childhood brain tumor, we recently identified pathogenic germline variants that account for 5% of all MB patients. Here, by extending our previous analysis to include all protein-coding genes, we discovered and replicated rare germline loss-of-function (LoF) variants across Elongator Complex Protein 1 (ELP1) on 9q31.3 in 15% of pediatric MBSHH cases, thus implicating ELP1 as the most common MB predisposition gene and increasing genetic predisposition to 40% for pediatric MBSHH. Inheritance was verified based on parent-offspring and pedigree analysis, which identified two families with a history of pediatric MB. ELP1-associated MBs were restricted to the molecular SHHa subtype and were characterized by universal biallelic inactivation of ELP1 due to somatic loss of chromosome 9q. The majority of ELP1-associated MBs exhibited co-occurring somatic PTCH1 (9q22.32) alterations, suggesting that ELP1-deficiency predisposes to tumor development in combination with constitutive activation of SHH signaling. ELP1 is an essential subunit of the evolutionary conserved Elongator complex, whose primary function is to enable efficient translational elongation through tRNAs modifications at the wobble (U34) position. Biochemical, transcriptional, and proteomic analyses revealed that ELP1-associated MBSHH are characterized by a destabilized core Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response (UPR), consistent with deregulation of protein homeostasis due to Elongator-deficiency in model systems. Our findings suggest that genetic predisposition to proteome instability is a previously underappreciated determinant in the pathogenesis of pediatric brain cancer. These results provide strong rationale for further investigating the role of protein homeostasis in other pediatric and adult cancer types and potential opportunities for novel therapeutic interference.

  Study EGAS00001004126

• The Lung Genomics Research Consortium (LGRC)

  Chronic lung diseases represent a broad spectrum of chronic fibrosing/inflammatory lung conditions that are for the most part poorly responsive to treatment and often fatal. COPD/emphysema is the fourth leading cause of death in the United States and the incidence and rate of death from pulmonary fibrosis is increasing each year. Although progress has been made in interpretation of the clinical, radiological, and pathological features of chronic lung disorders, and progress in determining the pathobiology continues, the causes, biologic mechanisms, and therapeutic options remain obscure. Moreover, predicting individuals or populations at risk for developing any of these complex diseases, at present, is not possible. To address this challenge, we plan to create a genetic, molecular, and quantitative clinical phenotyping data warehouse with bioinformatic tools that will empower investigators to make fundamental discoveries in disease pathogenesis, refine diagnostic criteria, and lead to real gains in personalized medicine. The composite genetic, genomic, and epigenetic signature combined with quantitative clinical phenotypes has the potential to characterize the dynamic biological state of a complex disease and complement existing diagnostic approaches that are reliant on traditional clinical measures of disease. In the proposed project, we plan to extend the scope and impact of the NHLBI Lung Tissue Research Consortium (LTRC) biorepository by creating the Lung Genomics Research Consortium (LGRC), a comprehensive genetic, molecular, and quantitative clinical phenotyping warehouse. Our overall hypothesis is that a genetic, molecular, and quantitative clinical phenotyping warehouse combined with a rich clinical database will enable the lung research community to make fundamental discoveries in disease pathogenesis, refine diagnostic criteria, and lead to real gains in personalized medicine. We plan to pursue this hypothesis through the following aims. Specific Aim 1: Establish a genetic, genomic, and epigenetic molecular library to complement the existing clinical database in the LTRC. Specific Aim 2: Develop a quantitative clinical phenotyping platform using existing LTRC data, as well as an enhanced data set including novel quantitative CT and histology imaging analyses. Specific Aim 3: Establish a publicly-accessible database that would integrate the genetic, molecular, and quantitative phenotyping data with the existing clinical data in the LTRC and provide query and data exploration tools that are easily accessible to the lung research community. These discoveries will enable clinicians to Identify individuals at risk of developing chronic lung diseases; Diagnose these conditions earlier; Identify novel mechanisms that cause these diseases; Reclassify disease entities into categories more representative of molecular and cellular pathogenic mechanisms regardless of traditional disease categories; develop personalized approaches to treatment.

  Study phs000624

• Precision Medicine for Dilated Cardiomyopathy in European and African Ancestry

  The DCM Precision Medicine Study is a multi-site consortium-based cross-sectional study of families with an embedded open-label randomized controlled trial. The aims of the study are to test the hypothesis that dilated cardiomyopathy (DCM) has a substantial genetic basis and to evaluate the effectiveness of a family communication intervention in improving the uptake of preventive screening and surveillance in at-risk first-degree relatives. The Study goal was to recruit 1,300 individuals (600 non-Hispanic African ancestry, 600 non-Hispanic European ancestry, and 100 Hispanic; 50% female) meeting rigorous diagnostic criteria for idiopathic DCM (probands) and 2,600 of their relatives. The probands were inpatients or outpatients identified by heart failure and cardiac transplant cardiovascular physicians and clinical research personnel in heart failure/heart transplant programs at sites in the DCM Consortium. The DCM phenotype was selected for this study because of its prevalence and its prior inclusion in the development of virtually all pharmacotherapy for non-ischemic heart failure from reduced ejection fraction. Study procedures included obtaining family history, cardiac history, medical record review, surveys, and blood sample collection. Exome data from 1219 idiopathic DCM probands and 127 idiopathic DCM relatives are included in dbGaP.

  Study phs002641

• Dynamics of circulating tumor DNA in acute myeloid leukemia (AML) patients who undergo allogeneic transplantation

  Allogeneic hematopoietic cell transplantation (allo-HCT) is the only curative option for many patients with acute myeloid leukemia (AML). With the increasing use of non-myeloablative conditioning regimens, it is widely assumed that the cytotoxic conditioning itself does not eradicate all leukemia cells. Instead, the donor-derived immune cells are believed to eliminate residual leukemia cells over time. This so-called graft-versus-leukemia (GvL) is postulated to be the primary mechanism by which allo-HCT achieves sustained remissions in patients with AML. However, the precise quantification of GvL effects and its contribution to leukemia eradication has not yet been demonstrated by sequential, highly sensitive measurements of residual disease at various time points following allo-HCT. In the current study, we employed a novel, highly sensitive and specific plasma-based assay to track mutations in the leukemia cells of 14 patients before and after allo-HCT. If the primary therapeutic benefit of allo-HCT is truly mediated through a GvL effect, we hypothesized that leukemia cells would persist following cytotoxic conditioning and would often be reduced after post-transplant immunosuppression was discontinued. In the majority of patients (11 of 14, 79%), the conditioning used for allo-HCT did not eradicate the leukemia cells. In seven of these 11 patients, the leukemia cells persisted until immunosuppression was discontinued, at which time the persistent leukemia cells were reduced or eradicated. These results demonstrate the feasibility of using circulating tumor DNA (ctDNA) as a dynamic marker of GvL as well as minimal residual disease for patients with AML undergoing alloHCT, and have substantial implications for their management.

  Study EGAS00001007969

• Genetic Study of Present-Day Populations of Northern Kenya

  Human populations in Africa are the most genetically diverse in the world, having a rich history, and yet are severely understudied. The purpose of this study is to understand the population history of the Turkana. This study aims to measure the extent of genetic variation using whole genome and whole exome sequencing in this population, with the goal to better understand the broader evolutionary history of these populations and to add to the current knowledge of population genetics in Africa.

  Study phs002219

• Genetic Study of Northern Kenya Pastoral Populations

  Human populations in Africa are the most genetically diverse in the world, having a rich history, and yet are severely understudied. The purpose of this study is to understand the population history of four ethnolinguistic groups in northern Kenya - the Turkana, Samburu, Rendille, and Borana. This study aims to measure the extent of variation among several genetic systems in these populations, with the goal to better understand the broader population history in northern Kenya and to add to the current knowledge of population genetics in Africa.

  Study phs002654

• Tam-seq of germline samples for HGSOC copy-number signatures study

  This dataset contains targeted amplicon sequencing of Germline DNA extracted from 56 blood samples. They were sequenced on Illumina HiSeq 2500 and aligned to human genome assembly GRCh37 (hg19)to produce 127 bam files (2-3 technical replicates per sample).

  Dataset EGAD00001004172

• Genomics to select patients with metastatic breast cancer for targeted therapy (microarray_cytoscan)

  Cancer progression is driven in part by genomic alterations located in oncogenes or tumor suppressor genes. The genomic characterization of cancers has shown a large interpatient heterogeneity regarding the driver alterations, leading to the concept that generating a genomic profiling by multigene sequencing in patients with cancer could allow selecting effective targeted therapies. While this concept has been broadly implemented in daily practice, there is no evidence that such approach improves patient outcome, and how to optimally select the therapy to administer. A genomic profiling using next generation sequencing and copy number analyses was performed 1462 patients with Her2-non overexpressing metastatic breast cancer included in SAFIR02 Breast trial. 238 of these patients were randomized in two trials between a targeted therapy matched to genomic alteration and a maintenance chemotherapy. The trial shows that targeted therapies matched to genomics improves progression free survival (PFS) when genomic alterations are classified level I/II according to ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) (adjusted HR: 0.41, 90% CI: 0.27-0.61, p<0.001), but not when alterations are classified beyond level II (unadjusted HR: 1.15, 95% CI: 0.76-1.75). This trial provides evidence that the treatment decision led by genomics should be driven by a framework of target actionability in patients with mBC.

  Study EGAS00001005584

• Genomics to select patients with metastatic breast cancer for targeted therapy (microarray_oncoscan)

  Cancer progression is driven in part by genomic alterations located in oncogenes or tumor suppressor genes. The genomic characterization of cancers has shown a large interpatient heterogeneity regarding the driver alterations, leading to the concept that generating a genomic profiling by multigene sequencing in patients with cancer could allow selecting effective targeted therapies. While this concept has been broadly implemented in daily practice, there is no evidence that such approach improves patient outcome, and how to optimally select the therapy to administer. A genomic profiling using next generation sequencing and copy number analyses was performed 1462 patients with Her2-non overexpressing metastatic breast cancer included in SAFIR02 Breast trial. 238 of these patients were randomized in two trials between a targeted therapy matched to genomic alteration and a maintenance chemotherapy. The trial shows that targeted therapies matched to genomics improves progression free survival (PFS) when genomic alterations are classified level I/II according to ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) (adjusted HR: 0.41, 90% CI: 0.27-0.61, p<0.001), but not when alterations are classified beyond level II (unadjusted HR: 1.15, 95% CI: 0.76-1.75). This trial provides evidence that the treatment decision led by genomics should be driven by a framework of target actionability in patients with mBC.

  Study EGAS00001005586