11001 results for "fc 26 coins u7buy Visit Buyfc26coins.com Megkaptam az FC 26 érméket a garantált idő előtt. Mindig bonuszként!.HNTf"

in 19.42 milliseconds.

• 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 (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001003137

• 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 (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001003139

• Healthy_ageing_thymus

  Single cell RNA sequencing of immune and non-immune cells from healthy ageing thymus Thymus is a primary lymphoid organ that creates an environment for the T lymphocyte precursors differentiation into the naive T cells, which involves TCR gene rearrangement, negative and positive selection. Despite thymus critical function for the recognition of the pathogens it starts to atrophy very early in life. Thymic Epithelial Space (TES), where thymocyte education occurs, starts to decline rapidly just after birth, while with the onset of puberty thymus is also progressively replaced with adipose tissue. This leads to a reduced naive T cell output,which decreases an organism's ability to recognize pathogens. In our lab, we have already collected and characterized cell type composition and gene regulatory networks of the fetal tand adult human thymus (Park et al, Science 2020). In the current project we plan to expand the number of paediatric and adult samples in the study with the aim to understand how the process of thymic involution happens. We will use single-cell transcriptomics to zoom on changes that occur in immune and non-immune cell types in different phases of thymic involution with the hope to understand which gene expression changes are causal for the thymic involution process and how naïve T cell production can be increased in elderly. 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 EGAS00001004311

• Colorectal cancer study

  Matrix metalloproteinase-11 (MMP11) is an enzyme with proteolytic activity against matrix and non-matrix proteins. Although most MMPs are secreted as inactive proenzymes and they are later activated extracellularly, MMP11 is activated intracellularly by furin within the constitutive secretory pathway. It is a key factor in physiological tissue remodeling and its alteration may play an important role in the progression of epithelial malignancies and other diseases. TCGA colon and colorectal adenocarcinoma data showed that upregulation of MMP11 expression correlates with tumorigenesis and malignancy. Here, we provide evidence that a germline variant in the MMP11 gene (NM_005940: c.232C>T; p.(Pro78Ser)), identified by whole exome sequencing, can increase the tumorigenic properties of colorectal cancer (CRC) cells. P78S is located in the prodomain region, which is responsible for blocking MMP11’s protease activity. This variant was detected in the proband and all the cancer-affected family members analyzed, while it was not detected in healthy relatives. In silico analyses predict that P78S could have an impact on the activation of the enzyme. Furthermore, our in vitro analyses show that the expression of P78S in HCT116 cells increases tumor cell invasion and proliferation. In summary, our results show that this variant could modify the structure of the MMP11 prodomain, producing a premature or uncontrolled activation of the enzyme that may contribute to an early CRC onset in these patients. The study of this gene in other CRC cases will provide further information about its role in CRC development, which might improve patient treatment in the future.

  Study EGAS00001006489

• 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

• Efficacy of nivolumab in pediatric cancers with high mutation burden and mismatch-repair deficiency

  Purpose: Checkpoint-inhibitors have limited efficacy for children with unselected solid and brain tumors. We report the first prospective pediatric trial (NCT02992964) using nivolumab exclusively for refractory non-hematological cancers harboring tumor mutation burden (TMB) ≥5 mutations/megabase (mut/Mb) and/or mismatch-repair deficiency (MMRD). Patients and methods: Twenty patients were screened, and ten ultimately included in the response cohort of whom nine had TMB >10mut/Mb (three initially eligible based on MMRD) and one patient had TMB between 5-10 mut/Mb. Results: Delayed immune responses contributed to best overall response of 50%, improving on initial objective responses (20%) and leading to 2-year overall survival (OS) of 50% (95% CI; 27, 93). Four children, including three with refractory malignant gliomas are in complete remission at a median follow-up of 37-months (range: 32.4-60), culminating in 2-year OS of 43% (95% CI; 18.2, 100). Biomarker analyses confirmed benefit in children with germline MMRD, microsatellite instability, higher activated and lower regulatory circulating T-cells. Stochastic mutation accumulation driven by underlying germline MMRD impacted the tumor microenvironment, contributing to delayed responses. No benefit was observed in the single patient with a MMR-proficient tumour and TMB 7.4 mut/Mb. Conclusions: Nivolumab resulted in durable responses and prolonged survival for the first time in a pediatric trial of refractory hypermutated cancers including malignant gliomas. Novel biomarkers identified here need to be translated rapidly to clinical care to identify children who can benefit from checkpoint-inhibitors, including for upfront management of their cancers.

  Study EGAS00001007393

• Clinical and genetic factors associated with tumor response to neoadjuvant (chemo)radiotherapy, survival and recurrence risk in rectal cancer

  Rectal cancer poses challenges in preoperative treatment response, with up to 30% achieving a complete response (CR). Personalized treatment relies on accurate identification of responders at diagnosis. This study aimed to unravel CR determinants, overall survival (OS), and time to recurrence (TTR) using clinical and targeted sequencing data. Analyzing 402 patients undergoing preoperative treatment, tumor stage, size, and treatment emerged as robust response predictors. CR rates were higher in smaller, early-stage, and intensively treated tumors. Targeted sequencing analyzed 216 cases, while 120 patients provided hotspot mutation data. KRAS mutation dramatically reduced CR odds by over 50% (odds ratio [OR]=0.3 in the targeted sequencing and OR=0.4 hotspot cohorts, respectively). In contrast, SMAD4 and SYNE1 mutations were associated with higher CR rates (OR=6.0 and 6.8, respectively). Favorable OS was linked to younger age, CR, and low baseline carcinoembryonic antigen levels. Notably, CR and an APC mutation increased TTR, while a BRAF mutation negatively affected TTR. Beyond tumor burden, SMAD4 and SYNE1 mutations significantly influenced CR. KRAS mutations independently correlated with radiotherapy resistance, and BRAF mutations heightened recurrence risk. Intriguingly, nonresponding tumors with initially small sizes carried a higher risk of recurrence. These findings offer insights into rectal cancer treatment response, guiding personalized therapeutic strategies. By uncovering factors impacting CR, OS, and TTR, this study underscores the importance of tailored approaches for rectal cancer patients. These findings, based on extensive analysis and mutation data, pave the way for personalized interventions, optimizing outcomes in the challenges of rectal cancer preoperative treatment.

  Study EGAS00001007501

• Peripheral blood DNA methylome in adalimumab-treated patients with rheumatoid arthritis

  Background and aims Rheumatoid arthritis (RA) patients are currently treated with biological agents mostly aimed at cytokine blockade such as anti-TNFα therapy. Currently, there are no biomarkers to predict therapy response to these agents. Here, we aimed to predict response to adalimumab (ADA) treatment in RA patients using DNA methylation in peripheral blood Methods DNA methylation profiling on whole peripheral blood from 92 RA patients before the start of adalimumab (ADA) was determined using Illumina HumanMethylationEPIC BeadChip Array. After 6 months, treatment response was assessed according to the Alliance of Associations for Rheumatology (EULAR) criteria for disease response. Patients were classified as responders (DAS28<3.2 or decrease of 1.2 points) or as non-responders (DAS28>5.1 or decrease of less than 0.6 points). Machine learning models were built with gradient boosting and stability selection models to predict response prior to ADA treatment with predictor DNA methylation markers. Results We demonstrated a 27-feature panel of DNA methylation markers or CpG classifiers that predict response in RA patients treated with ADA. Forty-nine patients were assigned as responder and 43 patients assigned as non-responders. We differentiate responders from non-responders with a high sensitivity (AUC 0.76). The predictor CpGs annotated to genes involved in immunological- and pathophysiological pathways related to RA such as T-cell signaling, B-cell pathology and angiogenesis. Conclusion Our findings indicate that DNA methylation signatures discriminate responders and non-responders to ADA treatment and can serve as a tool for therapy prediction.

  Study EGAS00001007578

• Field Studies of Human Immunity to Amebiasis in Bangladesh (NIH Birth Cohort) and Exploration of the Biologic Basis for Underperformance of Oral Polio and Rotavirus Vaccines in Bangladesh (PROVIDE)

  NIH birth cohort study Amebiasis is a common cause of diarrhea and is associated with malnutrition in grade-school aged children in an urban slum of Dhaka, Bangladesh. Field Studies of Human Immunity to Amebiasis in Bangladesh was designed to determine the contribution of amebiasis to illness in the first 2 years of life when most deaths due to diarrhea occur, and understand the immunologic and genetic factors that protect children from amebiasis. The hypothesis underlying the study is that susceptibility to amebiasis is determined by host innate and acquired immune responses that vary between individuals in part due to: human genetic polymorphisms; environmental influences including malnutrition and concurrent geohelminth infection; and virulence differences among Entamoeba histolytica genotypes. Specific aims proposed in the design of the study were to: a) Measure the incidence of amebiasis and correlate it with human and parasite genetic polymorphisms, immune responses, and environmental factors such as geohelminth infection and malnutrition; b) Test the hypothesis that protective immunity is mediated both by innate immune responses initiated via TLR stimulation as well as by mucosal IgA against the Gal/GalNAc lectin and systemic IFN-γ; c) Test for the association of common genetic polymorphisms in host innate and acquired immune genes with incidence of amebiasis. 629 newborn babies were enrolled and followed regularly through bi-weekly surveillance for diarrheal episodes, anthropometry at 3-month interval until 60 months of age. The infants that were consented for GWAS analysis were genotyped in 3 separate batches at different times, on 3 different arrays. Quality control was performed on the 3 separate data sets and then jointly after merging. Genetic data available on 447 infants together with their phenotype data is made available in this submission PROVIDE (Performance of Rotavirus and Oral Polio Vaccines in Developing Countries) Study Oral polio and rotavirus vaccines are significantly less effective in children living in the developing world. Environmental enteropathy, which is associated with intestinal inflammation, decreased absorption and increased permeability, may contribute substantially to oral vaccine failure in developing country settings. The primary objective of the study was to determine the association of environmental enteropathy with the efficacy of oral polio and rotavirus vaccines in children in Bangladesh. Secondary and exploratory objectives were designed to address other possible causes of oral vaccine underperformance including malnutrition, interference with maternal or breastmilk antibodies, changes in gut microbiota, and genetic susceptibility. The PROVIDE study was structured as a 2x2 clinical trial with a prospective birth cohort enrollment of 700 infants and their mothers in the urban slum of Mirpur, Dhaka, Bangladesh. All children received the full series of Bangladesh's Expanded Program on Immunization vaccines, including oral polio vaccine (OPV) and followed for their first 2 years of life. Half the children were randomized to receive an inactivated polio vaccine (IPV) for their 4th dose at 39 weeks instead of the standard OPV dose. In the other trial, half the infants received the 2-dose rotavirus vaccine (Rotarix) with delayed dosing at 10 and 17 weeks of age. A detailed description of the study design and procedures can be obtained from PROVIDE methods publication: Kirkpatrick B.D., Colgate R.E., Mychaleckyj J.C., Haque R., Dorothy D.M., Carmolli M.P., et al. (2015) Am J Trop Med Hyg 92, 744-751 The Poliovirus trial and results are described in Mychaleckyj et al, Vaccine 2016 The Rotavirus trial and results are described in Colgate et al, Clin Infect Dis 2016 The PROVIDE infants were genotyped on a custom Affymetrix Axiom array (30K SNPs) at the University of Virginia Center for Public Health Genomics; and on a pre-production version of the Illumina MEGA v2 chip at the Wellcome Trust Sanger Institute, UK. The latter genotyping was performed under the auspices of the VaccGene Consortium. Analyses are ongoing to identify variants associated with the included phenotypes. A manuscript describing the genotyping methods and analysis is in preparation for the initial phenotypes. The Infection Malnutrition Bangladesh Cohort is utilized in the following dbGaP sub-studies. To view genotypes, other molecular data, and derived variables collected in these sub-studies, please click on the following sub-studies below or in the "Sub-studies" box located on the right hand side of this top-level study page phs001475 Infection Malnutrition Bangladesh Cohort. phs001476 Amebiasis Immunity phs001478 Polio Rotavirus Vaccines phs001665 Cryptosporidiosis Enteropathogens

  Study phs001475

• Whole Genome Scan for Pancreatic Cancer Risk in the Pancreatic Cancer Cohort Consortium and Pancreatic Cancer Case-Control Consortium (PanScan)

  Within the framework of the NCI-sponsored Cohort Consortium, investigators from 12 prospective epidemiologic cohorts formed the Pancreatic Cancer Cohort Consortium in 2006. This study, also known as "PanScan", is funded by the National Cancer Institute (NCI) and involves conducting a genome-wide association study (GWAS) of common genetic variants to identify markers of susceptibility to pancreatic cancer. In 2007, the study was expanded to include 8 case-control studies. The study team includes scientists from the cohorts comprising the Consortium, the NCI and the Pancreatic Cancer Case Control Consortium (PanC4). PanScan I and II were conducted in 12 cohort studies and 8 case-control studies, leading to the discovery of four novel regions in the genome associated with risk for pancreatic adenocarcinoma. The third phase of PanScan (PanScan III) was conducted using recently identified incident pancreatic cancer cases drawn from fourteen cohorts from the cohort consortium, including nine prospective cohorts who participated in PanScan I, and five newly joined cohorts. The nine cohort studies that participated in PanScan I and had new genotyping of cases in PanScan III include ATBC, CPS-II, EPIC, HPFS, NHS, PHS, PLCO, SMWHS, and WHI; the five newly joined cohort studies include the Agricultural Health Study (AHS), the Multiethnic Cohort Study (MEC), the Melbourne Collaborative Cohort Study (MCCS), the Vitamins and Lifestyle Study (VITAL), and Selenium and Vitamin E Cancer Prevention Trial (SELECT). In addition to the cases from cohorts, we also included cases from the Gastrointestinal Cancer Clinic of Dana-Farber Cancer Institute Study (DFCI-GCC); from the University Hospital in Heidelberg, Germany, which is part of a larger European clinical case-control study (PANDoRA); and from clinic-based cases from eastern Spain (PANKRAS-II). The dbGaP datasets available include all subjects previously made available from PanScan I and II, plus 1,582 new incident pancreatic cancer cases of European descent from prospective cohorts, case-control studies or case series (genotyped as part of PanScan III). Also included are 61 pancreatic cancer cases and 67 control subjects from PanScan I as well as 173 pancreatic cancer cases from PanScan III of Asian ancestry from the Shanghai Men's and Women's Health Study (Supplemental Table 10, Wolpin et al. (Nat Genet, 2014)). The control population used in the analysis for the Wolpin et al. manuscript included cancer-free individuals from the prospective cohorts that contributed pancreatic cancer cases to PanScan III and controls from the Spanish Bladder Cancer SBC/EPICURO study that were previously genotyped using the OmniExpress, Omni 1M or Omni 2.5M SNP arrays. The data from these control subjects were posted to dbGaP under the GWAS in which they were initially genotyped and will not be made available in duplicate under this dbGaP study.The summary statistics for PanScan I-III were generated as detailed in Wolpin BM. et al., Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer, Nature Genetics 2014; 46(9):994-1000 (https://www.nature.com/articles/ng.3052), and Klein, A. et al., Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer, Nature Communications, 2018;9(1):556 (https://www.nature.com/articles/s41467-018-02942-5). The dataset includes results from an association study of 5,117 individuals diagnosed with pancreatic ductal adenocarcinoma (PDAC) and 8,845 control individuals, or a total of 13,962 subjects of European ancestry (as compared to the genotype and phenotype information under this project that includes 9,437 individuals (PanScan I and II PDAC case and control individuals and PanScan III PDAC cases only). This is due to the fact that PanScan III “borrowed” GWAS data from control individuals genotyped separately from the PanScan GWAS project and are therefore not included as raw genotypes in phs000206.v5.p3. Association analysis was performed separately for PanScan I-II and PanScan III, followed by a meta-analysis of the two datasets. Results were filtered based on a minor allele frequency (MAF) < 0.01, an imputation INFO score < 0.3 and a heterogeneity P-value < 1x10-10 leaving a total of 9,758,390 variants. Columns in the summary statistics dataset are as follows: ID: variant rsIDChr: chromosome numberPosition: position in the chromosome, genome build GRCh37/hg19MarkerName: variant identifierAllele1: reference alleleAllele2: alternative alleleFreq1: allele frequency for allele2FreqSE: standard error of the allele frequencyMinFreq: the minimal allele frequency across studiesMaxFreq: the max allele frequency across studiesEffect: effect size for allele2StdErr: standard errorP-value: meta-analysis p-valueDirection: summary of effect direction for each studyHetISq: I^2 statistic which measures heterogeneity on scale of 0-100%HetChiSq: chi-squared statistic in simple test of heterogeneityHetDf: degrees of freedom for heterogeneity statisticHetPVal: P-value for heterogeneity statistic

  Study phs000206