12536 results for ""non-traditional+communal+storytelling+approach"+novel+segment+noted+in+critical+commentary"

in 26.25 milliseconds.

• 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

• Genetic heritage of the Baphuthi highlights an over-ethnicised notion of 'Bushman' in the Maloti-Drakensberg, southern Africa

  Using contemporary people as proxies for ancient communities is a contentious but necessary practice in anthropology. In southern Africa, the distinction between the Cape KhoeSan and eastern KhoeSan remains unclear as ethnicity labels have been changed through time and most communities were decimated if not extirpated. The eastern KhoeSan may have had genetic distinctions from neighbouring communities who speak Bantu languages and KhoeSan further away, alternatively the identity may not have been tied to any notion of biology, instead denoting communities with a nomadic 'lifeway' distinct from African agro-pastoralism. The Baphuthi of the 1800s in the Maloti-Drakensberg, southern Africa had a substantial KhoeSan constituency and a lifeway of nomadism, cattle raiding, and horticulture. Baphuthi heritage could provide insights into the history of the eastern KhoeSan. We examine genetic affinities of 23 Baphuthi to discern whether the narrative of KhoeSan descent reflects distinct genetic ancestry. Genome-wide SNP data (Illumina GSA) were merged with 52 global populations, for 160K SNPs. Genetic analyses show no support for a unique eastern KhoeSan ancestry distinct from other KhoeSan or southern Bantu-speakers. The Baphuthi have strong affinities with early-arriving southern Bantu-speaking (Nguni) communities, as the later-arriving non-Nguni show strong evidence of recent African admixture possibly related to Late-Iron Age migrations. The references to communities as 'San',and 'Bushman' in historic literature has often been misconstrued as notions of ethnic/biological distinctions. The terms may have reflected ambiguous references to non-sedentary polities instead, as seems to be the case for the eastern ‘Bushman’ heritage of the Baphuthi.

  Study EGAS00001007080

• T-cell receptor sequencing of tumor-infiltrating lymphocytes (TIL) in breast cancer

  The spatial distribution of tumor-infiltrating lymphocytes (TIL) predicts breast cancer outcome and response to systemic therapy, highlighting the importance of an intact tissue structure for characterizing patients’ tumors. Here, we present ST-FFPE, a spatial transcriptomics method for the analysis of formalin-fixed paraffin-embedded samples, which opens the possibility of interrogating widely available archival tissue. The method involves extraction, exome capture and sequencing of RNA from different tumor compartments microdissected by laser-capture, and can be used to study the cellular composition of various tumor environments. Focusing on triple-negative breast cancer (TNBC), we characterized T cells, B cells, dendritic cells, fibroblasts and endothelial cells in both stromal and intra-epithelial compartments. We found a highly variable spatial distribution of immune cell subsets among tumors. This analysis revealed that the immune repertoires of intra-epithelial T and B cells were consistently less diverse than those of stromal T and B cells. T-cell receptor (TCR) sequencing confirmed a reduced diversity and revealed higher clonality of intra-epithelial T cells relative to the corresponding stromal T cells. Analysis of the top ten dominant clonotypes in the two compartments showed a majority of shared but also some unique clonotypes both in stromal and intra-epithelial T cells. Hyperexpanded clonotypes were more abundant among intra-epithelial than stromal T cells. These findings validate the ST-FFPE method and suggest an accumulation of antigen-specific T cells within tumor core. Because ST-FFPE is readily applicable for analysis of previously collected tissue samples, it could be useful for rapid assessment of intratumoral cellular heterogeneity in multiple disease and treatment settings.

  Study EGAS00001007125

• A study of the genetic basis of evation by Acute Myeloid Leukaemia of Graft vs Leukaemia effects after allogeneic bone marrow transplantation

  Acute myeloid leukaemia (AML) is an aggressive and molecularly diverse disease with a poor overall survival of 20-25%. With an annual incidence of 2.9 per 100,000, AML is currently the commonest myeloid malignancy in Europe, yet the two main therapeutic options for this disease, anthracyclines and purine analogues, have remained unchanged for over 20 years. Currently patients are stratified at diagnosis according to a series of clinicopathological parameters (e.g. age, white cell count and presence/absence of previous clonal haematological disease) and molecular markers (e.g. chromosomal translocations/deletions, aneuploidy and mutations in genes such as FLT3 and NPM1). Patients with adverse prognostic features, whose prognosis is particularly poor (e.g. <15% long-term survival) are offered treatment with allogeneic bone marrow transplantation (allo-BMT) if a sibling or unrelated donor is available. This can significantly improve survival (e.g. up to 40% long-term survival in some contexts), albeit at the expense of significant toxicity and transplant-related mortality (TRM). Allo-BMT is thought to work in part by allowing the delivery of large doses of chemotherapy followed by haemopoietic "rescue" with donor haemopoietic stem cells (haemopoietic failure would otherwise ensue). However, potentially the most potent effect of allo-BMT is the cytotoxic effect of donor lymphocytes against AML blasts, a phenomenon known as graft-vs-leukaemia (GVL) effect. Increasingly, transplants using reduced chemotherapy intensity (mini-allografts) are being used that partially circumvent the toxicity from chemotherapy and rely on GVL to effect cure. Nevertheless, AML relapse after allo-BMT still occurs at a significant rate of up to 80% depending on the type of transplant. There is accumulating evidence that genetic events in residual leukaemic cells enable them to evade immunodetection and therefore survive the GVL effect and expand to cause relapse. The most striking example of this is the loss of HLA antigens after transplants in which donor and recipient are not fully HLA-matched. In these cases, the leukaemia "deletes" the genomic region containing the disparate HLA antigen which was preferentially targeted as "foreign" by the GVL effect. However, the genetic basis of immune evasion in the majority of transplants, which are fully HLA matched, is not known. One possibility is that loss of genes coding for antigens outside the HLA locus but which are also targets of GVL may operate, alternatively genetic events that affect processes downstream of immunological cytotoxicity may be responsible. The identification of genetic events that mediate immune evasion would not only facilitate the understanding of this process but can help plan therapeutic interventions that improve the outcomes of allogeneic transplantation for AML and other disorders. We intend to study this by conducting exome sequencing on 6 cases of AMLs from patients that attend my clinic at Addenbrooke's hospital and have relapsed after allogeneic transplantation. Samples from AML diagnosis, remission/normal and AML relapse (total n=18) will be studied to identify somatic mutations in the primary AML and those acquired by the relapsed clone. The 18 samples will also be studied by array CGH to detect regions of genomic amplification or deletion.

  Dataset EGAD00001000404

• Whole genome and transcriptome sequencing of lung cancer patients and cell lines at Genentech

  Version 1 Whole genome sequencing was applied to tumor and adjacent normal lung tissue in an individual non-small-cell lung cancer patient. We present an analysis of somatic changes identified throughout the tumor genome, including single-nucleotide variants, copy number variants, and large-scale chromosomal rearrangements. Over 50,000 high-confidence single-nucleotide variants were identified, revealing evidence of substantial smoking-related DNA damage as well as distinct mutational pressures within the tumor resulting in uneven distribution of somatic mutations across the genome. Version 2 Lung cancer is a highly heterogeneous disease in terms of both underlying genetic lesions and response to therapeutic treatments. We performed deep whole genome sequencing and transcriptome sequencing on 19 lung cancer cell lines and 3 lung tumor/normal pairs. Overall, our data show that cell line models exhibit similar mutation spectra to human tumor samples. Smoker and never-smoker cancer samples exhibit distinguishable patterns of mutations. A number of epigenetic regulators are frequently altered by mutations or copy number changes. A systematic survey of splice-site mutations identified over 100 splice site mutations associated with cancer specific aberrant splicing, including mutations in several known cancer-related genes. Differential usages of splice isoforms were also studied. Taken together, these data present a comprehensive genomic landscape of a large number of lung cancer samples and further demonstrate that cancer specific alternative splicing is a widespread phenomenon that has potential utility as therapeutic biomarkers.

  Study phs000299

• Prostate Cancer Upgrading Reference Set

  This study aimed to investigate clinical, demographic, and molecular features of men diagnosed with low-risk prostate cancer [ISUP Grade Group 1 (GG1)] at biopsy who underwent radical prostatectomy, and for whom an increased tumor grade (ISUP Grade Group 2 or above) was subsequently detected in the resected prostate. This phenomenon is termed upgrading. In collaboration with the Early Detection Research Network (EDRN), a blinded reference set was established to facilitate upgrading biomarker detection and validation. A prospective, multi-institutional, cohort of men with the GG1 prostate cancer and intention to undergo prostatectomy was recruited. Biospecimens (blood, urine) were collected and this biorepository comprises the official EDRN Upgrading Reference Set (URS). Recording of case-control status (case = upgrading at prostatectomy, control = no upgrading at prostatectomy) was coordinated by the Data Management and Coordinating Center (DMCC) of the EDRN, who ensured blinding of all participating researchers. A subset of the reference set (n = 192) was chosen to undergo whole genome sequencing (WGS) for the investigation of a germline genomic biomarker of upgrading. Variant calls from all sequenced URS whole genomes are available through dbGaP, with the exception of one sample for which sequencing was not successful. Among investigated clinical features, prostate-specific antigen (PSA) density and percent of cancer in pre-prostatectomy positive biopsy cores were significantly associated with upgrading. Two polygenic risk score-based biomarkers were computed in the genetic sub-cohort and tested against case-control status. Neither was predictive of upgrading.

  Study phs003670

• Risk Factors for Asymptomatic Diverticulosis

  Data for this analysis came from a prospective study of colonic diverticulosis at the University of North Carolina Hospital in Chapel Hill, North Carolina (NIH R01DK094738). This is a case-control genetic and transcriptomic study to identify the genetic and cellular determinants underlying colonic diverticulosis and the relationship with other gastrointestinal disorders. The study inclusion and exclusion are described below. DNA and RNA sequencing were performed on colonic tissue from 404 patients with (N=172) and without (N=232) diverticulosis. We assessed variation in the transcriptome associated with diverticulosis and integrated this variation with human intestine single-cell RNA-seq data. We integrated our expression quantitative trait loci with GWAS using Mendelian Randomization. A polygenic risk score analysis examined associations between severity of diverticulosis and other gastrointestinal disorders. We identified 38 genes with differential expression and 17 genes with varied transcript usage linked to diverticulosis. Our results suggest tissue remodeling as a primary mechanism for diverticula formation. The presence of diverticulosis was linked to stromal and epithelial cells in the colon including endothelial cells, myofibroblasts, fibroblasts, goblet, tuft, enterocytes, neurons, and glia. MR highlighted five genes including CCN3, CRISPLD2, ENTPD7, PHGR1, and TNFSF13. In diverticulosis cases, ENTPD7 upregulation was confirmed. A greater burden of diverticula was positively correlated with genetic predisposition to diverticulitis. The data related to the study including total RNA-Seq, SNP array and imputed genotypes will be available through dbGaP.

  Study phs003556

• 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

• 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

• Evolution of the African pygmy phenotype

  The evolutionary history of the human ‘pygmy’ phenotype (small body size), a characteristic of African and Southeast Asian rainforest hunter-gatherers, is largely unknown. Here we use a genome-wide admixture mapping analysis to identify 16 genomic regions that are significantly associated with the pygmy phenotype in the Batwa, a rainforest hunter-gatherer population from Uganda (East Central Africa). The identified genomic regions have multiple attributes that provide supporting evidence of genuine association with the pygmy phenotype, including enrichments for SNPs previously associated with stature variation in Europeans and for genes with growth hormone receptor and regulation functions. To test adaptive evolutionary hypotheses we computed the haplotype-based iHS statistic and the level of population differentiation (FST) between the Batwa and their agricultural neighbors, the Bakiga, for each SNP. Both |iHS| and FST values were significantly higher for SNPs within the Batwa pygmy phenotype-associated regions than the remainder of the genome, a signature of polygenic adaptation. In contrast, when we expanded our analysis to include Baka rainforest hunter-gatherers from Cameroon and Gabon (West Central Africa) and Nzebi and Nzime neighboring agriculturalists, we did not observe elevated |iHS| or FST values in these genomic regions. Together, these results suggest adaptive and at least partially convergent origins of the pygmy phenotype even within Africa, supporting the hypothesis that small body size confers a selective advantage for tropical rainforest hunter-gatherers but raising questions about the antiquity of this behavior.

  Study EGAS00001000908