14658 results for "PLOS+ONE+Pennsylvania+German+ACS+language+code+pdc+open+access+study"

in 18.87 milliseconds.

• White blood cell and cell-free DNA analyses for detection of residual disease in gastric cancer

  Liquid biopsies are providing new opportunities for detection of residual disease in cell-free DNA (cfDNA) after surgery but may be confounded through identification of alterations arising from clonal hematopoiesis. Here, we identify circulating tumor-derived DNA alterations (ctDNA) through ultrasensitive targeted sequencing analyses of matched cfDNA and white blood cells from the same patient. We apply this approach to analyze samples from patients in the CRITICS trial, a phase III randomized controlled study of perioperative chemotherapy in patients with operable gastric cancer. After filtering alterations derived from matched white-blood cells, the presence of ctDNA predicts recurrence when analyzed within nine weeks after preoperative treatment and after surgery in patients eligible for multimodal treatment. These analyses provide a facile method for distinguishing ctDNA from other cfDNA alterations and highlight the utility of ctDNA as a predictive biomarker of patient outcome to perioperative cancer therapy and surgical resection in patients with gastric cancer.

  Study EGAS00001004114

• Integrative genomic and transcriptomic analysis of adult leiomyosarcoma (HIPO-028, HIPO-018, HIPO-021)

  Leiomyosarcoma (LMS) is an aggressive mesenchmyal malignancy with few therapeutic options. The mechanisms underlying LMS development, including clinically actionable genetic vulnerabilities, are largely unknown. We performed genomic and transcriptomic profiling of a large cohort of LMS tumors and identified substantial mutational heterogeneity, near-universal inactivation of TP53 and RB1, widespread DNA copy number alterations, chromothripsis, and frequent whole-genome duplication. Furthermore, we discovered recurrent alterations in telomere maintenance genes such as ATRX, RBL2, and RPA1, resulting in alternative lengthening of telomeres in 78% of cases. Finally, most tumors displayed hallmarks of “BRCAness”, including alterations in various homologous recombination DNA repair genes, multiple structural rearrangements, and enrichment of specific mutational signatures, and cultured LMS cells were sensitive towards olaparib and cisplatin treatment. This first comprehensive study of genetic alterations in LMS has uncovered key biological features that may inform future experimental research and enable the design of novel therapeutic strategies for this disease.

  Study EGAS00001002437

• Targeted sequencing of head and neck squamous cell carcinomas

  Overall survival remains very poor for patients diagnosed with head and neck squamous cell carcinoma (HNSCC). Identification of additional biomarkers and novel therapeutic strategies are important for improving patient outcome. Patient-derived xenografts (PDXs), generated by implanting fresh tumor tissue directly from patients into immune-deficient mice, recapitulate many of the features of their corresponding clinical cancers, including histopathological and molecular profiles. Using a large collection of PDX models of HNSCC we demonstrate that rapid engraftment into immune-compromised mice is highly prognostic, and show that genomic deregulation of the G1/S checkpoint pathway correlates with engraftment. Furthermore, CCND1 and CDKN2A genomic alterations are predictive of response to the CDK4/6 inhibitor abemaciclib. Overall, our study supports the pursuit of CDK4/6 inhibitors as a therapeutic strategy for a substantial proportion of HNSCC patients, and demonstrates the potential of using PDX models to identify novel targeted therapies for those patients who have the poorest outcomes.

  Study EGAS00001002979

• Single-cell landscapes of primary glioblastomas and matched organoids and cell lines reveal variable retention of inter- and intra-tumor heterogeneity

  Glioblastomas (GBMs) are aggressive primary malignant brain tumors characterized by extensive levels of inter- and intra-tumor genetic and phenotypic heterogeneity. Patient-derived organoids (PDOs) have recently emerged as useful models to study such heterogeneity. Here, we present bulk exome as well as single-cell genome and transcriptome profiles of primary IDH wild type GBMs from ten patients, including two recurrent tumors, as well as PDOs and brain tumor-initiating cell (BTIC) lines derived from these patients. We find that PDOs are genetically similar to and variably retain gene expression characteristics of their parent tumors. At the phenotypic level, PDOs appear to exhibit similar levels of transcriptional heterogeneity as their parent tumors, whereas BTIC lines tend to be enriched for cells in a more uniform transcriptional state. The datasets introduced here will provide a valuable resource to help guide experiments using GBM-derived organoids, especially in the context of studying cellular heterogeneity.

  Study EGAS00001005227

• Differential expression profile of gluten-specific T cells identified by single-cell RNA-seq

  Gluten-specific CD4+ T cells drive the pathogenesis of celiac disease and circulating gluten-specific T cells can be identified by staining with HLA-DQ:gluten tetramers. In this first single-cell RNA-seq study of tetramer-sorted T cells from untreated celiac disease patients blood, we found that gluten-specific T cells showed distinct transcriptomic profiles consistent with activated effector memory T cells that shared features with Th1 and follicular helper T cells. Compared to non-specific cells, gluten-specific T cells showed differential expression of several genes involved in T-cell receptor signaling, translational processes, apoptosis, fatty acid transport, and redox potentials. Many of the gluten-specific T cells studied shared T-cell receptor with each other, indicating that circulating gluten-specific T cells belong to a limited number of clones. Moreover, the transcriptional profiles of cells that shared the same clonal origin were transcriptionally more similar compared with between clonally unrelated gluten-specific cells.

  Study EGAS00001005517

• The chromatin accessibility signature of human immune aging stems from CD8+ T cells

  Aging is linked to deficiencies in immune responses and increased systemic inflammation. To unravel the regulatory programsbehind these changes, we applied systems immunology approaches and profiled chromatin accessibility and the transcriptomein PBMCs, purified monocytes, and B and T cells. Analysis of samples from 77 young and elderly donors revealed a novel androbust aging signature in PBMCs, with simultaneous systematic chromatin closing at promoters and enhancers associated withT cell signaling and a potentially stochastic chromatin opening mostly found at quiescent and repressed sites. Combined analysesof chromatin accessibility and the transcriptome uncovered immune molecules activated/inactivated with aging andidentified the silencing of the IL7R gene and the IL-7 signaling pathway genes as potential biomarkers. This signature is borneby memory CD8+ T cells, which exhibited an aging-related loss in binding of NF-κB and STAT factors. Thus, our study providesa unique and comprehensive approach to identifying candidate biomarkers and provides mechanistic insights into aging-associatedimmunodeficiency.

  Study EGAS00001002605

• The genomic landscape of cutaneous squamous cell carcinoma from immunosuppressed and immunocompetent patients reveals common drivers and a novel mutational signature associated with chronic azathioprine exposure

  Cutaneous squamous cell carcinoma (cSCC) has a high tumour mutational burden (50 mutations per megabase DNA pair). Combining whole exome analyses from 40 primary cSCC tumours, comprising 20 well differentiated and 20 moderately/poorly differentiated tumours, with accompanying clinical data from a longitudinal study of immunosuppressed and immunocompetent patients, coupled with integration of independent gene expression studies has allowed the identification of commonly mutated genes and altered pathways and processes. Mutational signature analysis revealed the presence of a novel signature (signature 32), which was found exclusively in the tumours from immunosuppressed patients who had been exposed to azathioprine. Characterisation of a panel of 15 keratinocyte cancer cell lines derived from tumours from immunocompetent and immunosuppressed patients reveals that they accurately reflect the mutational signatures and genomic alterations of primary tumours and provide a resource for the validation of tumour drivers and therapeutic targets.

  Study EGAS00001002612

• scRNA-seq of LN and lymphoma stroma

  The activities of non-haematopoietic cells (NHCs), including mesenchymal stromal cells and endothelial cells, in lymphomas, reportedly underlie lymphomagenesis. However, understanding of lymphoma NHCs has been hampered by unexplained NHC heterogeneity, even in normal human lymph nodes (LNs). Here, we constructed a single-cell transcriptome atlas of >100,000 NHCs collected from 27 human samples, including LNs and various nodal lymphomas, revealing 30 distinct subclusters, including some that were previously unrecognized. Notably, this atlas was highly useful for comparative analysis with lymphoma NHCs, which revealed an unanticipated landscape of subcluster-specific changes in gene expression and interaction with malignant cells in follicular lymphoma NHCs, facilitating our understanding of stromal remodelling in lymphoma and potentially suggesting novel biomarkers. Our study largely updates NHC taxonomy in human LNs and pertains to analysis of disease status, providing a rich resource and deeper insights into LN and lymphoma biology and offering to advance lymphoma management and therapy.

  Study EGAS00001005732

• Human Pancreatic Beta Cell lncRNAs Control Cell-Specific Regulatory Networks

  Recent studies have uncovered thousands of long non-coding RNAs (lncRNAs) in human pancreatic β cells. β cell lncRNAs are often cell type specific and exhibit dynamic regulation during differentiation or upon changing glucose concentrations. Although these features hint at a role of lncRNAs in β cell gene regulation and diabetes, the function of β cell lncRNAs remains largely unknown. In this study, we investigated the function of β cell-specific lncRNAs and transcription factors using transcript knockdowns and co-expression network analysis. This revealed lncRNAs that function in concert with transcription factors to regulate β cell-specific transcriptional networks. We further demonstrate that the lncRNA PLUTO affects local 3D chromatin structure and transcription of PDX1, encoding a key β cell transcription factor, and that both PLUTO and PDX1 are downregulated in islets from donors with type 2 diabetes or impaired glucose tolerance. These results implicate lncRNAs in the regulation of β cell-specific transcription factor networks.

  Study EGAS00001002865

• Heritable pulmonary arterial hypertension in a large Iberian family

  Data from a study of a large Iberian family (n=65 subjects, 5 generations) affected by pulmonary arterial hypertension (PAH) and segregating with the BMPR2 missense mutation p.Arg491Gln (rs137852749, c.1472G>A). PAH is a rare disease characterized by an abnormal rise in mean pulmonary arterial pressure (> or equal to 25 mmHg at rest), which, in turn, leads to a progressive increase in pulmonary vascular resistance and ultimately to death, due to right ventricular failure. Heritable PAH has an overall prevalence below 1 case per million adults and is defined by either the presence of a known genetic defect linked to the disease or a positive family history. Heritable PAH is inherited as an autosomal dominant disease. However, not all BMPR2 mutation carriers develop the disease, highlighting the presence of reduced penetrance. In this family, there are 22 mutation carriers from which 8 were diagnosed with heritable PAH and the other 14 were healthy at the time of examination.

  Study EGAS00001003123