12528 results for ""non-traditional+communal+storytelling+approach"+novel+segment+noted+in+critical+commentary"

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• Somatic Mutations in 3,929 HPV-Positive Exfoliated Cervical Cell Samples

  We investigated the detection, timing, and HPV type specificity of cervical somatic hotspot mutations (i.e., previously reported cancer driver mutations) in 3,929 HPV-positive exfoliated cervical cell samples from individuals undergoing routine cervical screening in the U.S. using deep-targeted sequencing of 20 candidate genes. Our study included samples from 3,351 women with the following infection outcomes: 1,478 HPV16-, HPV18- and/or HPV45-positive controls (i.e., HPV infections that did not progress to precancer and/or subsequently cleared), 1,712 cervical precancers, and 161 invasive cervical cancers. We utilized residual exfoliated cervical cell samples from women routinely screened for cervical cancer precursors at Kaiser Permanente Northern California (KPNC) as part of the prospective KPNC-NCI HPV Persistence and Progression (PaP) cohort. We included 3,929 samples collected from these 3,351 women, including 974 serial sample from 396 women collected prior to their most recent screening visit to evaluate somatic hotspot mutation detection prior to diagnosis.

  Study phs003691

• Nivolumab plus chemotherapy or ipilimumab in gastroesophageal cancer: CheckMate 649 biomarker analyses

  First-line nivolumab-plus-chemotherapy demonstrated superior overall survival (OS) versus chemotherapy for advanced gastroesophageal adenocarcinoma (CheckMate 649). Nivolumab-plus-ipilimumab provided durable responses and higher survival rates versus chemotherapy; however, the prespecified OS significance boundary was not met. To identify biomarkers predictive of differential efficacy outcomes, exploratory analyses were performed using whole-exome sequencing and RNA sequencing. Nivolumab-based therapies demonstrated improved efficacy versus chemotherapy in hypermutated and, to a lesser degree, Epstein Bar Virus-positive tumors compared with chromosomally unstable and genomically stable tumors. Within the KRAS-altered subgroup, only patients treated with nivolumab-plus-chemotherapy demonstrated improved OS benefit versus chemotherapy. Low stroma gene expression signature scores were associated with OS benefit with nivolumab-based regimens; high regulatory T-cell signatures were associated with OS benefit only with nivolumab-plus-ipilimumab. Our analyses suggest that distinct and overlapping pathways contribute to the efficacy of nivolumab-based regimens in gastroesophageal adenocarcinoma.

  Study EGAS50000000747

• Early evolutionary branching across spatial domains predisposes to clonal replacement under chemotherapy in neuroblastoma

  Neuroblastoma (NB) is one of the most lethal childhood cancers due its propensity to treatment resistance. By spatial mapping of subclone geographies before and after chemotherapy across 89 tumor regions from 12 NBs, we find that densely packed territories of closely related subclones present at diagnosis are replaced under effective treatment by islands of distantly related survivor subclones, originating from a different most recent ancestor compared to lineages dominating before treatment. Conversely, in tumors that progressed under treatment, ancestors of subclones dominating later in disease are present already at diagnosis. Chemotherapy treated xenografts and cell culture models replicates these two contrasting scenarios and shows branching evolution to be a constant feature of proliferating NB cells. Phylogenies based on whole genome sequencing of 505 individual NB cells indicate that a rich repertoire of parallel subclones, emerges already with the first oncogenic mutations and lays the foundation for clonal replacement under treatment.

  Study EGAS00001007650

• Repli-seq data for 'Replication timing alterations are associated with mutation acquisition during tumour evolution in breast and lung cancer'

  The essential process of DNA replication timing during each cell cycle is highly regulated ensuring the correct duplication of the genome. The extent and importance of alterations in this process during malignant transformation has not been extensively explored. Here, we evaluate the impact of altered replication timing (ART) on cancer evolution by analysing replication-timing sequencing of cancer and normal cell lines and 952 whole-genome sequenced lung and breast tumours. We find 6%-18% of the cancer genome displays ART. Genomic regions with a change from early to late replication exhibit an increased mutation rate and distinct mutational signatures, while regions changing from late to early contain genes with increased expression and present a preponderance of APOBEC3-mediated mutation clusters and associated driver mutations. We demonstrate that ART is a relatively early event during cancer evolution and that ART may have a stronger correlation with mutation acquisition than alterations in chromatin structure.

  Study EGAS00001007773

• Custom long non-coding RNA capture enhances detection sensitivity in different human sample types.

  Long non-coding RNAs (lncRNAs) are a heterogeneous group of transcripts that lack protein coding potential and display regulatory functions in various cellular processes. As a result of their cell- and cancer-specific expression patterns, lncRNAs have emerged as potential diagnostic and therapeutic targets. The accurate characterization of lncRNAs in bulk transcriptome data remains challenging due to their low abundance compared to protein coding genes. To tackle this issue, we describe a unique short-read custom lncRNA capture sequencing approach that relies on a comprehensive set of 565,878 capture probes for 49,372 human lncRNA genes. This custom lncRNA capture approach was evaluated on various sample types ranging from artificial high-quality RNA mixtures to more challenging formalin-fixed paraffin-embedded tissue and biofluid material. The custom enrichment approach allows the detection of a more diverse repertoire of lncRNAs, with better reproducibility and higher coverage compared to classic total RNA-sequencing.

  Study EGAS00001005418

• Determination of cell specific regulatory enhancers in hematopoetic models

  The BLUEPRINT project is a large-scale project investigating epigenetic mechanisms involved in blood formation, in health and disease. The human variation workpackage (WP10, led by NS) of the project seeks to characterize the effect of common sequence variation on the epigenome status of a cell. To do this, the project will use highly purified blood cells to minimise "experimental noise" and therefore enhance the power to discover modest effects. Two peripheral blood cell types, the CD14+CD16- monocyte (an important central orchestrator of adaptive immunity and a bridge between innate and adaptive immunity) and the CD65+CD9- neutrophilic granulocyte (the frontline cell for innate immunity) have been selected for this purpose. The two types of cells will be obtained at high purity from adult blood (AB) of 200 healthy males and females, respectively. Cells will be purified by using already validated and fully operational protocols that are based on density gradient centrifugation of the buffy coat obtained from whole blood, followed by magnetic bead-based purification using monoclonal antibodies against Cluster of Differentiation (CD) lineage-specific cell surface markers. Units of 475 ml of AB will be obtained from consenting volunteers of the Cambridge BioResource (CBR), a panel of 10,000 healthy volunteers local to Cambridge who have already consented to participate in biomedical research and of whom biological samples (DNA, plasma, serum) and lifestyle data have been deposited in a repository and database, respectively. We are requesting funding from the Human Diversity project to sequence the genomes of the 200 CBR volunteers at low pass (6x coverage). Nuclei, DNA and RNA will be recovered from the purified cells and made available for RNA-seq, DNA-seq and ChIP-seq and genomic DNA for entire genome sequencing will be recovered from the DNA repository.

  Dataset EGAD00001002205

• Identification of gene mutations and fusion genes in patients with Sézary Syndrome

  Sezary syndrome (SS) is a leukemic form of cutaneous T-cell lymphoma (CTCL) with an aggressive clinical course. The goal of our study is to understand the genetic basis of the disease by looking for driver gene mutations and fusion genes in 15 erythrodermic patients with circulating Sezary cels, fourteen of them fulfilling the diagnostic criteria of SS. Peripheral blood samples were collected for each patient and CD4+ T-lymphocytes and Granulocytes were isolated. DNA and RNA was extracted for matched normal and tumor materials. Whole exome sequencing was performed on matched normal and tumor tissues of 12 patients and RNA sequencing was performed on 10 patients. For 7 of these patients, we have both exome as well as RNA sequencing data. In this study, we present a complex genomic landscape of Sezary syndrome with several point mutations, copy number variations and fusion events which could contribute to the pathogenesis of SS.

  Study EGAS00001001706

• Co-infection of fungi and bacteria in brain tissue from elderly persons and patients with Alzheimer's disease.

  Dac EGAC00001000797

• Wargo Group Data Access Committee for Neodjuvant Immune Checkpoint Blockade in High-Risk Resectable Melanoma

  Dac EGAC00001001008

• DAC - Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML

  Dac EGAC00001001461