12501 results for ""non-traditional+communal+storytelling+approach"+novel+segment+noted+in+critical+commentary"

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• The_contribution_of_POT1_variants_to_sporadic_melanoma_development

  A case-control series of melanoma cases from Leeds, UK have been sequenced in the Fluidigm platform to identify genetic variants associated with sporadic melanoma development. Samples in which potentially contributing variants have been detected are being sequenced in an orthogonal platform for variant confirmation.

  Study EGAS00001001964

• Variant Calling used in ABB project

  This dataset has two Variants Files in VCF format used in ABB project (https://github.com/Francesc-Muyas/ABB). One has the variants found in a Rare Variant Association Study performed in CLL patients. This has 1217 samples represented. The other variant file has 209 SNPs predicted in 10 samples by GATK HaplotypeCaller and selected for Sanger Sequencing Validation. Raw reads were aligned against the Human Reference genome (Hg19) with BWA mem and variants were obtained using GATK HaplotypeCaller.

  Dataset EGAD00001004132

• VRK3 depletion in Pontine Diffuse Midline Glioma DMG-K27 altered cells

  In order to investigate possible mechanisms underlying the phenotype of cell fitness decline observed following decrease of VRK3 in pontine DMG-K27 altered cells 7, we examined differences in global gene expression. RNA-seq was performed 44h and 60h post-transduction with two distinct shRNAs targeting VRK3 to be able to evaluate the early impact of VRK3 knock-down (KD) in four independent in vitro models of DMG

  Dataset EGAD00001010097

• ChIP-Seq of TFEB in LT-HSC

  ChIP-Seq of TFEB in LT-HSC

  Study EGAS00001005462

• Molecular Characterization of Hemimegalencephaly

  Somatic mutations, in which a fraction of the cells in the body have a deleterious mutation, are well recognized in cancer but only recently appreciated in neurological disease. Given a somatic mutation in a population of progenitor cells, all daughter cells inherit the mutation and are able to express the resultant phenotype as a function of the differentiation program. We recently identified the first de novo somatic mutations in the developing brain in the condition hemimegalencephaly (HME), a catastrophic focal epilepsy condition associated with a malformation of cerebral cortical development (MCD). HME is one of the most severe MCD syndromes, characterized by massive hamartomatous overgrowth of either of the two cerebral hemispheres. Cerebral hemispherectomy is a frequent treatment for refractory epilepsy, allowing the sampling of diseased tissue. By comparing DNA from a diseased brain with DNA from blood/saliva, we identified de novo somatic mutations in PIK3CA, AKT3 or MTOR, part of the mTOR pathway. Mutations were present in 8-40% of sequenced alleles in various brain regions sampled during surgery and in some codons known to activate proteins.• Population informationPatient samples were collected from multiple centers. The population is Caucasian and Hispanic• Molecular technologies employedWhole-exome sequencing• Principal findings of the studyWe were the first to describe mTOR-related and non-mTOR mutations causing hemimegalencephaly, and we described two-hit mutational models to explain the genetic pathogenesis of hemimegalencephaly

  Study phs002156

• Platelet RNAseq data for SLFN14 K219N patients

  Pathogenic missense variants in SLFN14, which encodes an RNA endoribonuclease protein that regulates rRNA degradation, are known to cause inherited thrombocytopenia with impaired platelet aggregation and ATP secretion. Despite rather mild laboratory defects, these patients display an obvious bleeding phenotype. The function of SLFN14 in megakaryocyte (MK) and platelet biology is unknown. This study aims to characterize the platelet transcriptome in patients with a SLFN14 K219N variant and model the disease in the immortalized megakaryocyte cell line imMKCL. Total platelet RNA was sequenced for two patients and 19 healthy controls. Differential gene expression analysis yielded a total of 2999 and 2888 significantly (|log2FC|>1, FDR<0.05) up- and downregulated genes, respectively. Remarkably, these downregulated genes were not enriched for any biological pathway while upregulated genes were enriched for pathways involved in (mitochondrial) translation and transcription with a significant upregulation of 134 ribosomal protein genes (RPG). Heterozygous and homozygous SLFN14 K219N imMKCL showed a defect in MK differentiation that aggravated during cell passaging of undifferentiated cells and in proplatelet formation. SLFN14 defective platelets and MK showed signs of rRNA degradation while this was absent in undifferentiated imMKCL cells. Upregulation of RPG through increased mTOR signaling in SLFN14 K219N MK seems to be a compensatory response for rRNA degradation. Indeed, mTOR inhibition with rapamycin resulted in further enhanced rRNA degradation in SLFN14 K219N MK. Taken together, our study indicates dysregulation of mTOR-regulated ribosomal biogenesis as the disease mechanism for SLFN14-related thrombocytopenia.

  Study EGAS00001006339

• Genetic and epigenetic characterization of adenoid cystic carcinoma

  Translocation events are frequent in cancer and may create chimeric fusions or regulatory rearrangements that drive oncogene overexpression. Although regulatory rearrangements are increasingly recognized in hematopoietic and even solid tumors, the underlying mechanisms remain obscure. Here we identify super-enhancer translocations that drive overexpression of the oncogenic transcription factor MYB as a unifying theme in adenoid cystic carcinoma (ACC). Whole genome sequencing data and chromatin state maps for 13 primary tumors and xenografts reveal distinct chromosomal rearrangements that juxtapose super-enhancer clusters to the MYB locus. Chromosome conformation capture confirms that the translocated enhancers physically interact with the MYB promoter. Remarkably, the MYB product itself binds to the translocated enhancers, thus creating a positive feedback loop that sustains its own expression. MYB also binds a large number of active enhancers that drive opposing regulatory programs in alternate cell lineages in ACC. MYB cooperates with the transcription factor TP63 in the myoepithelial component of the tumors, but promotes a Notch program in the luminal epithelial component. Bromodomain inhibitors, which disrupt enhancer function, slow tumor growth in ACC primagraft models in vivo, but are ineffective against high grade tumors that harbor activating mutations in the Notch pathway. Thus, our study identifies super-enhancer translocations as a unifying feature of ACC, and provides insight into the mechanism by which sustained MYB overexpression drives alternate cell fates in this disease.Processed ChIP-seq data is available on GEO under accession number GSE76465.

  Study EGAS00001001457

• TREM2+ Cells in Human Basal Cell Carcinomas

  To explore the tumor immune microenvironment heterogeneity in sporadic human basal cell carcinoma tumors, we profiled two individual patient tumors by scRNA-Seq. We identified a population of TREM2+ macrophages, which have been implicated in promoting an immunosuppressive tumor microenvironment. We identify that TREM2+ can promote tumor epithelial proliferation in an immunosuppressive independent manner.

  Study phs003242

• Loss of RREB1 in pancreatic beta cells reduces cellular insulin content and affects endocrine cell gene expression

  Genome-wide studies have uncovered multiple independent signals at the RREB1 locus associated with altered type 2 diabetes (T2D) risk and related glycemic traits. However, little is known about the function of the zinc finger transcription factor RREB1 in glucose homeostasis or how changes in its expression and/or function influence diabetes risk. We studied its function using three transcriptomic strategies, profiling gene expression when RREB1 is knocked out or knocked down in the Endo-betaH1 cell line, in addition to the in vitro differentiation in hiPSCs.

  Dataset EGAD00001009740

• The role of the mammalian SWI/SNF chromatin remodeling complex in neuroendocrine prostate cancer

  We sought to determine the effects of SMARCA4 and SMARCA2 depletion in prostate cancer cell lines. We performed siRNA-mediated knock-down of SMARCA4 and SMARCA2 in an androgen-sensitive (LNCaP) cell line and in a castration-resistant prostate cancer (CRPC)-adenocarcinoma cell line (22Rv1) and compared global transcriptional alterations using RNA-seq.

  Study EGAS00001004177