13406 results for ""60+mice"+"6+weeks"+diet+study+2014+2017+DOI"

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• Single-Nuclei Paired Multiomic Analysis of Young, Aged, and Parkinson's Disease Human Midbrain Reveals Age-Associated Glial Changes and Their Contribution to Parkinson's Disease

  Age is the primary risk factor for Parkinson's disease (PD), but how aging to change the expression and regulatory landscape of the brain remains unclear. Here, we present a single-nuclei multiomic study profiling shared gene expression and chromatin accessibility of young, aged and PD post-mortem midbrain samples. Combined multiomic analysis of midbrain nuclei along a pseudo-pathogenesis trajectory reveals that all glial cell types are affected by age, but microglia and oligodendrocytes are further altered in PD. We present evidence for a novel disease-associated oligodendrocyte subtype and identify genes lost over the aging and disease process, including CARNS1, that may predispose healthy cells to develop a disease-associated phenotype. Peak-gene association analysis from paired data identifies 89 PD-associated SNP loci, including five in MAPT, that only correlate with gene expression in disease-associated oligodendrocytes. Our study suggests a previously undescribed role for oligodendrocytes in aging and PD pathogenesis.

  Study phs002819

• BarcUVa-Seq (Biology of Colorectal Cancer Risk Enhancers)

  This study was designed to generate a cohort of normal colon mucosal biopsies from the "average risk" population. Its primary aims included the development of an RNA-seq dataset of normal colon mucosal biopsies across three colon regions (ascending, transverse and descending). Further, we aimed to provide plausible prioritization to genetic components of colorectal cancer risk by employing methods such as expression quantitative trait loci analysis. In doing so, we provide a novel reference dataset for the study of colon cancer risk in the healthy colon epithelium. RNA-seq was performed in batches on an Illumina HiSeq 2500 (batch 1-7) or NovaSeq 6000 (batch 8) on a total of 463 samples. Matched genotyping data was generated on the Illumina OncoArray BeadChip. Phasing was carried out using Minimac 3 and imputation was performed using The Haplotype Reference Consortium panel on the Michigan Imputation Server.Genotype and RNA-seq data will be made available in dbGaP.

  Study phs003338

• Deciphering craniopharyngioma subtypes: Single-cell analysis of tumor microenvironment and immune networks

  Craniopharyngiomas, including both adamantinomatous (ACP) and squamous papillary (PCP) types, present significant challenges in treatment due to their proximity to critical pituitary structures. In this study, we conducted a single-cell RNA analysis to examine the tumor microenvironments (TME) of ACP and PCP. Single-cell clustering revealed a wide range of cell types, which were further categorized based on gene expression patterns. For ACP, these categories included developing epithelia, calcification, and immune response, while PCP showed developing epithelia, cell cycle, and immune response as prominent categories. Subclustering analysis unveiled different types of immune cells in both ACP and PCP TMEs, with specific patterns of immune responses. Interestingly, smaller tumors were associated with particular immune cell ratios. Furthermore, we identified specific cell-to-cell interactions within the tumor cells. In conclusion, our study has led to the development of a comprehensive cell atlas, shedding light on the molecular characteristics and intricate interplay of immune cells within the TMEs of ACP and PCP.

  Study JGAS000722

• Processing of tissue and cfDNA samples of CRC patients using Active-seq

  In this study, we have developed a novel technology called Active-Seq (Azide Click Tagging for In Vitro Epigenomic sequencing), a base conversion-free technology used to profile the DNA methylation status of a sample, based on the isolation of DNA containing unmodified CpG sites using a mutated bacterial methyltransferase enzyme and a synthetically prepared cofactor analogue. We procured samples from colorectal cancer (CRC) patients including tumour tissue as well as normal adjacent tissues. The data enabled us to identify CRC-specific markers that could then be used to track and monitor the presence of tumour DNA in cell-free DNA plasma (cfDNA) samples procured in the same patients. The FASTQ files of all the colorectal cancer tissues, normal adjacent tissues as wells as the cfDNA samples are available in this submission. The data made available in this study have been used to outline an approach for tumour-informed disease profiling in colorectal cancer cfDNA samples using Active-Seq.

  Study EGAS50000001226

• Sequencing cancer mutations in various types of lung cancer using the long-read, portable sequencer

  In this study, we used a long-read and portable sequencer MinION to identify cancer mutations in lung adenocarcinoma cells. We performed cDNA amplicon sequencing for various types of mutations such as point mutations in EGFR and KRAS and oncogenic fusion transcripts in ALK and RET. Using the long reads of MinION, we also conducted mutation phasing of EGFR TKI-sensitive and resistant mutations, which would provide useful information to next thrapeutic approaches for cancers. We applied this method to identify mutation genotypes of eight clinical samples from Japanese lung adenocarcinomas. This method could provide new sequencing-based diagnostic approaches for lung cancers. Additinally we also performed cancer mutation identification of risk-dependent unique samples. Usual interstitial pneumonia (UIP) is a risk factor for lung carcinogenesis. This study was performed to characterize mutagenesis and mutational target genes underlying lung carcinogenesis in patients with UIP.We performed whole exome sequencing of lung adenocarcinoma with usual interstitial pneumonia.

  Study JGAS000065

• Adult granulosa cell tumor WGS data cohort with corresponding reference germline WGS data

  Adult granulosa cell tumors (AGCTs) harbor a somatic FOXL2 c.402C>G mutation in ~95% of cases and are mainly surgically removed due to limited systemic treatment effect. In this study, potentially targetable genomic alterations in AGCTs were investigated by whole genome sequencing on 46 tumor samples and matched normal DNA. Copy number variant (CNV) analysis confirmed gain  of chromosome 12 and 14, and loss of 22. Pathogenic TP53 mutations were identified in three patients with highest tumor mutational burden and mitotic activity, defining a high-grade AGCT subgroup. Within-patient tumor comparisons showed 29-80% unique somatic mutations per sample, suggesting tumor heterogeneity. FOXL2-wildtype AGCTs had DICER1, TERT(C228T) and TP53 mutations and similar CNV profiles as FOXL2-mutant tumors. Our study confirms that absence of the FOXL2 c.402C>G mutation does not exclude AGCT diagnosis. The lack of overlapping variants in targetable cancer genes, indicates the need for personalized treatment for AGCT patients 

  Study EGAS00001004249

• Whole-exome ultra-high throughput sequencing in brain samples of suicide victims who had suffered from major depressive disorder and control subjects who had died from other causes

  We carried out whole-exome ultra-high throughput sequencing in brain samples of suicide victims who had suffered from major depressive disorder and control subjects who had died from other causes. This study aimed to reveal the selective accumulation of rare variants in the coding and the UTR sequences within the genes of suicide victims. We also analysed the potential effect of STR and CNV variations, as well as the infection of the brain with neurovirulent viruses in this behavioural disorder. As a result, we have identified several candidate genes, among others three calcium channel genes that may potentially contribute to completed suicide. We also explored the potential implication of the TGF-β signalling pathway in the pathogenesis of suicidal behaviour. To our best knowledge, this is the first study that uses whole-exome sequencing for the investigation of suicide.

  Study EGAS00001002818

• Impact of mutational profiles on response of primary oestrogen receptor-positive breast cancers to oestrogen deprivation

  Presurgical studies allow study of the relationship between mutations and response of estrogen receptor positive (ER+) breast cancer to aromatase inhibitors (AIs) but have been limited to small biopsies. Here in Phase I of this study, we perform exome sequencing on baseline, surgical core-cuts and blood from 60 patients (40 AI treated, 20 Controls). In poor responders (based on Ki67 change) we find significantly more somatic mutations than good responders. Subclones exclusive to baseline or surgical cores   occur in approximately 30% of tumours. In Phase II we combine targeted sequencing on another 28 treated patients with Phase I. We find six genes frequently mutated: PIK3CA, TP53, CDH1, MLL3, ABCA13 and FLG with 71% concordance between paired cores. TP53 mutations are associated with poor response. We conclude that multiple biopsies are essential for confident mutational profiling of ER+ breast cancer and TP53 mutations are associated with resistance to oestrogen deprivation therapy.

  Study EGAS00001001940

• Next_gen_seq_of_eye_cancers

  Retinoblastoma (RB), the commonest eye cancer in children was the first cancer for which a genetic cause was identified: the Rb1 gene is a tumour suppressor gene that is mutated in RB. The Rb1 gene defect alone does not predict the clinical outcome. We propose to study other possible mechanisms: 1. Stepwise further mutations occur in RB, increasing its carcinogenesis. We will sequence the whole genome in RB tissue, and relate the different genes expressed to the treatments used. 2. Extracellular matric proteins contribute to a tumour permissive environment for RB to continue to grow. This includes Samll Leucine Rich Proteoglycans (SLRP), a family of 15 secreted extracellular matrix proteins involved in eye development. 3. Cancer stem cells (CSC), a subpopulation of treatment resistant cells, drive RB tumours, and whether these stem cells can be manipulated for new therapies. The aim of this study is to assist finding targeted diagnostic techniques and treatments for RB.

  Study EGAS00001002309

• A biobank of patient-derived pediatric brain tumor models

  Brain tumors are the leading cause of cancer-related death in children. Genomic studies have provided insights into molecular subgroups and oncogenic drivers of pediatric brain tumors that may lead to novel therapeutic strategies. To evaluate new treatments, better preclinical models adequately reflecting the biological heterogeneity are needed. Through the Children’s Oncology Group ACNS02B3 study, we have generated and comprehensively characterized 30 patient-derived orthotopic xenograft models and 7 cell lines representing 14 molecular subgroups of pediatric brain tumors. Patient-derived orthotopic xenograft models were found to be representative of the human tumors they were derived from in terms of histology, immunohistochemistry, gene expression, DNA methylation, copy number, and mutational profiles. In vivo drug sensitivity of targeted therapeutics was associated with distinct molecular tumor subgroups and specific genetic alterations. These models and their molecular characterization provide an unprecedented resource for the cancer community to study key oncogenic drivers and to evaluate novel treatment strategies.

  Study EGAS00001002536