Search Results - EGA European Genome-Phenome Archive

MPNST - 10X single nucleus RNAseq

Understanding the spatial and temporal dynamics of tumour evolution is crucial for determining the drivers of cancer progression. Here, we comprehensively profile a primary malignant peripheral nerve sheath tumour (MPNST) and its recurrence with a multi-omic and spatial approach at single-cell resolution. Leveraging the extensive heterogeneity in copy number aberrations (CNAs) as a native barcoding system, we fully resolve the evolutionary tree of this tumour revealing multi-furcations suggestive of ongoing chromosomal instability. We show gene dosage effects contribute to phenotypic diversity and are predominantly linear with the exception of FOS in a specific subclone. Using laser capture microdissection, we performed spatial lineage tracing in a human tumour, elucidating the relationship between local expansions and interactions between tumour cells and the microenvironment.

Study EGAS50000001787

A dataset compiled as a resource a for orthogonal assessment of exon CNV calling in NGS data

The dataset includes high-quality sequencing data from a targeted NGS assay (the TruSight Cancer Panel) together with Multiplex Ligation-dependent Probe Amplification (MLPA) results for 96 independent samples. 66 samples contain at least one validated exon CNV and 30 samples have validated negative results for exon CNVs in 26 genes. The dataset includes 46 exon CNVs in BRCA1, BRCA2, TP53, MLH1, MSH2, MSH6, PMS2, EPCAM and PTEN, giving excellent representation of the cancer predisposition genes most frequently tested in clinical practice. Moreover, the validated exon CNVs include 25 single exon CNVs the most difficult exon CNV to detect. The full dataset includes FASTQ files, target BED file, and MLPA results.

Study EGAS00001002428

Genome-wide DNA methylation profiles of NSCLC xenograft and primary lung tissues for the identification of epigenetic predictive biomarkers.

Non-small cell lung cancers (NSCLC) are the most common cause of cancer-related deaths worldwide and primarily treated with platinum-based drugs like cisplatin and carboplatin, radiation and surgery. The major challenge in the management of NSCLC are intrinsic or acquired resistance mechanisms with only few published molecular markers which can predict the outcome of the patients. On the other side, changes in DNA methylation are observed in nearly all cancer types making them suitable as biomarker. Here genome-wide methylation profiles from MeDIP-Seq and gene expression profiling data of 22 primary NSCLC, adjacent normal tissue and PDX samples are provided. For each PDX tumor growth rates were measured in absence or presence of chemotherapy.

Study EGAS00001002479

Whole genome sequencing of 50 trios, where the child is affected with ID, and the parents are unaffected

50 trios were whole genome sequenced with Complete Genomics to a depth of 80x. Each trio the child was affected with severe ID, and the parents were unaffected. All trios were negative for array, targetted gene and whole exome screening.

Study EGAS00001000769

Comprehensive genetic analysis of uveal melanoma heterogeneity during metastatic progression

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Despite improvement of diagnosis and treatment of the primary tumor, there is no effective treatment of metastatic disease and approximately half of patients will die within one year or less following metastases detection. Tumor heterogeneity has been proposed as a key factor of drug resistance. However, it has been scarcely studied in UM. The present project aims searching for specific drivers of the metastatic progression, describing the genomic and transcriptomic landscape of metastatic UM, exploring tumor heterogeneity and investigating its role in drug resistance. Thus whole exome sequencing and transcriptomics have been performed on constitutional, primary tumor and metastatic samples from 28 UM patients.

Study EGAS00001002761

Genome-wide NanoRCS sequencing of cfDNA and ctDNA from liquid biopsies of healthy individuals and cancer patients

Levels of circulating tumor DNA (ctDNA) in liquid biopsies may serve as a sensitive biomarker for real-time, minimally-invasive tumor diagnostics and monitoring. However, detecting ctDNA is challenging, as much fewer than 5% of the cell-free DNA in the blood typically originates from the tumor. To detect lowly abundant molecules, extremely sensitive sequencing methods are required. We developed a new technique, NanoRCS, which is based on Oxford Nanopore sequencing of concatenated copies of a single DNA molecule for genome-wide sequencing, and applied this to plasma of healthy individuals, Esophageal cancer patients and Granulosa cell tumor patients and ascites of Ovarian cancer patients. We also sequenced these samples on Illumina Novaseq, to compare the two techniques.

Study EGAS50000000154

Capmatinib shows superior efficacy for MET-fusion driven pediatric high-grade glioma and synergizes with radiotherapy

Pediatric high-grade glioma (pHGG) is the most frequent malignant brain tumor in children and can be subclassified into multiple entities. Fusion genes activating the MET receptor tyrosine kinase often occur in infant-type hemispheric glioma (IHG) but also in other pHGGs, and are associated with devastating morbidity and mortality. To identify new treatment options, we established and characterized two novel orthotopic mouse models harboring distinct MET fusions. These included an immunocompetent, murine allograft model and patient-derived orthotopic xenografts (PDOX) from a MET-fusion iHG patient who failed conventional therapy and targeted therapy with cabozantinib. With these models, we analyzed the efficacy and pharmacokinetic properties of three MET inhibitors, capmatinib, crizotinib and cabozantinib, alone or combined with radiotherapy (RT).

Study EGAS50000000137

Mapping Genotypes to Chromatin Accessibility Profiles in Single Cells

In somatic tissue differentiation, chromatin accessibility changes govern priming and precursor commitment towards cellular fates1–3. Therefore, somatic mutations likely alter chromatin accessibility patterns, as they disrupt differentiation topologies leading to abnormal clonal outgrowth. However, defining the impact of somatic mutations on the epigenome in human samples is challenging due to admixed mutated and wild-type cells. To chart how somatic mutations disrupt epigenetic landscapes in human clonal outgrowths, we developed Genotyping of Targeted loci with single-cell Chromatin Accessibility (GoT-ChA). This high-throughput platform links genotypes to chromatin accessibility at single-cell resolution, across thousands of cells within a single assay. We applied GoT-ChA to CD34+ cells from myeloproliferative neoplasm (MPN) patients with JAK2V617F-mutated hematopoiesis.

Study EGAS50000000164

NGS-based monitoring of the T cell receptor repertoire in living donor kidney transplant patients undergoing combination cell therapy

Tolerance induction through mixed chimerism is a promising approach to achieve long term graft patency without or only low dose maintenance immunosuppression. In this phase I/IIa academic trial kidney transplant recipients in the case group were co-transplanted with bone marrow from the same donor and received an autologous cell product. The control group did not receive donor bone marrow or an autologous cell product. Peripheral blood mononuclear cells were collected at multiple timepoints before and after transplantation and the recipients native T-cell receptor (TCR) repertoire at time points 0, 1, 3 and 6 months after transplantation as well as their donor reactive TCR repertoire were analysed using NGS-based TCR sequencing.

Study EGAS50000000210

Tracing tumor evolution and heterogeneity of pleomorphic carcinoma of the lung

Pulmonary pleomorphic carcinoma (PPC) is an aggressive and highly heterogeneous non-small-cell lung carcinoma whose underlying biology is still poorly understood. Forty-two tumor areas including 39 primary tumors and 3 metastases from 20 PPC patients were microdissected and the histologically distinct components were subjected to whole exome sequencing (WES) separately. Twenty non-tumor areas from matched PPC patients were also subjected to WES. Twist Human Core Exome + RefSeq + Mito-Panel kit (Twist Bioscience) was used for the whole exome capturing according to manufacturer’s guidelines. Paired-end 100-bp reads were generated on the Illumina NovaSeq 6000. After the sequencing, reads were aligned against the reference human genome GRCh38 using Burrows-Wheeler Aligner (BWA, v0.7.12)

Study EGAS50000000314

Characterization of the cellular microenvironment in fibrostenotic Crohn’s disease

Crohn's disease (CD) is marked by recurring intestinal inflammation and tissue injury, often resulting in fibro-stenosis and bowel obstruction, necessitating surgical intervention with high recurrence rates. To elucidate to the mechanisms underlying fibro-stenosis in CD, we analysed the transcriptome of cells isolated from the transmural ileum of CD patients, including a trio of lesions from each patient: non-affected, inflamed, and stenotic ileum samples, and compared them with samples from non-CD patients. Our computational analysis revealed that pro-fibrotic signals from a subset of monocyte-derived cells induced a disease-specific fibroblast population, resulting in chronic inflammation and tissue fibrosis. Our findings suggest that the myeloid-stromal axis may offer a promising therapeutic target to prevent fibro-stenosis in CD.

Study EGAS50000000382

AYA glioma NGS

Gliomas are a major cause of cancer-related death in adolescents and young adults (AYA, ages 15-39 years). Different molecular alterations drive gliomas in children and adults leading to distinct biology and clinical consequences. At the convergence of these age groups - the AYA population – little is known about the implications of pediatric vs adult-type alterations. To address this, we analyzed a population-based cohort of 1456 clinically and molecularly characterized gliomas aged 0-39 years. Potentially targetable pediatric-type alterations were found in 31% of AYA gliomas and conferred superior outcomes compared to adult-type alterations. This submission includes the generated NGS data for children, adolescent, and young adults with gliomas. Data includes targeted panel of glioma genes and low-pass WGS (1x coverage).

Study EGAS50000000383

Whole Exome Sequencing in Multiple Myeloma

By whole exome sequencing (WES) our group observed the accumulation of mutations in receptor tyrosine kinases (RTKs), adhesion molecules and their effectors and developed a signaling network that was affected by at least one mutation in almost 100% of MM patients and by more than one mutation in around 50% of MM patients which we decided to call inter- and intra-individual pathway redundancy. Interestingly, the extension of our WES dataset to 67 primary MM samples with correspond normal tissue which were collected at the Medizinische Klinik and Poliklinik II in Würzburg within the frame of the CRU216 has tentatively led to the designation of three molecular subgroups based on their mutation profile: "adhesion only", "adhesion & downstream" and "RTK & adhesion & downstream

Study EGAS00001003227

Exome sequencing of 1000 population control samples from the UK 1958 birth cohort

Exome sequencing from 1,000 UK population samples (the ICR1000 Exome series), using samples from the 1958 Birth Cohort Collection, a population-based collection of all individuals born in the UK in one week in 1958 (http://www.cls.ioe.ac.uk). DNA libraries were prepared from genomic DNA using the Illumina TruSeq sample preparation kit. DNA was fragmented using Covaris technology and the libraries were prepared without gel size selection. Target enrichment was performed in pools of six libraries using the Illumina TruSeq Exome Enrichment kit. The captured DNA libraries were PCR amplified using the supplied paired-end PCR primers. Sequencing was performed with an Illumina HiSeq2000 (v3 flow cell, one pool per lane) generating 2x100-bp reads.

Study EGAS00001000971

Pervasive H3K27 acetylation and ERV expression in H3.3K27M gliomas present a therapeutic vulnerability

High-grade gliomas (HGG) defined by histone 3 K27M driver mutations exhibit global loss of H3K27 trimethylation and reciprocal gain of H3K27 acetylation, respectively shaping repressive and active chromatin landscapes. We generated tumor-derived isogenic models bearing this mutation and show that it leads to pervasive H3K27ac deposition across the genome. In turn, active enhancers and promoters are not created de novo and instead reflect the epigenomic landscape of the cell of origin. H3K27ac is enriched at repeat elements, resulting in their increased expression, which in turn can be further amplified by DNA demethylation and histone deacetylase inhibitors providing an exquisite therapeutic vulnerability. These agents may therefore modulate anti-tumor immune responses as a therapeutic modality for this untreatable disease.

Study EGAS00001003572

Pilot_experiment_on_functional_genomics_in_osteoarthritis_RNA

The aim of this work is to apply an integrated systems approach to understand the biological underpinnings of large joint (hip and knee) osteoarthritis which culminates in the need for total joint replacement (TJR). In this pilot we will assess the feasibility of the approach in the relevant tissue. We will obtain diseased and non-diseased tissue (cartilage and endochondral bone) following TJR, coupled with a blood sample, from 12 patients. We will characterise the 12 pairs of diseased and non-diseased tissue samples in terms of transcription (RNASeq) The pilot will help assess the feasibility of isolating sufficient levels of starting material for the different approaches, and will instigate the development of analytical approaches to synthesising the resulting data.

Study EGAS00001001203

TRAIP promotes DNA damage response during genome replication and is mutated in primordial dwarfism

DNA lesions encountered by replicative polymerases threaten genome stability and cell cycle progression. Here we report the identification of mutations in TRAIP, encoding an E3 RING ubiquitin ligase, in patients with microcephalic primordial dwarfism/Seckel syndrome. We establish that TRAIP relocalizes to sites of DNA damage where it is required for optimal phosphorylation of H2AX and RPA2 during S-phase in response to UV irradiation, as well as fork progression through UV-induced DNA lesions. TRAIP is necessary for efficient cell cycle progression and mutations in TRAIP therefore limit cellular proliferation, providing a potential mechanism for microcephaly and dwarfism phenotypes. Human genetics thus identifies TRAIP as a novel component of the DNA damage response to replication-blocking DNA lesions.

Study EGAS00001001501

PCa-LINES

PCa-LINES: Ribo-minus RNA-seq of 4 patient samples and 2 PCa cell lines ---- Detection of fusion transcripts and their genomic breakpoints from RNA sequencing data Youri Hoogstrate, Malgorzata A. Komor, René Böttcher, Job van Riet, Harmen J. G. van de Werken, Stef van Lieshout, Ralf Hoffmann, Evert van den Broek, Anne S. Bolijn, Natasja Dits, Daoud Sie, David van der Meer, Floor Pepers, Chris H. Bangma, Geert J. L. H. van Leenders, Marcel Smid, Pim French, John W.M. Martens, Wilbert van Workum, Peter J. van der Spek, Bart Janssen, Eric Caldenhoven, Christian Rausch, Mark de Jong, Andrew P. Stubbs, Gerrit A. Meijer, Remond J.A. Fijneman, Guido Jenster bioRxiv 2021.05.17.441778; doi: https://doi.org/10.1101/2021.05.17.441778 https://www.biorxiv.org/content/10.1101/2021.05.17.441778v1

Study EGAS00001004613

16 Year Life History and Genomic Evolution of an ER+ HER2- Breast Cancer

We reconstructed the genomic evolution through the sixteen year history of an ER+ HER2- breast cancer patient to investigate molecular mechanisms of disease relapse and treatment resistance after long term exposure to hormonal therapy. Genomic and transcriptomic profiling was performed on primary breast tumor (2002), initial recurrence (2012) and liver metastasis (2015) tumor samples. Cell free DNA analysis was performed at eleven timepoints (2015-2017).This phylogenetic reconstruction of the life history of a single patient's cancer as well as monitoring tumor progression through liquid biopsies with the detection of a resistant clone harboring a de-novo ESR1 E380Q mutation allowed for uncovering the molecular mechanisms leading to initial relapse, metastatic spread and treatment resistance.

Study EGAS00001004624

Aberrant ERBB4-SRC Signaling as a Hallmark of Group 4 Medulloblastoma Revealed by Integrative Phosphoproteomic Profiling

The four main medulloblastoma subgroups are characterized by distinct biology, clinicopathological features and clinical outcomes. While the WNT and SHH subgroups are characterized by clearly defined aberrant signaling of developmental pathways, the underlying biology of Group 3 and 4 remains poorly understood. Here, we delineate distinct post-translational regulation orchestrating active oncogenic signaling networks in Groups 3 and 4. Specifically, aberrant ERBB4-SRC signaling constitutes a novel hallmark feature of Group 4, with great promise as a novel oncogenic mechanism and potential vulnerability for therapeutic intervention in the most common subgroup. Altogether, this novel integrative proteogenomic landscape demonstrates the added value of proteomics and phosphoproteomics analysis to discover and exploit unexpected oncogenic mechanisms in medulloblastoma and beyond.

Study EGAS00001002757

Neuroblastoma tumor heterogeneity and cell plasticity (from patients)

Two cell identities, noradrenergic and mesenchymal, have been characterized in neuroblastoma cell lines according to their epigenetic landscapes relying on specific core regulatory circuitries of transcription factors. Yet, their relationship and relative contribution in patient tumors remain to be defined. Here, we document a spontaneous plasticity between the noradrenergic and mesenchymal identities in a subset of cell lines. Strikingly, mesenchymal neuroblastoma cells revert to a noradrenergic phenotype in vivo. Consistently, tumor cells with a mesenchymal identity are detected in single-cell transcriptomic analyses of neuroblastoma tumors and PDX models. Our data also highlight neuroblastoma intra-tumor heterogeneity with the co-existence of distinct tumor populations, including sympathoblast-like and chromaffin-like cells suggesting that neuroblastoma cells arise from a common sympatho-adrenal progenitor.

Study EGAS00001005322

Genome Asia 100K Project

The underrepresentation of non-European individuals in human genetic studies so far has limited the diversity of individuals in genomic datasets and led to reduced medical relevance for a large proportion of the world’s population. Population-specific reference genome datasets as well as genome-wide association studies in diverse populations are needed to address this issue. Here we describe the pilot phase of the GenomeAsia 100K Project. This includes a whole-genome sequencing reference dataset from 1,739 individuals of 219 population groups and 64 countries across Asia. We catalogue genetic variation, population structure, disease associations and founder effects. We also explore the use of this dataset in imputation, to facilitate genetic studies in populations across Asia and worldwide.

Study EGAS00001002921

Mitochondrial DNA sequencing of iPSC, parental cells, and iPSC derived cardiomyocytes

The aim of this work was to analyze to which extent mitochondrial DNA (mtDNA) variants in human induced pluripotent stem cells (iPSC) originate from their parental cells or from de novo mutagenesis, and whether dynamics in variant heteroplasmy levels during prolonged expansion culture of iPSC are caused by inter- or intra-cellular selection or genetic drift. Hence, mtDNA of 26 early passage iPSC clones from, in total, 10 donors and the corresponding parental cell populations (here endothelial cells) were sequenced. Furthermore, 7 iPSC clones were expanded up to passage 50 and the change in variant heteroplasmy levels was monitored. Lastly, the effect of differentiation on the variant heteroplasmy levels was investigated during directed cardiomyocyte differentiation of 4 iPSC clones.

Study EGAS00001005560

WGS_of_healhy_mesothelial_cells_and_primary_mesothelima_cell_lines

Mesothelioma is a rare and aggressive cancer associated with previous exposure to asbestos. Currently there are no effective treatments for mesothelioma and majority of patients will die within a year after diagnosis. Although a large number of preclinical and clinical trials assessed the efficacy of various therapuetic modes, none of the tested molecules entered the clinic. Thus, to better understand what drives mesothelioma carcinogenesis and to identify novel targets for therapy, here we aim at performing WGS of heathy mesothelial cells and a panel of mesothelioma cells lines. Primary mesothelial cell lines were established in prof. Marciniak lab from human pleural specimens, while primary mesothelioma cell lines were obtained from MesobanK. Both models constitute low passage cell lines and therefore should closely represent genetics of the original tissue.

Study EGAS00001005559

Heterogeneous metabolic signatures are linked to cancer cell differentiation in colorectal cancer

Colorectal cancer (CRC) is characterized by functional intratumor heterogeneity that shares many similarites with the hierarchical organization of the normal intestinal epithelium. In order to relate transcriptional subtypes to functional tumor cell heterogeneity we applied scRNA-seq to 12 patient-derived CRC spheroid cultures. We identified shared expression programs that relate to intestinal lineages and revealed metabolic signatures that are linked to cancer cell differentiation. In addition, we validated and complemented sequencing results by quantitative microscopy using live-dyes and multiplexed RNA fluorescence in situ hybridization, thereby revealing metabolic compartmentalization and potential cell-cell interactions. FInally, we demonstrate functional differences between metabolically distinct lineage subtypes that might have strong implications for future treatment strategies of CRC.

Study EGAS00001004064

Targeted deep sequencing on Pediatric MDS

Targeted NGS using custom panels with SAMD9, SAMD9L genes and 22 single nucleotide polymorphisms (SNP) on chromosome 7q (allele frequency >35% in all ethnic sub-populations in gnomAD) (Ampliseq #IAD10417) was performed in 667/669 cases. Additionally, 559 cases were sequenced using 28 pediatric MDS genes (GATA2, RUNX1, HOXA9, CEBPA, GATA1, KRAS, NRAS, CBL, PTPN11, ASXL1, EZH2, SETBP1, FLT3, KIT, JAK2, JAK3, CSF3R, MPL, SH2, BCOR, BCORL1; RAD21, STAG2, CTCF, TP53, PTEN, CALR, VPS45; Ampliseq #IAD51150). Libraries for targeted NGS were prepared using NEBNext Ultra II DNA library prep kit (New England BioLabs, cat#E7645S/L) per manufacturer’s instruction and samples were sequenced on an Illumina Miseq 2000 with 2 x 150 bp reads. The BAM files are uploaded here.

Study EGAS00001005431

scRNA-seq of patient-derived PDAC organoids

We derived PDAC organoids from primary tumors of 18 patients, together with two matched samples from liver metastases. By single-cell RNA sequencing, we show that PDAC organoids consist of ductal cells with patient-specific expression of several gene groups, including genes which encode cell surface proteins. We report ‘classical’ and ‘basal-like’ cells coexisting within single primary tumors or metastases, with greater intratumor subtype heterogeneity linked to higher tumor grade. Single-cell transcriptome analysis of PDAC organoids and primary PDAC identified distinct tumor cell states shared across patients, including a cycling progenitor cell state and a differentiated secretory state. We show that these cell states are connected by a differentiation hierarchy, with ‘classical’ subtype cells concentrated at the endpoint of this hierarchy.

Study EGAS00001004661

STAT5 is a therapeutically targetable vulnerability in cutaneous T-cell lymphoma

Cutaneous T-cell lymphomas represent a heterogeneous group of lymphoproliferative disorders characterized by the infiltration and expansion of mature malignant T-cells into the skin. The disease encompasses distinct variants such as mycosis fungoides a skin resident variant, in which the malignant cells are restricted to skin lesions, and leukemic variant sézary syndrome characterized by circulating malignant T-cells. Here we integrated shallow whole genome sequencing and whole exome sequencing, on samples from four sézary syndrome patients and two advanced mycosis fungoides patients with blood involvement, to characterize genetic alterations and assess their therapeutic actionability. We identified an elevated copy number of 17q, resulting in increased STAT5 expression and activation, as a key factor in the pathophysiology of the disease.

Study EGAS00001004719

The transcriptomic response of skeletal muscle in life-long high-level trained and untrained men and women after acute exercise

To investigate the influence of lifelong exercise training on the response of skeletal muscle to a bout of acute exercise we generated global transcriptomic data from long-term endurance (8 men, 8 women) and strength (8 men, 8 women) trained individuals and healthy age-matched untrained controls (8 men, 8 women). Skeletal muscle biopsies were taken from M. vastus lateralis before, directly after, and after 1h and 3hrs following acute exercise. All subjects completed one bout of acute endurance exercise and one bout of acute resistance exercise, separated by 4-8 weeks. All 384 samples were multiplexed in 4 lanes and sequenced (2x250bp paired end) on the Illumina NovaSeq 6000.

Study EGAS00001006139

Clonal dominance defines metastatic dissemination in pancreatic cancer

Using patient-derived cells from a pancreatic ductal adenocarcinoma, we created orthotopic clonal replica tumors to trace in an unbiased fashion clonal lineage dynamics of unperturbed tumor expansion and dissemination over time. The model revealed the complex multifaced nature of tumor clonal expansion and uncovered brisk changes in fitness that lead to a continuous reshuffling of tumor clonal architecture and alternating clonal dominance as a distinct feature of cancer growth. Paired analysis of clonal lineages in primary and secondary sites revealed fitness in the primary tumor as a major contributor to dissemination, although other clonal intrinsic and extrinsic factors may contribute to metastatic process. Molecular characterization of lineages with differential metastatic potential identified actionable strategy to suppress dissemination at the subclonal level.

Study EGAS00001006358

Genetic Alterations in Benign Breast Biopsies of Subsequent Breast Cancer Patients

Fibrocystic changes are associated with an increased risk of breast cancer (approximately 1.5-2 times that of the general population). Although the relative risk seems low, because of the high frequency of such changes, the absolute risk is significant. Genetic alterations have been found in fibrocystic changes with or without epithelial changes, suggesting that critical oncogenic events are occurring at an early stage. We investigated a unique collective of 17 breast cancer patients who, prior to the diagnosis of invasive breast cancer, underwent open surgical biopsy showing fibrocystic changes of the breast. Massive parallel sequencing targeting genes frequently mutated in breast cancer was performed on the fibrocystic breast tissue as well as the ensuing cancer tissue.

Study EGAS00001003563

Effect of 28-day administration of Urolithin A to sedentary elderly on muscle gene expression

Urolithin A (UA) is a natural dietary, microflora derived, metabolite shown to stimulate mitophagy and improve muscle health in old animals and pre-clinical models of aging. UA was administered for 28-day in a first-in-human clinical trial to sedentary elderly subjects. Muscle biopsies were collected before the first dosing, and at the end of the 28-day period, under fasted conditions. Gene expression was measured by microarray. Gene-set enrichment analysis of the gene expression data showed that UA increased the transcription of mitochondrial related genesets. These observed effects on mitochondrial biomarkers show that UA induces a molecular signature of improved mitochondrial and cellular health following regular oral consumption in humans.

Study EGAS00001003638

Reconstruction of the personal information from human genome reads in gut metagenome sequencing data

Human DNA present in fecal samples can result in a small number of human reads in gut shotgun metagenomic sequencing data. However, it is currently unclear how much personal information can be reconstructed from such reads and this has not been quantitatively evaluated. Such a quantitative evaluation is necessary to clarify the ethical concerns related to data sharing and to enable the efficient use of human genetic information in stool samples, such as for research and forensics. Here, we used genomic approaches to reconstruct personal information from fecal metagenomes of 343 Japanese individuals with associated human genotype data. Our approach can be used to quantify the personal information contained within gut metagenome data.

Study EGAS00001007027

A PROSTATE TUMORGRAFT PANEL TO ACCELERATE PRECISION MEDICINE

The management of advanced prostate cancer (PCa) has strongly evolved in the last decade with the introduction of the next generation of androgen receptor pathway inhibitors which have considerably improved patient outcomes. Most recently, the investigation of genomic landscape has provided targetable molecular alterations such as homologous gene DNA repair defects correlated with response to PARP inhibitors. Despite these significant advances, while localized PCa is generally associated with favorable outcome, metastatic PCa is currently considered incurable. For further investigations in precision treatment, the development of preclinical models representing the complex prostate tumor heterogeneity are mandatory. Accordingly, we aimed to establish a resource of patient-derived xenograft (PDX) models that exemplify each phase of this multistage disease for accurate and rapid evaluation of candidate therapies.

Study EGAS00001007033

RNA sequencing on intestinal biopsies from inflammatory bowel disease patients treated with vehicle control, MEK inhibitor, or infliximab

By investigating an intergenic haplotype on chr21q22, independently linked to inflammatory bowel disease (IBD), ankylosing spondylitis, primary sclerosing cholangitis and Takayasu’s arteritis, we discover that the causal gene, ETS2, is a master regulator of inflammatory responses in human macrophages and delineate how the risk haplotype increases ETS2 expression. Using a database of cellular signatures, we identified drugs that could modulate this pathway. To validate the anti-inflammatory activity of one class of small molecules ex vivo, we obtained biopsies from patients with active IBD and cultured these biopsies with a selective, non-ATP competitive MEK inhibitor (PD-0325901), infliximab (positive control), or DMSO (vehicle control) for 18 hours, then performed RNA sequencing.

Study EGAS00001007534

13306 results for ""pdc"+"heritage+language"+census+study"

in 32.01 milliseconds.