690 results for ""PhD+2001"+"Professor+of+Bioinformatics"+2012+18000+citations+profile"

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• A Clinical Trial of Pembrolizumab in Patients with Hepatitis B Virus-related Hepatocellular Carcinoma, with Parallel Study on Baseline and Serial Change in the Immune Environment

  This is a single-arm Phase II trial of pembrolizumab in patients with hepatitis B virus-related hepatocellular carcinoma with parallel study on baseline and serial change in the immune environment. Subjects should have a confirmed diagnosis of HCC (in accordance with the AASLD guideline) and confirmed chronic infection with hepatitis B virus as defined by positivity for HBsAg. Antiviral therapy for HBV must be given for at least 12 weeks and HBV viral load must be less than 100 IU/mL prior to first dose of study drug. They must have disease not amenable to a curative treatment approach or loco-ablation. Subject must be fit and agreeable with baseline and post-treatment biopsy of tumor. Subjects must have at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, an Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1 and adequate organ functions. 30 subjects will be enrolled to receive pembrolizumab 200 mg IV every 3 weeks(Q3W). Pre-treatment and on-treatment biopsy after 2 cycles of Pembrolizumab will be preformed. Treatment will be stopped when progression of disease or intolerable toxicity occurs. The primary objectives of this trial are to study the efficacy and safety of pembrolizumab in patients with HBV-related HCC and to study the serial change in RNA expression of immune-related gene panel in post-treatment biopsy tissue. The secondary objectives of this trial are to study the serial change in cytokine profile between pre-treatment and post-treatment samples, to study the PD-L1 immunohistochemical (IHC) expression in tumor sample at baseline and post-treatment tissue samples and to study the presence of tumor infiltrating lymphocytes in the baseline and post-treatment tumor samples. The exploratory objective of this trial is to evaluate the possibility of using baseline and the serial change in RNA expression of immune-related gene panel or PD-L1/2 IHC to predict treatment response.

  Dataset EGAD50000001872

• The cellular immune and airway epithelial profile throughout childhood and in response to COVID-19 at multi-omic single cell level.

  Single-cell data gene expression data set (5’Chromium 10X) of healthy paediatric volunteers, and paediatric and adult COVID-19 patients. Gene expression was determined from samples of nasal, tracheal and bronchial brushings and blood (PBMCs). In addition to gene expression, PBMC’s were assayed by CITE-seq. A subset of samples have VDJ sequencing data for T cell receptors (TCR) and B cell receptors (BCR).

  Dataset EGAD00001007718

• RNA-sequencing of human skin samples obtained from SSc patients and healthy controls.

  Patient information SSc patients were recruited at the Department of Rheumatology of the Leiden University Medical Center (Leiden, The Netherlands). All patients met the American Rheumatism Association classification criteria for SSc (Subcommittee for scleroderma criteria 1980), and were classified according to LeRoy and Medsger criteria as either limited or diffuse cutaneous disease (LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger TA Jr, Rowell N 1988). Institutional review board approval and written informed consent was obtained before patients entered this study. Two 4 mm skin biopsies were taken from a standardized location on the most proximal part of the lower arm, distal from the elbow. In 10 patients the skin biopsy came from a clinically affected area and in 4 patients the skin was locally unaffected. One sample was used for RNA sequencing and one sample was used for immunohistochemistry. Skin biopsies from healthy individuals were commercially sourced (Tissue Solutions, UK) and collected from donors undergoing skin resection surgery and after informed consent. To match the healthy skin with patients as much as possible, skin biopsies from healthy controls were also taken from a similar position (the under-arm (for 4 controls) and leg (for 2 controls)). Healthy skin donors were selected to match the age and sex of the SSc patient cohort. Biopsies from patients and controls were equally treated and were both stored at -80°C until RNA isolation was performed. RNA from frozen skin biopsies was isolated using RNeasy kit from fibrous tissue (Qiagen, the Netherlands). RNA quantity was determined by using SimplyNano 2000 and quality was assessed on Tapestation (Agilent, the Netherlands). All samples included in the study had a RIN score above 7.0. Transcriptome characterisation and analysis RNA sequencing was performed using polyA selection and a stranded protocol using Ion Torrent next generation sequencing technology (Service XS, The Netherlands). The Ion PI Template OT2 200 Kit v3 and Ion PI Sequencing 200 Kit v3 were used according to the manufacturer’s instructions. 20 samples were run on 11 PI chips. PI chip analyses, base calling and quality checks were performed using the Torrent Server Suite. An average of 42 million 100 bp reads was generated per sample. Following quality control, reads were aligned to the human genome (Homo sapiens GRh38.78) using Bowtie2 and STAR (Dobin et al. 2013; Langmead and Salzberg 2012). Reads were first aligned with STAR. For the unmapped reads from STAR, a second alignment step was performed using bowtie2 (local very sensitive options)

  Dataset EGAD00001003832

• Environmental Influences on Child Health Outcomes (ECHO) - PATHWAYS - Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE)

  Pregnant women are exposed daily to multiple chemical and non-chemical stressors, including air pollutants, phthalates, and psychosocial stress. The Developmental Origins of Health and Disease model (DOHaD) states that exposure to these stressors in pregnancy affects fetal development in a manner that impacts offspring health across the life course. Yet epidemiologic data in these areas is limited, particularly with U.S. samples. It is also poorly understood whether these exposures prenatally affect childhood neurodevelopment and airway health in an independent or combined manner, and likely moderators of effects, such as the sex of the child, are infrequently addressed. We propose to unify three diverse extant pregnancy cohorts: TIDES (N=717, 2010-12), GAPPS (N=1133, 2012-16), and CANDLE (N=1385, 2007-11), for a combined sample size of 3235 mother-child dyads in the PATHWAYS study. PATHWAYS will investigate how chemical (air pollutants and phthalates) and non-chemical (psychosocial stress) exposures during pregnancy are related to placental gene expression (transcriptome) and childhood neurodevelopment and airway health (at ages 4-6, 8-9, and 10-11 years). Each cohort has rich resources of prenatal data and banked specimens (urine, blood, and placenta) that will be harmonized for the PATHWAYS study and will contribute to the ECHO consortium. We will develop a national model with high spatiotemporal resolution of key air pollutants and assess urinary markers of maternal exposure. A composite measure will capture multilevel maternal psychosocial stress across pregnancy, and urinary phthalate and blood stress hormone [Corticotropin-releasing hormone (CRH)] levels in the second and third trimesters will provide individual assessment of those exposures in potential critical periods. We will characterize the placental transcriptome using RNA sequencing (RNA-Seq) and will assess neurodevelopment and airway health prospectively into middle childhood. PATHWAYS will examine how these prenatal exposures are related to the placental transcriptome and child health outcomes in main effect and interactive models, with emphasis on sex-specific associations. For both neurodevelopment and airway health, we propose to measure both phenotypic precursors of health outcomes (i.e. fluid cognition, lung function growth), which yield dimensional tests of proposed associations, as well as clinically meaningful and policy relevant outcomes (i.e. asthma, mental health). Our study is powered to assess interactive effects of chemical and non-chemical stressors and will be the first study to characterize how prenatal environmental exposures relate to placental transcriptome pathways in relation to childhood health outcomes. This represents a significant scientific advance in testing DOHaD hypotheses. Major contributions to the ECHO Consortium include: 1) the development of a state of the art national model of air pollution, 2) a large, diverse pregnancy cohort with extensive biorepositories and extant prenatal and postnatal biomarkers, placental transcriptome, psychosocial and environmental data, and 3) an experienced, interdisciplinary team that will contribute meaningfully to the ECHO program of work.The sequencing data in this submission pertains only to the 794 subjects from the CANDLE study for whom placental tissue transcriptomics was performed.

  Study phs003619

• Environmental Influences on Child Health Outcomes (ECHO) - PATHWAYS - Global Alliance to Prevent Prematurity and Stillbirth (GAPPS)

  Pregnant women are exposed daily to multiple chemical and non-chemical stressors, including air pollutants, phthalates, and psychosocial stress. The Developmental Origins of Health and Disease model (DOHaD) states that exposure to these stressors in pregnancy affects fetal development in a manner that impacts offspring health across the life course. Yet epidemiologic data in these areas is limited, particularly with U.S. samples. It is also poorly understood whether these exposures prenatally affect childhood neurodevelopment and airway health in an independent or combined manner, and likely moderators of effects, such as the sex of the child, are infrequently addressed. We propose to unify three diverse extant pregnancy cohorts: TIDES (N=717, 2010-12), GAPPS (N=1133, 2012-16), and CANDLE (N=1385, 2007-11), for a combined sample size of 3235 mother-child dyads in the PATHWAYS study. PATHWAYS will investigate how chemical (air pollutants and phthalates) and non-chemical (psychosocial stress) exposures during pregnancy are related to placental gene expression (transcriptome) and childhood neurodevelopment and airway health (at ages 4-6, 8-9, and 10-11 years). Each cohort has rich resources of prenatal data and banked specimens (urine, blood, and placenta) that will be harmonized for the PATHWAYS study and will contribute to the ECHO consortium. We will develop a national model with high spatiotemporal resolution of key air pollutants and assess urinary markers of maternal exposure. A composite measure will capture multilevel maternal psychosocial stress across pregnancy, and urinary phthalate and blood stress hormone [Corticotropin-Releasing Hormone (CRH)] levels in the second and third trimesters will provide individual assessment of those exposures in potential critical periods. We will characterize the placental transcriptome using RNA sequencing (RNA-Seq) and will assess neurodevelopment and airway health prospectively into middle childhood. PATHWAYS will examine how these prenatal exposures are related to the placental transcriptome and child health outcomes in main effect and interactive models, with emphasis on sex-specific associations. For both neurodevelopment and airway health, we propose to measure both phenotypic precursors of health outcomes (i.e., fluid cognition, lung function growth), which yield dimensional tests of proposed associations, as well as clinically meaningful and policy relevant outcomes (i.e., asthma, mental health). Our study is powered to assess interactive effects of chemical and non-chemical stressors and will be the first study to characterize how prenatal environmental exposures relate to placental transcriptome pathways in relation to childhood health outcomes. This represents a significant scientific advance in testing DOHaD hypotheses. Major contributions to the ECHO Consortium include: 1) the development of a state of the art national model of air pollution, 2) a large, diverse pregnancy cohort with extensive biorepositories and extant prenatal and postnatal biomarkers, placental transcriptome, psychosocial and environmental data, and 3) an experienced, interdisciplinary team that will contribute meaningfully to the ECHO program of work.The sequencing data in this submission pertain only to the 408 subjects from the GAPPS study for whom placental tissue transcriptomics was performed.

  Study phs003620

• DNA methylomes of monozygotic twins clinically discordant for multiple sclerosis

  Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Although genetic susceptibility is important, a modest concordance rate for MS in monozygotic (MZ) twins suggests that interaction with other risk factors is required to develop clinical symptoms. In this study, we examined whether DNA methylation differences contribute to the discordant clinical manifestation of MS in MZ twins, and studied the impact of MS treatments on the DNA methylome. Genome-wide DNA methylation profiles of peripheral blood mononuclear cells (PBMCs) of 45 MZ twins clinically discordant for MS were generated using the Illumina HumanMethylationEPIC array. Repetitive element methylation and selected differentially methylated positions (DMPs) were validated using targeted deep bisulfite sequencing (TDBS). In addition, we performed whole genome bisulfite sequencing (WGBS) to profile CD4+ memory T-cells of a subset of four MS discordant MZ twins. Our results show that interferon treatment causes robust DNA methylation changes and several epigenetic biomarkers for interferon treatment response were identified. However, overall the PBMC-based methylomes of the MS discordant MZ twins were highly similar, since large systematic methylation differences (>5%) were absent in the data. This suggests that previously reported large methylation changes are probably caused by genetic rather than epigenetic differences. In addition, our data does not support the hypothesis that the observed maternal parent-of-origin effect in MS is due to genomic imprinting errors, and no evidence was found that copy number variations explain the discordant phenotype in these MZ twins. Although not genome-wide significant, a couple of DMPs associated with the MS phenotype were identified and successfully technically replicated using TDBS, including a differentially methylated region (DMR) in the promoter of the transmembrane protein encoding gene TMEM232. Another MS-associated DMP, located in an enhancer in the gene body of the transcription factor ZBTB16, was also associated with medium-term glucocorticoid treatment history. WGBS analysis confirmed this DMP as a promising epigenetic biomarker for glucocorticoid treatment. In conclusion, this epigenome-wide association study (EWAS) in genetically identical twins identified a DMR in the TMEM232 promoter as a candidate loci associated with the clinical manifestation of MS. In addition, epigenetic biomarkers for MS treatments were identified, revealing that not only short-term, but also medium-term treatment effects are detectable in immune cells, which should be taken into account in future EWAS designs.

  Study EGAS00001003147

• The subclonal architecture of metastatic breast cancer: Results from a prospective community-based rapid autopsy program 'CASCADE'

  Background: Understanding the cancer genome is seen as a key step in improving outcomes for cancer patients. Genomic assays are emerging as a possible avenue to personalised medicine in breast cancer. The majority of work in this area has targeted primary tumours however, and very few studies have performed comprehensive profiling of advanced disease. Evolution of the cancer genome during the natural history of breast cancer is largely unknown, as is the profile of disease at death. We sought to study in detail these aspects of advanced breast cancers that have resulted in lethal disease. Methods and Findings: Three patients with ER-positive, HER2-negative breast cancer and one patient with triple negative breast cancer underwent rapid autopsy as part of an institutional prospective community-based rapid autopsy program. Cases represented a range of management problems in breast cancer, including late relapse after early stage disease; de novo metastatic disease; discordant disease response and disease refractory to treatment. Between 5 and 12 metastatic sites were collected at autopsy together with available primary tumours and longitudinal metastatic biopsies taken during life. Samples underwent paired tumour-normal whole exome sequencing and single nucleotide polymorphism arrays. Subclonal architectures were inferred by jointly analysing all samples from each patient. Mutations were validated using high depth amplicon sequencing.Between cases, there were significant differences in mutational burden, driver mutations, mutational processes and copy number variation. Within each case, we found dramatic heterogeneity in subclonal structure from primary to metastatic disease and between metastatic sites, such that no single lesion captured the breadth of disease. Metastatic cross seeding was found in each case and treatment drove subclonal diversification. Subclones displayed parallel evolution of treatment resistance in some cases, and apparent augmentation of key oncogenic drivers as an alternative resistance mechanism. We also observed the key role of mutational processes in subclonal evolution.Limitations of this study include the potential for bias introduced by joint analysis of formalin fixed archival specimens with fresh specimens, and the difficulties in resolving subclones with whole exome sequencing. Other alterations that could define subclones such as structural variants or epigenetic modifications were not assessed. Conclusions: This study highlights the variety of mechanisms that shape the genome of metastatic breast cancer, and the value of studying advanced disease in detail. Treatment drives significant genomic heterogeneity in breast cancers which has implications for disease monitoring and treatment selection in the personalised medicine paradigm.

  Study EGAS00001002153

• Environmental Arsenic and Diabetes Mellitus (Chihuahua Cohort)

  The Chihuahua Cohort was established as part of a larger NIEHS-funded project that used laboratory models (tissue culture and mice) and human subjects to examine the association between exposure to arsenic and diabetes, including identification of mechanisms underlying this association. All procedures involving human subjects were approved by institutional review boards at the University of North Carolina at Chapel Hill and Cinvestav-IPN (Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico City, Mexico). All participants provided signed informed consent. A total of 1,160 adults (≥ 18 years old) with a minimum 5-year uninterrupted residency in the Chihuahua study area were recruited between 2008 and 2012. Samples of drinking water were obtained from the participants' households. Data on residency, occupation, drinking-water sources and use, smoking, alcohol consumption, and medical history were recorded by a study questionnaire. Spot urine and fasting venous blood were collected during medical examination that included an oral glucose tolerance test (OGTT) with blood drawn 2 hr after a 75-g glucose dose. Plasma from both fasting and 2-hr blood samples was collected. Body mass index (BMI) of each participant was calculated from body weight and height. BMI cutoffs of ≥ 25.0, ≥ 30, and < 18.5 kg/m2 were used to define overweight, obese, and underweight individuals, respectively. Participants' waist circumference was also measured. Blood pressure was assessed using a manual sphygmomanometer. Three measurements were taken at intervals of at least 1 min, with a 5-min rest before obtaining the first reading; the mean of the last two measurements was used. The concentrations of arsenic in drinking water and arsenic species in urine were measured by hydride generation-atomic absorption spectrometry. The limit of detection for As in water as well as for As species in urine was 0.01 µg As/L. Creatinine concentration in urine was determined using an established colorimetric assay. DNA was isolated from blood for genotyping analysis.The following measures were taken: glucose concentration in fasting blood (FBG) and in blood collected 2 hours into OGTT (2HBG); concentrations of triglycerides, HDL and total cholesterol (TC) in fasting plasma; and LDL was calculated using the Friedewald equation. Diabetes was classified by FPG ≥ 126 mg/dL, 2HPG ≥ 200 mg/dL, or self-reported diabetes diagnosis or medication use (WHO/International Diabetes Federation 2006). Prediabetes was defined as the absence of diabetes with FPG ≥ 110 mg/ dL or 2HPG ≥ 140 mg/dL. Elevated fasting levels of each lipid were defined as plasma TG ≥ 150 mg/dL, TC ≥ 200 mg/dL, and LDL ≥ 130 mg/dL. Fasting HDL < 40 mg/dL in men and < 50 mg/dL in women were designated as low. Hypertension was defined by systolic blood pressure (SBP) > 140 mm Hg, diastolic blood pressure (DBP) > 90 mmHg, or self-reported use of anti-hypertensive medication. Genotyping analysis, which will be available in version 2 of this study, was carried out in a subset of ~600 subjects with focus on enzymes involved in the metabolism of arsenic, including AS3MT, GSTs.All data collected during the medical exams or generated by the above-described chemical and biochemical analysis of water, urine and blood/plasma, as well as results of the genotyping analysis are included in dbGaP. Data generated by metabolomics and epigenetic analyses in small subsets of the Chihuahua cohort are not included, but are available in published articles.

  Study phs002139

• Disease Variant Landscape of a Large Multiethnic Population of Moyamoya Patients by Exome Sequencing

  We report a significant advance in Moyamoya disease (MMD) research through our unique access to a large MMD patient population combined with high depth exome sequencing and bioinformatics. We confirm a reported RNF213 founder mutation (FM), provide evidence for its ethnic specificity and identify novel variants in other genes that associate with Caucasian and non-RNF213 FM MMD. This work has a broader impact in vascular research by highlighting novel genetic aspects of cerebrovascular disease. Moyamoya Disease (MMD) is a rare cerebrovascular disorder characterized by unilateral or bilateral progressive stenosis or occlusion of the internal carotid artery, with frequent involvement of the anterior cerebral artery and the middle cerebral artery (MCA). Fragile collateral vessels subsequently develop and are particularly prone to hemorrhage. MMD patients are usually diagnosed angiographically following presentation of developmental delays, seizures, migraines, ischemia, and/or hemorrhage. The most common approach to re-establish normal blood flow is bypass surgery. While some progress has been made in identifying disease-associated genes, the underlying disease biology is not well understood. Moyamoya disease (MMD) is a rare cerebrovascular disease. Our unique access to a large MMD patient population combined with high depth exome sequencing and bioinformatics has led to a significant advance in the field. We confirm a reported RNF213 founder mutation (FM), provide evidence for its ethnic specificity and identify novel variants in other genes that associate with Caucasian and non-RNF213 FM MMD. This work has a broader impact in vascular research by highlighting novel genetic aspects of cerebrovascular disease. The 125 ethnically diverse, unrelated MMD patients were matched based on sex and broad ethnic category to 125 controls. Control DNA from the 1000 Genomes project was used to design a control Library by Personalis. 125 controls were selected from this Personalis Control DNA Library for our study. (The 1000 Genomes Project Consortium 2012). Genomic DNA was extracted using the Gentra Puregene kit (Qiagen, Valencia, CA). Libraries were prepared from approximately 3 µg of high quality genomic DNA (50-200 ng/µl) using Illumina TruSeq Genomic DNA High throughput Sample Prep Kits (Illumina, San Diego, CA) and exome enrichment (targeting 62Mb) was accomplished using the TruSeq Exome Target Enrichment kit (Illumina, San Diego, CA), all according to manufacturer's protocols. Target enrichment validation was confirmed by determining the concentration of the library by PicoGreen-based quantitation. Library yields ranged from 100-1000ng of DNA, a portion of which was run on the Bioanalyzer HS DNA chip (Agilent, Santa Clara, CA), with an average size of 300-550nt for DNA fragments. Exome Sequencing. Sequencing was performed using Illumina Hiseq2000 or HiSeq2500 sequencers with single lane, paired-end 2X100bp reads. DNA fragments were generated and amplified using Clonal Single Molecule Array technology (Illumina, San Diego, CA). The sequences were determined using the Clonal Single Molecule Array and Sequencing-by-Synthesis using Illumina's instrumentation and Reversible Terminator Chemistry. Each sequencing lane interrogated the DNA sequences of a pool of 3 individual sample libraries each carrying a unique index. Sequencing reads of at least 2x100bp in length for a total of approximately 8 Gb of sequence data were generated for each sample.

  Study phs001700

• Metagenomic Analysis of the Structure and Function of the Human Gut Microbiota in Crohn's Disease

  Inflammatory bowel diseases (IBD), such as Crohn's disease, are chronic, immunologically mediated disorders that have severe medical consequences. The current hypothesis is that these diseases are due to an overly aggressive immune response to a subset of commensal enteric bacteria. Studies to date on IBD have suggested that the disorder may be caused by a combination of bacteria and host susceptibility; however the etiologies of these diseases remain an enigma. In this application, we propose to develop and demonstrate the ability to profile Crohn's disease at an unprecedented molecular level by elucidation of specific biomarkers (bacterial strains, genes, or proteins) that correlate to disease symptoms. To achieve this goal, we will employ a multidisciplinary approach based on metagenomic and metaproteomic molecular tools to elucidate the composition of the commensal microbiota in monozygotic twins that are either healthy or exhibit Crohn's disease (for concordant, both are diseased; for discordant, one is healthy and one is diseased). The central hypotheses of this proposal are (1) that specific members and/or functional activities of the gastrointestinal (GI) microbiota differ in patients with Crohn's disease as compared to healthy individuals, and (2) that it will be possible to elucidate microbial signatures which correlate with the occurrence and progression of this disease by integration of data obtained from 16S rRNA-based molecular fingerprinting, metagenomics, and metaproteomics approaches. To address these hypotheses, three specific aims are proposed: 1) Obtain data on community gene content (metagenome) in a subset of healthy twins and twins with Crohn's Disease to assess potential differences in the metabolic capabilities of the gut microbiota associated with CD, 2) Obtain data on community protein content (metaproteome) in a subset of healthy twins and twins with Crohn's Disease to assess the state of expressed proteins associated with CD, 3) Apply various statistical clustering and classification methods to correlate/associate microbial community composition, gene and protein content with patient metadata, including metabolite profiles and clinical phenotype. The ultimate goal of these efforts is to identify novel biomarkers for non-invasive diagnostics of CD and to eventually identify drug targets (i.e. bacterial strains) for cure or suppression of disease symptoms. PUBLIC HEALTH RELEVANCE: This study aims to unravel the contribution of the bacteria that normally inhabit the human gastrointestinal tract to Crohn's disease by using a multidisciplinary approach to study changes in the structure and function of gut microbial communities in three sets of patient cohorts who have Crohn's disease. These results will be compared with those obtained from the study of healthy individuals and have the potential to identify new biomarkers of disease severity, location, and progression.

  Study phs000257