14478 results for "PLOS+ONE+Pennsylvania+German+ACS+language+code+pdc+open+access+study"

in 20.12 milliseconds.

• MOSAIC Window Ovarian Data

  This dataset will include Spatial Transcriptomics from the 10x Genomics Visium SD technology, Single-Cell RNA-Seq from the 10x Genomics Chromium Flex protocol, Bulk RNA-Seq (sequenced on Illumina), WES (sequenced on Illumina), H&E, and Clinical data from 15 Ovarian patients. For Visium and Chromium data we are sharing the outputs of respectively Space Ranger and Cell Ranger. For Bulk RNA-Seq we are including processed files such as counts.tsv, FPKM.tsv, fusion_genes.tsv, TPM count matrix.tsv, DESeq2 count matrix.tsv, multiqc_report. For WES, we are sharing the presence or absence of single nucleotide variants (SNVs), small insertions and deletions (indels), and copy number variants (CNVs).* Researchers from private or public institutions outside the MOSAIC Consortium will be able to apply to access this data and, pending approval, use the data for their research.

  Dataset EGAD50000001704

• MOSAIC Window Mesothelioma Data

  This dataset will include Spatial Transcriptomics from the 10x Genomics Visium SD technology, Single-Cell RNA-Seq from the 10x Genomics Chromium Flex protocol, Bulk RNA-Seq (sequenced on Illumina), WES (sequenced on Illumina), H&E, and Clinical data from 10 Mesothelioma patients. For Visium and Chromium data we are sharing the outputs of respectively Space Ranger and Cell Ranger. For Bulk RNA-Seq we are including processed files such as counts.tsv, FPKM.tsv, fusion_genes.tsv, TPM count matrix.tsv, DESeq2 count matrix.tsv, multiqc_report. For WES, we are sharing the presence or absence of single nucleotide variants (SNVs), small insertions and deletions (indels), and copy number variants (CNVs).* Researchers from private or public institutions outside the MOSAIC Consortium will be able to apply to access this data and, pending approval, use the data for their research.

  Dataset EGAD50000001706

• Center for Craniofacial and Dental Genetics: Study of Dental Caries and Cleft Lip/Palate in Guatemala

  This study provides an opportunity to investigate the genetics of both dental caries and orofacial clefts (OFCs) in one set of families ascertained in Guatemala. This study is part of the Gene Environment Association Studies initiative (GENEVA, http://www.genevastudy.org), which was developed through the trans-NIH Genes, Environment, and Health Initiative (GEI). Furthermore this study brings together multiple research priorities of the University of Pittsburgh Center for Craniofacial and Dental Genetics (www.ccdg.pitt.edu). A genome-wide panel of 610,000 SNPs was genotyped at the Broad Institute to be comparable to our other pertinent GENEVA studies that are also part of dbGaP (dbGaP accession number phs000095, "Dental Caries: Whole Genome Association and Gene x Environment Studies" and dbGaP accession number phs000094, "International Consortium to Identify Genes and Interactions Controlling Oral Clefts"). The goal of this study is to investigate genetic determinants to dental caries and to OFCs in a novel study population. To date, most genetic studies of dental caries have been conducted in Caucasians, and of OFCs in Caucasians and Asians. The Guatemalan population under study is rural and ethnically mixed with a high proportion of Native-South-Americans. Thirty-six Guatemalans from this dataset were also part of the recent GWAS studies of cleft lip and cleft palate (Beaty et al., 2010 and 2011, dbGaP Study Accession: phs000094, "International Consortium to Identify Genes and Interactions Controlling Oral Clefts"). In addition to the families ascertained in Guatemala, some subjects were genotyped with this cohort to augment the data in the parent GENEVA study (Dental Caries: Whole Genome Association and Gene x Environment Studies, dbGaP accession number phs000095), in particular individuals from the IOWA and PITT GENEVA study sites. Their data are available with the parent study. Dental caries (also known as tooth decay) remains the most common chronic disease of childhood, five times more common than asthma and seven times more common than environmental allergies, with more than 40% of children exhibiting caries when they enter kindergarten. In 2005, it was estimated that dental health care costs were approximately $84 billion, of which 60% or about $50 billion were related to treatment of dental caries. The etiology of dental caries has been studied for many years. Multiple factors contribute to a person's risk for caries, including: 1) environmental factors such as diet, oral hygiene, fluoride exposure and the level of colonization of cariogenic bacteria and 2) host factors such as salivary flow, salivary buffering capacity, position of teeth relative to each other, surface characteristics of tooth enamel and depth of occlusal fissures on posterior teeth. In spite of all that is known about this disease, there are still individuals who appear to be more susceptible to caries and those who are extremely resistant, regardless of the environmental risk factors to which they are exposed, implying that genetic factors also play an important role in caries etiology. This conclusion is supported by studies in both humans and animals, with the most compelling evidence coming from studies of twins reared apart in which investigators found significant resemblance within monozygotic (MZ) but not dizygotic (DZ) twin pairs for percentage of teeth and surfaces restored or carious and estimated the genetic contribution to caries as 40%. Other recent studies of twins reared together estimated the heritability for caries, adjusted for age and gender, as ranging from 45-64%. In our study populations of families, we also estimated caries heritability as approximately 54%-70% of variation in primary dentition caries scores and 35%-55% in the permanent dentition (Wang et al., 2010). Orofacial clefts (OFCs), particularly cleft lip with or without cleft palate (CL/P) and isolated cleft palate (CP) are a major public health problem, affecting one in every 500-1000 births worldwide thus representing the most common facial birth defect and one of the most common of all congenital anomalies. CL/P is a major structural birth defect that is notable for significant lifelong morbidity and complex etiology. The extensive psychological, surgical, speech and dental involvement emphasize the importance of understanding the underlying causes of CL/P. Therefore, many research groups have attempted to elucidate the etiology of CL/P, with some recent success by our research group and others (see Beaty et al., 2010, 2011; Dixon et al., 2011). It is clear that CL/P can occur as part of Mendelian syndromes, that certain chromosomal abnormalities include CL/P in the phenotype, and that certain teratogens can increase the risk of having an offspring with CL/P. However, phenotypes of known etiology comprise only a small portion of all individuals with a CL/P or CP, and the major focus of research into OFCs is to develop an understanding of the etiology of nonsyndromic (NS) forms of clefting. A major focus of the University of Pittsburgh CCDG has been to study additional phenotypes within nonsyndromic OFC families in order to identify sub-clinical expressions of OFC risk genes or risk variants, e.g. SNPs (see Weinberg et al., 2006). A detailed oral exam is conducted as part of these extended phenotypic studies, including a dental caries exam. Note that although there are some reports in the literature of higher caries experience in individuals with clefts, the most recent meta-analysis of those literature reports concluded that individuals born with these defects do not have a higher frequency of caries (Hasslöf and Twetman, 2007). Notably, we investigated the association of CL/P and caries in three of our study populations (including part of the Guatemalan population in this GWAS study) and also found no increase in caries rates of CL/P cases versus controls (Jindal et al., 2011). This study is part of the Gene Environment Association Studies initiative (GENEVA, http://www.genevastudy.org), which was developed through the trans-NIH Genes, Environment, and Health Initiative (GEI). The overarching goal is to identify novel genetic factors that contribute to dental caries and oral clefts through large-scale genome-wide association studies of well-characterized Guatemalan families and individuals. Genotyping was performed at the Broad Institute of MIT and Harvard. The study was supported by the National Institute of Dental and Craniofacial Research (NIDCR, U01-DE018903). Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington.

  Study phs000440

• Natural Killer Cell Therapies for Hematologic Malignancies

  The "Natural Killer Cell Therapies for Hematologic Malignancies" study is an umbrella repository for data pertaining to multiple related clinical trials that aim to assess NK cell therapies as part of treatment strategies for a range of hematologic malignancies. Here, data from two trials, NCT03068819 and NCT02782546, are presented.Cytokine Induced Memory-like NK Cell Adoptive Therapy for Relapsed AML after Allogeneic Hematopoietic Cell Transplant in Children and Adults (NCT03068819)Pediatric and young adult (YA) patients with acute myeloid leukemia (AML) who relapse after allogeneic hematopoietic cell transplantation (HCT) have extremely poor prognosis. Standard salvage chemotherapy and donor lymphocyte infusions (DLI) have little curative potential. Previous studies showed that natural killer (NK) cells can be stimulated ex vivo with interleukin-12 (IL-12), IL-15, and IL-18 to generate memory-like (ML) NK cells with enhanced anti-leukemia responses. We treated nine pediatric/YA patients with post-HCT relapsed AML with donor ML NK cells on a phase I trial. Patients received fludarabine, cytarabine, and filgrastim followed two weeks later by infusion of DLI and ML NK cells from the original HCT donor. ML NK cells were successfully generated from haploidentical, matched-related and matched-unrelated donors. Following infusion, donor-derived ML NK cells expanded and maintained ML multidimensional mass cytometry phenotype for over 3 months. Furthermore, ML NK cells exhibited persistent functional responses as evidenced by leukemia-triggered IFN-gamma production. Following DLI and ML NK cell adoptive transfer, 4 of 8 evaluable patients achieved complete remission at day 28. Two patients maintained a durable remission for over 3 months with one patient in remission for greater than two years. No significant toxicity was experienced. This study demonstrates that in a compatible immune environment post-HCT, donor ML NK cells robustly expand and persist with potent anti-leukemic activity in the absence of exogenous cytokines. ML NK cells in combination with DLI present a novel immunotherapy platform for AML that has relapsed after allogeneic HCT. This trial was registered at https://www.clinicaltrials.gov/study/NCT03068819.A Phase II Study of Cytokine Induced Memory-like NK Cell Adoptive Therapy after Haploidentical Donor Hematopoietic Cell Transplantation (NCT02782546)Natural killer (NK) cells are innate lymphoid cells that eliminate cancer cells, produce cytokines, and are being investigated as a nascent cellular immunotherapy. Impaired NK cell function, expansion, and persistence remain key challenges for optimal clinical translation. One promising strategy to overcome these challenges is cytokine-induced memory-like (ML) differentiation, whereby NK cells acquire enhanced anti-tumor function following stimulation with IL-12, IL-15, and IL-18. Here, reduced-intensity conditioning (RIC) for HLA-haploidentical hematopoietic cell transplantation (HCT) was augmented with same-donor ML NK cells on Day 7 and 3 weeks of N-803 (IL-15 superagonist) to treat patients with relapsed/refractory acute myeloid leukemia (AML) in the clinical trial (NCT02782546). In 15 patients, donor ML NK cells were well-tolerated and 87% of patients achieved a composite complete response at Day 28, which corresponded with clearing high-risk mutations, including TP53 variants. NK cells were the major blood lymphocytes for two months post-HCT with prolific expansion (1104-fold) over 1-2 weeks. Multidimensional mass cytometry and CITE-seq identified donor ML NK cells as distinct from conventional NK cells and persisting for over two months. ML NK cells expressed CD16, CD57, and high granzyme B and perforin, along with a unique transcription factor profile. ML NK cells differentiated in patients had enhanced ex vivo function compared to conventional NK cells from both patient and healthy donors. Overall, same-donor ML NK cell therapy with 3 weeks of N-803 support safely augmented RIC haplo-HCT for AML, with ML NK cells demonstrating enhanced in vivo persistence and functionality, overcoming barriers in the field.

  Study phs002681

• The International Consortium for Prostate Cancer Genetics Genome Wide Association Study of Familial Prostate Cancer

  Initially, the ICPCG focused largely on high-risk prostate cancer pedigrees using linkage analysis. However, association studies have also been informative to find prostate cancer susceptibility variants in the genome. We hypothesize that genome-wide (GW) association studies of familial cases of prostate cancer will have the power to identify rarer and perhaps less penetrant risk variants associated with prostate cancer than have been identified to date. Our approach will be to examine evidence for association in selected, independent cases from high-risk pedigrees; we hypothesize that they represent a more homogeneous set of cases with potentially different associations. Use of the 5M plus exome SNP platform will allow us to include in our search more rare variants in our search than have ever been investigated for prostate cancer. Aim 1. Identify a set of independent prostate cancer cases selected from ICPCG high-risk prostate cancer pedigrees that have 3 or more related prostate cancer cases and have an average age at diagnosis ≤ 75 years. Identify appropriate matched controls from participating ICPCG groups/ populations. Aim 2. Perform GW SNP genotyping with the Illumina 5M plus exome SNP set on the set of independent prostate cancer cases and controls described in Aim 1. Aim 3. Perform association analyses appropriately matching controls for different ICPCG populations and groups. There will be a two-stage design for confirmation. Aim 4. Test reported associations using the extensive sample set available to us by collaboration with the PRACTICAL consortium that has access to 50 000 DNA samples from 34 groups internationally (over 7,000 of whom are positive for prostate cancer family history).

  Study phs000733

• Diabetic Retinopathy Genomics Study (DRGen) - Genetic Biomarkers of Diabetic Retinopathy

  Using a well-defined, clinically supported phenotypic strategy, we seek to better understand the role of common and rare genetic variants in the progression of diabetic retinopathy (DR). Whole exome/whole genome sequencing (WES/WGS) was used to systematically search the human genome to detect DR susceptibility genes or genes that protect people from developing advanced DR. Clinical data and bio specimens were obtained from clinically defined DR phenotypes such as, (i) No/Mild NPDR (non-proliferative DR) with a subset of extreme phenotype, ii) Diabetic macular edema (DME) alone and iii) Proliferative diabetic retinopathy (PDR) alone. In this ongoing comprehensive genomic study, we wish to i) Identify potential common and rare variants that may influence the phenotypic differentiation of DR into DME or PDR, ii) Define genetic variants stratified based on the "extreme phenotype," and iii) Characterize genetic factors that determine the differential response to anti-VEGF drugs in DME patients. Definition of Diabetic Retinopathy and classification of groups Study 1. Proliferative diabetic retinopathy (PDR). Anybody showing evidence of retinal neovascularization on the disc (NVD) or elsewhere (NVE) with or without pre-retinal and vitreous hemorrhage will be considered PDR. We will include only those "active" PDR patients. The total number of consented subjects in this study is 182. Study 2. Isolated Phenotype: Varied response with anti-VEGF treatment is a significant limiting factor for better clinical outcomes. We quantify the response to anti-VEGF treatment based on visual acuity changes and anatomic features of DME assessed by optical coherence tomography (OCT). Depending on the response at one month following three monthly intravitreal anti-VEGF injections, we have observed two phenotypes: 1) Good responders: Participants were considered "good responders" if the anatomical outcome to anti-VEGF treatment resulted in a significant reduction of baseline central retinal thickness (CRT) > 25% after three anti-VEGF injections. 2) Poor Responders: Participants were classified as "poor responders" if the outcome of anti-VEGF treatment resulted in a reduction of CRT < 20% or in any increase in CRT after three monthly injections. The total number of consented subjects in this study is 17.

  Study phs002501

• Dataset of methylation data from whole blood DNA

  This dataset includes raw data (.idat) for the Illumina Human450k beadchip and methylation levels (.txt files). Methylation level were treated for normalization and background substraction. We removed probes with at least one of the following characteristics: (1) weak signal (p > 0.01) (2128 CpG sites), (2) SNP-enriched sites (4100 sites), (3) out of a CpG context (not on a CG) (3149 sites), or (4) located on sex chromosomes (11,129 sites). A total of 465,071 CpG sites were analyzed initially. Signal was then normalized, first by scaling to the internal controls using the methylumi R package, then by applying the method of subset-quantile within array normalization (SWAN) implemented in the minfi R package.

  Dataset EGAD00010001593

• Transcriptome of memory B cells with autoproliferation in MS

  Transcriptional profile of resting/hi and autoproliferating/Dim memory B cells in Multiple sclerosis patients. In brief, non-proliferating (CFSEhi) and AP+ (CFSEdim) CD19+ CD27+ B cells from PBMCs of 5 natalizumab-treated female RRMS (NAT) patients were sorted following 7 days of autoproliferation. Transcriptome libraries were constructed from the same samples, except for one sample pair, which was excluded due to limited input material (5 donors as for Methylome, D1; D2, D3, D5, D6; samples from donor D4 unfortunately technically failed). SMARTer Total Stranded RNA-seq library construction with ribosomal depletion was performed and then sequenced on NovaSeq S4 lane.

  Dataset EGAD50000001270

• 10X CD4 auto-antigens

  Ex vivo CD4 T-cells from 4 donors were stimulated with antigen-coupled beads to aCD3, ABD, EBNA1, ANO2 or CRYAB and the LiveCD3+CD4+CFSEdim cells were sorted by flow cytometry. Cells were labelled with barcoded antibodies to identify the original stimulus. All stimulations from each donor were pooled into four reactions, i.e. one reaction per donor. Libraries were assembled with the 10X Chromium Next GEM Single Cell 5’ Kit for TCR and transcriptome with feature barcodes. Dataset contains raw fastq reads as well as supplementary information needed to link fastq files to modality, i.e. gene-expression, protein or VDJ, and includes supplementary information to de-multiplex the reactions by stimulation condition.

  Dataset EGAD50000002201

• Preeclampsia InterPregGen Consortium: Whole Genome Sequencing of 100 unrelated Kazakhs (DNA samples from the Scientific Center of Obstetrics, Gynecology and Perinatology, Almaty, Kazakhstan; Gulnara Svyatova, Principal Investigator

  Whole genome sequencing of 100 unrelated Kazakhs in order to impute genotypes into PE cases and controls from Kazakhstan and to provide genetic data and infrastructure for future genetic studies in Kazakhstan and Central Asia more generally and to fill a gap in worldwide information as Central Asia is not adequately represented in available genomic data. This dataset is one component of the InterPregGen FP7 project. DNA samples for this component were collected by InterPregGen Consortium collaborators at the Scientific Center of Obstetrics, Gynecology and Perinatology, Almaty, Kazakhstan (Gulnara Svyatova, Principal Investigator)

  Dataset EGAD00001005467

• Inter and intra - tumor heterogeneity in Colorectal Cancer

  The dataset consists of two main sample groups. 1) The inter-tumour sample group contains a total of 97 samples from 27 patients. Each patient has a single normal and primary sample as well as one or more metastases. All samples were sequenced using IonTorrent PGM and a custom colorectal cancer (CRC) panel. 2) The intra-tumour sample group contains a total of 68 samples from a single tumour as well as a normal tissue sample. All 68 samples were sequenced using IonTorrent PGM and a custom CRC panel. Shallow whole genome sequencing was additionally applied to 10 of the samples using Illumina HiSeq 4000.

  Dataset EGAD00001003131

• Single-cell RNA-seq of human kidney tumors

  Fresh nephrectomy samples were collected from a total of 5 untreated ccRCC patients. Out of these 5 patients, 7 samples were obtained. Two samples consisted of fresh versus frozen single cells from the primary tumor site of one patient. Two other samples consisted of matched primary and distant thrombus sites (the vena cava) of a second patient. The three remaining samples came from the primary tumor sites of three distinct ccRCC patients. Single-cells were captured into 10x barcoded gel beads and RNA-sequencing library preparation was done using Chromium Single Cell 3' v2 chemistry. Sequencing was performed on a Illumina HiSeq 4000 sequencer.

  Dataset EGAD00001009306

• C9orf72 region reads of 3001 samples

  This dataset includes cram files from 3,001 samples. These cram files include all read pairs where at least one of the reads aligns within 1kb of the C9orf72 repeat expansion. Additionally, these cram files also contain reads that are aligned to any of 29 pre-determined off target locations where the aligners are known to mis-align reads associated with this repeat expansion. These samples were sequenced using a combination of 2x100bp reads on an Illumina HiSeq2000 and 2x150bp reads on an Illumina HiSeqX sequencer and aligned using the Isaac aligner.

  Dataset EGAD00001004834

• LLDeep DAG2+: scRNA-seq in PBMCs

  Single cell transcriptomics of PBMCs of 47 donors from the Lifelines Deep cohort (general population, Northern part of the Netherlands). Cells of five or six different donors were pooled together in one sample pool, resulting in eight different sample pools. In total, 28.855 cells were captured and their transcriptomes were sequenced to an average depth of 74k. Genotype data was available for each donor, which allowed us to use the Demuxlet method that uses variable SNPs between the pooled individuals to determine which cell belongs to which individual. Since genotype information is lacking of 2 individuals, the transcriptome of only 45 individuals could be retrieved.

  Dataset EGAD00001003459

• ICR639 CPG NGS Validation series

  The dataset includes sequencing data generated using the TruSight Cancer Panel (TSCP) a targeted NGS assay for analysis of CPGs and orthogonally generated data supporting at least one pathogenic variant in a CPG for a total of 645 pathogenic CPG variants. The set of pathogenic CPG variants includes strong representation of some of the most challenging types of pathogenic variants, with 339 indels, including 16 complex indels and 24 insertions or deletions with length greater than 5bp, and 74 exon CNVs, including 23 single exon CNVs. There are 502 pathogenic variants in BRCA1 or BRCA2, making this an important first-line validation dataset for laboratories performing NGS testing of BRCA1 and BRCA2.

  Dataset EGAD00001004134

• Single cell RNA-seq, TCR-seq and bulk TCR-seq on HNSCC patients treated with ICB

  We performed single cell RNA- and TCR-sequencing (10x Genomics) on immune infiltrates (CD45+ cells) from 18 HNSCC patients enrolled in the IMCISION trial (Vos et al. 2021). Viable immune cells were isolated from pre-treatment and post-treatment primary tumor biopsies of 10 patients responding (1 partial pathological response and 9 major pathological responses) and 7 patients non-responding to anti-PD-1 and anti-CTLA4 combination immunotherapy. One patient treated with anti-PD-1 monotherapy (1 major pathological response) was included in the dataset. Bulk TCR-seq was performed on the PBMCs of responding patients, pre- and post-treatment.

  Dataset EGAD00001011311

• CRU-Ukrainian National Research Center for Radiation Medicine Trio Study

  Data on transgenerational effects following nuclear accidents are important for understanding fully the consequences of parental exposure to ionizing radiation. Few studies to date have had adequate statistical power to detect effects of the magnitude expected based on animal data, and most have not been of low-dose, protracted exposures associated with nuclear accidents and their aftermath. Although, to date, scant use has been made of the new genomic technologies, in Chernobyl-exposed areas of Ukraine and Belarus, excess minisatellite mutations have been seen in children born after the accident. We propose a study of parent-child trios in which at least one parent was exposed to Chernobyl radiation as a clean-up worker (mean dose>=100 mGy) and/or evacuee from a contaminated area (mean >=50 mGy). The specific aims are to investigate the transgenerational and de novo mutation rates of the spectrum of genetic variants in trios, in particular looking at effects in children and mapping them to possible parental origin of the chromsoome. Together with long-term collaborators at the Research Center for Radiation Medicine (RCRM) in Kiev, epidemiologic data will be collected for up to 450 trios of parents with preconceptional doses and their unexposed offspring. We will use state-of-the-art genomic technologies to characterize the landscape of the genomes of the trios to determine whether parental radiation exposure is associated with genetic mutations transmitted to the offspring, by examining de novo mutation rates, minisatellite mutations, copy number alterations, and variations in telomere length. The analysis will be conducted in peripheral blood and/or buccal samples (when blood is not available) from complete father-mother-child trios. Doses to the gonads from the time of the accident to the time of conception will be reconstructed for all parents using existing records supplemented by interview data. Trio subjects will be selected from representative populations exposed to radiation from Chernobyl who are under active follow-up in the Clinico-Epidemiologic Registry at RCRM. To help identify specific effects of paternal and maternal radiation exposure, we will initially select sets of trio subjects in five categories: (1) exposed father, unexposed mother; (2) unexposed father, exposed mother; (3) both parents exposed; (4) both parents unexposed; and (5) a group of high dose "emergency workers" with acute radiation syndrome. All trio members will be invited to the RCRM outpatient clinic for collection of a 20 ml blood sample (or buccal cells for those who refuse phlebotomy). Both parents will be asked to complete a general questionnaire to obtain demographic and lifestyle data. Then one or both will complete detailed dosimetry questionnaires, based on forms used in previous collaborations with RCRM and administered by specially trained interviewers. Once 50 trios have been recruited (10 from each of the 5 exposure categories), we will conduct an interim evaluation of participation rates, sample collection and quality, and dose reconstruction in order to modify the protocol as needed. The analytical approach will be to correlate the extent, especially for de novo events of genetic alterations in the offspring with parental pre-conceptional radiation dose overall and by parental origin. The statistical power in relation to de novo mutations is very high, in excess of 90%, but somewhat lower for trends in minisatellite mutations. Study findings will contribute importantly to knowledge of the heritable effects of moderate- and low-dose radiation exposure in humans and to radiation risk projection. Eventually data from the Trio Study may be shared with the international community through dbGap.

  Study phs001163

• Analysis of Donor Pancreata Defines the Transcriptomic Signature and Microenvironment of Early Neoplastic Pancreatic Lesions

  The adult healthy human pancreas has been poorly studied given lack of indication to obtain tissue from the pancreas in the absence of disease and rapid postmortem degradation. We obtained pancreata from brain dead donors thus avoiding any warm ischemia time. We found that neoplastic lesions occur frequently in healthy organs, in donors as young as in their 3rd decade of life. Using the 10X Genomics Platform, we performed single cell RNA sequencing on 7 donor pancreata, 6 of which we separately sequenced tissue from the pancreas head and tail, for a total of 11 sequencing runs. Of note, because one of our runs (containing sequencing from pancreas head and tail) did not pass qc, our final analysis in our study utilized 6 donor pancreata, 5 of which contained pancreas head and tail sequenced separately. This is a robust single-cell dataset of healthy, nonpathologic pancreas tissue and includes acinar, ductal, and non-epithelial cells (myeloid cells, fibroblasts, endothelial cells, lymphocytes).Briefly, the donor pancreas was dissected by a clinically-trained pancreatobiliary surgeon. The organ was dissected into head, body, and tail, with portions of each placed into DMEM media with 1% BSA/10µM Y27632. Tissue was minced into 1mm3 pieces, then digested with 1 mg/mL collagenase P for 20-30 min at 37°C with gentle agitation. Digested tissue was rinsed three times with DMEM/1% BSA/10µM Y27632, then filtered through a 40µm mesh. Resulting cells were submitted to the University of Michigan Advanced Genomics Core for single cell sequencing using the 10x Genomics Platform. FASTQ files of all sequencing runs along with clinical annotation of donors is available through this dbGaP submission.

  Study phs003229

• Mechanism of Action of Vitamin E in NAFLD

  We conducted a single-center prospective mechanistic randomized trial (clinicaltrials.gov NCT01792115). Adult patients with NAFLD were enrolled between May 2013 and November 2016. All patients underwent a 12 weeks run-in period of lifestyle intervention. Following the run-in phase, patients underwent a baseline evaluation including blood tests, glucose tolerance testing, measurement of liver fat content by 1H-magnetic resonance spectroscopy (MRS) and a percutaneous liver biopsy. Patients with no evidence of NAFLD on the entry liver biopsy ended their participation in the study at that point. Patients with histological confirmation of NAFLD (either NAFL or NASH) on the baseline biopsy were randomized at a 1:1:1 ratio to receive one of 3 doses of natural vitamin E (RRR-alpha-tocopherol, Pharmavite), 200, 400 or 800 IU/d, for 24 weeks, and were followed at a 1-8 week intervals in a parallel assigned design. While on vitamin E treatment, patients were encouraged to continue and adhere to the lifestyle and dietary guidelines of the run-in phase. On week 4 of vitamin E treatment, a repeat MRS and liver biopsy were performed. On week 24, a final MRS was performed to assess treatment response. The primary endpoint was the reduction of liver fat content by MRS from baseline (immediately prior to starting vitamin E) to week 24 of treatment, and a response was defined as a relative reduction of ≥25% in liver fat content by MRS between baseline and week 24. Early changes in the hepatic transcriptome were investigated at week 4 comparing non-responders to responder in a nested design.

  Study phs001930

• Genomic Analyses of Germline and Somatic Variation in High-Grade Serous Ovarian Cancer

  The goal of this study was to identify and characterize germline and somatic genetic variation in women with high grade serous ovarian cancers treated at a single cancer center and their associations with relapse-free and overall survival. We conducted paired tumor/normal targeted next-generation sequencing of 577 genes in pathways of DNA repair, response to DNA damage, cell-cycle regulation, programmed cell death, MAPK, and P13K/AKT/MTOR signaling in 114 tumors from 71 women. In addition, we investigated single copy number alterations (SCNAs) and loss of heterozygosity in a subset of 61 tumors. We validated our results with data from ovarian tumors in TCGA. Our results were similar to other studies of high-grade serous carcinomas. As an example, we found that approximately one third of the tumors harbored loss of function variants in homologous recombination genes and that >90% had TP53 somatic mutations. Through GISTIC analysis of the OncoScan data on tumor DNA from 61 cases, we identified several regions of high copy number alterations including including NOTCH3 and PIK3R2 that were significantly associated with an increase in cancer recurrence and a reduction in overall survival. We identified few changes in mutation profiles where we had multiple tissues, either from multiple surgeries or from the primary site to metastatic sites within the same surgery. However, we did not investigate copy number alterations in multiple tissues from the same individuals, and so it may be that copy number alterations are more important. Data available through dbGAP will be the BAM files and the phenotypic data on the tumor samples, the age, race, ethnicity of the participants and their outcomes, and the Oncoscan OSCHP files.

  Study phs003198

• Addictions: Genotypes, Polymorphisms, and Function/Human Genetic Correlates of Addictive Diseases

  Drug addiction continues to be a major medical and social problem. It is estimated that one million or more persons in the United States are currently addicted to heroin or prescription opioids, with millions more worldwide. Cocaine addiction and alcohol dependence are frequent comorbid conditions in persons with heroin/opioid dependence in addition to being major primary addictions. Many studies over the past thirty years have shown that these drugs disrupt physiologic systems, and that these disruptions may contribute to drug addiction and alcohol dependence and to relapse to drug or alcohol abuse following withdrawal and abstinence. Clinical observations suggest that individuals differ in their response to heroin, cocaine, and alcohol; however, little is known about specific underlying hereditary genetic factors which might influence individual susceptibility to the addictive properties of these substances. Studies also suggest that both common and distinct heritable factors account for the genetic variance in the susceptibility to the separate addictive diseases. We hypothesize that there is a heritable as well as environmental basis for the acquisition and persistence of, and relapse to, specific addictive diseases. Using samples from individuals without and with opioid and other specific drug dependence diagnoses and psychiatric comorbidities, genetic analyses will be used to determine association and linkage. All study subjects will be extensively characterized with respect to the addictive diseases, medical history, family medical addictive disease history; psychiatric comorbidity, and psychological profile, as well as ethnic/cultural background. A better understanding of the consequences of genetic contributions with respect to protection from, or susceptibility to, heroin/opioid addiction and related codependencies and comorbid conditions, could have enormous importance in both prevention and treatment of this problem.

  Study phs001109

• Genetic Epidemiology Network of Arteriopathy (GENOA)

  The Genetic Epidemiology Network of Arteriopathy (GENOA) is one of four networks in the NHLBI Family-Blood Pressure Program (FBPP). GENOA's long-term objective is to elucidate the genetics of target organ complications of hypertension, including both atherosclerotic and arteriolosclerotic complications involving the heart, brain, kidneys, and peripheral arteries. The longitudinal GENOA Study recruited European-American and African-American sibships with at least 2 individuals with clinically diagnosed essential hypertension before age 60 years. All other members of the sibship were invited to participate regardless of their hypertension status. Participants were diagnosed with hypertension if they had either 1) a previous clinical diagnosis of hypertension by a physician with current anti-hypertensive treatment, or 2) an average systolic blood pressure ≥ 140 mm Hg or diastolic blood pressure ≥ 90 mm Hg based on the second and third readings at the time of their clinic visit. The Family Blood Pressure Program (FBPP), GENOA's parent program, is an unprecedented collaboration to identify genes influencing blood pressure (BP) levels, hypertension, and its target-organ damage. This program has conducted over 21,000 physical examinations, assembled a shared database of several hundred BP and hypertension-related phenotypic measurements, completed genome-wide linkage analyses for BP, hypertension, and hypertension associated risk factors and complications, and published over 130 manuscripts on program findings. The FBPP emerged from what was initially funded as four independent networks of investigators (HyperGEN, GenNet, SAPPHIRe and GENOA) competing to identify genetic determinants of hypertension in multiple ethnic groups. Realizing the greater likelihood of success through collaboration, the investigators created a single confederation with program-wide and network-specific goals.

  Study phs001238

• Single-cell Transcriptome Profiling of Treatment-naïve and Post-treatment Colorectal Cancer: Insights into Putative Mechanisms of Chemoresistance

  Drug resistance remains a major clinical challenge in the treatment of colorectal cancer (CRC) with conventional chemotherapy. Investigation of cancer cells and tumor microenvironment (TME) following chemotherapy is critical for unraveling the mechanisms of resistance. In this study, we analyzed scRNA-Seq data from 56 CRCs including treatment-naïve tumors (25 microsatellite stable (MSS) tumors and 7 tumors with microsatellite instability (MSI)); and tumors treated with standard chemotherapy with the known response status (18 responders and 6 progressors). We observed in treatment-naïve MSS CRC that right-sided tumors are more immunogenic with higher numbers of B cells and CD8+ T memory effector cells than left-sided tumors. MSI CRC were even more immunogenic then MSS CRC and were characterized by elevated Tregs in their TME. In the post-treatment CRC there was a high prevalence of dendritic cells (DC) in the TME in the response group. The DC-derived signature was associated with better survival in a large CRC cohort from the TCGA. We also observed two fibroblast subtypes in CRC, one of which was enriched in progressors and was associated with poor survival in a CRC-TCGA cohort. Progressors also showed elevated exhausted CD8+ T memory cells and monocytes suggesting a pro-inflammatory TME. In tumor cells in progressor group we identified specific expression of chemo-protective markers MTRNR2L1 and CDX1; and their co-expression with stemness-related marker CD24. In summary, scRNA-Seq provides a valuable information for the discovery of prognostic markers, and reveals distinct features of CRC based on location, metastasis status, MSI status and treatment response status.

  Study EGAS50000000830

• DNA methylation-based prognostic subtypes of chordoma tumors in tissue

  Chordomas are rare malignant bone cancers of the skull-base and spine. Patient survival is variable and not reliably predicted using clinical factors or molecular features. This study identifies prognostic epigenetic chordoma subtypes that are detected noninvasively using plasma methylomes. Methylation profiles of 68 chordoma surgical samples were obtained between 1996 and 2018 across three international centers along with matched plasma methylomes where available. Consensus clustering identified two stable tissue clusters with a disease-specific survival difference that was independent of clinical factors in a multivariate Cox analysis (HR = 14.2, 95%CI: 2.1–94.8, P = 0.0063). Immune-related pathways with genes hypomethylated at promoters and increased immune cell abundance were observed in the poorperforming “Immune-infiltrated” subtype. Cell-to-cell interaction plus extracellular matrix pathway hypomethylation and higher tumor purity were observed in the better-performing “Cellular” subtype. The findings were validated in additional DNA methylation and RNA sequencing datasets as well as with immunohistochemical staining. Plasma methylomes distinguished chordomas from other clinical differential diagnoses by applying fifty chordoma-versusother binomial generalized linear models in random 20% testing sets (mean AUROC = 0.84, 95%CI: 0.52–1.00). Tissue-based and plasma-based methylation signals were highly correlated in both prognostic clusters. Additionally, leave-one-out models accurately classified all tumors into their correct cluster based on plasma methylation data. Here, we show the first identification of prognostic epigenetic chordoma subtypes and first use of plasma methylome based biomarkers to noninvasively diagnose and subtype chordomas. These results may transform patient management by allowing treatment aggressiveness to be balanced with patient risk according to prognosis.

  Study EGAS00001006406

• RNA seq on 19 samples of Radiation-Induced Meningiomas

  Purpose: Majority of pediatric cancers require the irradiation of the central nervous system (CNS), and as more patients survive into adulthood from improved oncological therapy the sequelae of brain radiation are increasing in prevalence. Radiation-induced meningiomas (RIMs), one such secondary effect, demonstrate a clinically more aggressive behaviour than sporadic meningiomas (SMs). We aimed to describe the genomic mutational landscape of RIMs.Methods: We analyzed a principal cohort of 18 RIMs, with 31 RIMs overall, from patients who received childhood radiation therapy and 30 SMs, as a comparator population. We performed a multiplatform integrative genomic analysis; including methylation, whole exome and RNA sequencing. Results: RIMs exhibited a five-fold increase in copy number alterations, commonly the loss of chromosome 1p (17/18 RIMs) and 22q (17/18 RIMs), which was significantly more than observed in sporadic meningiomas. Furthermore, RNA sequencing data revealed an NF2 gene fusion event in 35.3% of RIMs. In all 6 cases, there was a complete NF2 exon spliced into a complete exon of a reciprocal gene, suggesting that the breakpoints of genomic rearrangement are intronic. All tumours with the NF2 fusion also possessed monosomy of chromosome 22q, rendering the cells with homozygous disruption of NF2. Clinically, RIMs with the NF2 fusion exhibited ill-defined borders and a tendency to develop in anatomic frontal location. Also, targeted sequencing panel confirmed that RIMs had fewer nonsynonymous NF2 mutations (6.5% vs. 30% in SM) and absence of mutations in TRAF7, SMO, KLF4, PIK3CA and AKT1, genes traditionally involved in SMs.Conclusion: Our study demonstrates that RIMs have distinct genomic drivers of oncogenesis as compared to SMs, specifically NF2 inactivation through fusion event. Radiation therapy possibly triggers genomic structural rearrangements through error-prone repair of double-stranded DNA breaks.

  Study EGAS00001002318