12504 results for ""non-traditional+communal+storytelling+approach"+novel+segment+noted+in+critical+commentary"

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• Experimental PfSPZ Vaccine in Adults Without Malaria

  The study was performed to evaluate whole-blood transcriptomic profiles via RNA-seq before, during, and after immunization with the PfSPZ Vaccine in malaria-naïve, healthy adults enrolled in VRC 312 (NCT01441167). VRC 312 was the second study of the PfSPZ Vaccine and the first study to evaluate intravenous (IV) administration of this vaccine. The study was an open-label evaluation of the safety, tolerability, immunogenicity, and protective efficacy of the vaccine at successively higher administered by the IV route. The highest dosages were evaluated for protection against a malaria challenge after 4 to 6 vaccinations. The primary objectives of the study were related to the safety and tolerability of the vaccine at the 4 different dosage levels when administered IV; the secondary objectives were related to PfSPZ vaccine-mediated protection against Plasmodium falciparum (Pf) challenge at the 3 higher dosage levels, and the exploratory objectives were related to the immunogenicity of the PfSPZ Vaccine and defining an immune correlate of protection. To further determine potential molecular correlates of immunogenicity and/or protection, RNA-seq was performed on whole blood collected from subjects in all dose groups at time points before, during, and after immunization.

  Study phs002422

• Whole Genome Sequencing in the Inner City Asthma Consortium (ICAC) Cohorts

  We performed whole-genome sequencing on individuals from the Asthma Phenotypes in the Inner City (APIC) and Urban Environment and Childhood Asthma (URECA) study cohorts, which consist of children with asthma who live in low-income neighborhoods across 10 U.S. cities. APIC was a one-year, prospective, observational study of children ages 6-17 with asthma. URECA was a prospective, observational study featuring a birth cohort of children with a high risk of developing asthma based on family history. We performed whole-genome sequencing on 1,035 individuals (ages 5-17 yrs; 67% Black, 25% Hispanic; 66% with MD-diagnosed asthma; APIC=508, URECA=527). Sequence read processing, quality control, and variant calling were performed using the Genome Analysis Toolkit suite (GATK v4). Variant call sites were annotated according to the filters applied in our common variant (minor allele frequency ≥ 1%) association studies, based on predicted false positive rates, genotype quality and depth, and population-adjusted Hardy-Weinberg equilibrium. Principal components of ancestry were calculated using high quality, linkage-disequilibrium-pruned single-nucleotide variants, accounting for subject relatedness, using PC-Air and PC-Relate.

  Study phs002921

• Extracorporeal Life Support Survival in a Pediatric Hematopoietic Cellular Transplant Recipient with Presumed Graft Versus Host Disease-Related Fulminant Myocarditis

  We report the case of a 15-year-old female with hypodiploid pre-B acute lymphoblastic leukemia status post allogeneic hematopoietic stem cell transplantation (HCT) from a matched unrelated male donor who presented on transplant day +75 with cardiac arrest due to ventricular fibrillation associated with fulminant myocarditis. Using conventional diagnostics, an exhaustive search for microbial pathogens in the heart biopsy as well as nasopharynx, blood, urine, and endotracheal aspirate was performed but did not uncover a candidate pathogen. The family consented to a research study for the use of unbiased next-generation genomic sequencing for pathogen identification in the myocardial biopsy. DNA sequencing was performed on 1.5 x 108 sequencing pairs and no microbial pathogens were identified. Interestingly, a significant component of Y-chromosomal human DNA was identified, suggesting infiltration of at least 10 donor leukocytes per host cell. This finding is grossly consistent with the lymphocyte:myocyte ratio in the biopsy according to visual inspection at 40x magnification. This case merits discussion due to (1) her survival after 17 days of veno-arterial extracorporeal life support (ECLS) and (2) the possibility of cardiotropic graft versus host disease (GVHD).

  Study phs001336

• Yale SPORE in Skin Cancer Project 2

  Understanding the relationship between tumor and peripheral immune environments could allow longitudinal immune monitoring in cancer. Here, we examined whether T cells that share the same TCRab and are found in both tumor and blood can be interrogated to gain insight into the ongoing tumor T cell response. Paired transcriptome and TCRab repertoire of circulating and tumor-infiltrating T cells were analyzed at the single cell level from matched tumor and blood from patients with metastatic melanoma. The data shared here consist of gene expression matrix and fastq files obtained from sequencing single-cell libraries generated with the Chromium (TM) 5' technique. For each of 18 immunotherapy naive and 11 previously treated melanoma patients, T cells (Live/CD45+/TcRab+) were FACS-sorted from PBMCs and freshly resected tumors. Metadata associated with each individual cell consist of Patient I.D., biological sex, immunotherapy status, amino acid and nucleotide CDR3 sequence of the TCR alpha and beta chain (obtained from matched VDJ region enriched libraries), and sequencing batch. Further details about previous treatment history and other clinical parameters can be found in the associated manuscripts (Lucca et al., 2021: PMID: 33651881; Lu et al., PMID: 39609626).

  Study phs002289

• Genetic Studies of Homologous Recombination Deficiency in Hispanic Gastric Cancer

  Approximately 10% of gastric cancer cases show familial clustering and a hereditary cause is likely, however, only 1-3% cases result from known hereditary syndromes – which are predominantly associated with CDH1 and CTNNA1 genes. Hispanics are > 2 times more likely to be diagnosed and to die from gastric cancer compared to non-Hispanic whites. Not only does gastric cancer precision medicine lag behind other cancers – there is an urgent need to understand its etiology. Germline mutations in homologous recombination genes have been implicated as important risk factors for gastric cancer. The purpose of this study is to continue to generate knowledge to improve gastric cancer outcomes and disparities by 1) characterizing prevalence of germline mutations in homologous recombination genes and identify new genes associated with gastric cancer 2) perform molecular characterization of gastric tumors in Hispanic patients. Participants for germline analysis were enrolled from Chile, Colombia, Mexico, Portugal, Spain, Uruguay.Whole exome sequence capture was performed for all germline and somatic samples using Agilent SureSelect Human All Exon v7 Kit. All sequencing was performed on an Illumina NovaSeq 6000. Germline Analysis: Whole exome sequencing was performed on 536 Hispanic patients (290 males, 246 female)

  Study phs003251

• CSER: Evaluating Utility and Improving Implementation of Genomic Sequencing for Pediatric Cancer Patients in the Diverse Population and Healthcare Settings of Texas: The KidsCanSeq Study

  Through this Clinical Sequencing Evidence-Generating Research (CSER) with Enhanced Diversity project we are completing a clinical study (The Texas KidsCanSeq Study) comparing the results of targeted cancer panel sequencing versus genome-scale testing in pediatric cancer patients across diverse clinical settings. We will compare the targeted pediatric cancer panel to germline whole exome sequencing (WES) of unselected childhood cancer patients. We will also compare an RNA/DNA targeted pediatric cancer panel versus WES, transcriptome sequencing and copy number array of FFPE tumor samples for the subset of patients with high-risk tumors. Exome sequencing is performed from a blood or saliva sample of the pediatric age (0-18) patient. We are building on our success completing the CSER program BASIC3 exome sequencing trial (which included 60% Hispanic and African-American patients from a single large academic center) in this large multi-institutional study of an even more diverse patient population from six pediatric oncology healthcare settings across Texas. Data from the Texas KidsCanSeq study will be submitted through the CSER Data Coordinating Center for access in NIH-supported databases.

  Study phs002378

• Response to tumor-infiltrating lymphocyte adoptive therapy is associated with preexisting CD8+ T-myeloid cell networks in melanoma

  Adoptive cell therapy (ACT) using ex vivo–expanded tumor-infiltrating lymphocytes (TILs) can eliminate or shrink metastatic melanoma, but its long-term efficacy remains limited to a fraction of patients. Using longitudinal samples from 13 patients with metastatic melanoma treated with TIL-ACT in a phase 1 clinical study, we interrogated cellular states within the tumor microenvironment (TME) and their interactions. We performed bulk and single-cell RNA sequencing, whole-exome sequencing, and spatial proteomic analyses in pre- and post-ACT tumor tissues, finding that ACT responders exhibited higher basal tumor cell–intrinsic immunogenicity and mutational burden. Compared with nonresponders, CD8+ TILs exhibited increased cytotoxicity, exhaustion, and costimulation, whereas myeloid cells had increased type I interferon signaling in responders. Cell-cell interaction prediction analyses corroborated by spatial neighborhood analyses revealed that responders had rich baseline intratumoral and stromal tumor–reactive T cell networks with activated myeloid populations. Successful TIL-ACT therapy further reprogrammed the myeloid compartment and increased TIL-myeloid networks. Our systematic target discovery study identifies potential T-myeloid cell network–based biomarkers that could improve patient selection and guide the design of ACT clinical trials.

  Study EGAS50000001217

• High-coverage whole-genome sequencing reveals structural variations in triple-negative breast cancer

  Triple-negative breast cancer (TNBC) cells do not express estrogen receptors, progesterone receptors or human epidermal growth factor receptor 2 (HER2). Currently, apart from poly ADP-ribose polymerase (PARP) inhibitors, there are few effective therapeutic options for this cancer type. Here, we present a comprehensive characterization of genetic alterations in TNBC via high-coverage whole-genome sequencing along with transcriptomic and whole-exome sequencing. Silencing of BRCA1 gene impaired the homologous recombination (HR) pathway in a subset of TNBC, which exhibited similar phenotypes with tumors with BRCA1 mutations; they harbored many structural variations (SVs) with relative enrichment for tandem duplication. Clonal analysis suggested that TP53 mutations and methylation of CpG dinucleotides in the BRCA1 promoter were the early events of carcinogenesis. SVs were associated with driver oncogenic events such as amplification of MYC, NOTCH2 or NOTCH3 and impacted tumor suppressor genes including RB1, PTEN and KMT2C. We also identified a variety of oncogenes that could transform 3T3 mouse fibroblast cells, suggesting that individual TNBC tumors may undergo a unique driver event that can be targetable. Thus, we revealed several features of TNBC that had important clinical implications.

  Study JGAS000095

• Gut microbiome dynamics unravelled with metagenomics sequencing

  It has been already several years since we discovered that microbial therapeutics like Faecal Microbiota Transplantation can be used to treat Clostridium difficile infection (CDI) and Inflammatory bowel disease (IBD) with great success. The concept has challenged us to test the limits of our knowledge with the perspective to improve health in the most diverse conditions like Parkinson disease, depression, autism and obesity, just to mention a few. Note: the figure belongs to the original paper and is owned by the authors. Allyson L.Bird and colleagues from Genentech Inc. (San Francisco) recently published an interesting study building up on the key concept that “As microbial therapeutics are increasingly being tested in diverse patient populations, it is essential to understand the host and environmental factors influencing the microbiome.” The authors of this work analysed 1359 gut microbiome samples using shotgun metagenomics sequencing.  The results of the comparison done between microbiota composition across the different groups showed that biological sex is the strongest driver of diversity, while aging (age range studied: 20–69) appears to be the second factor. As smartly outlined in the authors’ own graphical abstract (figure to the left), Bacteroidota species consistently increased with donors' age while Actinobacteriota species, including Bifidobacterium, decreased. This study also integrated data from oncological patients to draw cancer-related evidences. After correcting the biases for technical and geographic differences, they found that cancer patients show significantly altered gut bacterial communities compared with their healthy counterparts. Eg. E.coli was found to be increased in cancer patients together with Bacteroidota/Firmicutes ratios. By comparing sequential samples taken from the same donors (413) within short-distance time points, the authors found that in the short term, intra-individual differences were less than the inter-individual ones, indicating a certain community stability being the norm. One of the pivotal points from this interesting study is that the data proceeds from extremely well-defined and selected donors. Specifically, the data for 949 selected healthy donors came from the Milieu Intérieur (MI) Consortium and extensive metadata, including demographic variables, serological measures, dietary information, and systemic immune profiles, are available. This precise stratification allowed for the robust detection of smaller changes, compared to former works. All sequencing data has been deposited in the EGA archive under the accession number EGAS00001004437. Enjoy this amazing open access paper published in the Experimental Journal of Medicine on January 2021.

  Blog gut-microbiome-dynamics-unravelled

• The mission of the BIOS Consortium is to create a large-scale data infrastructure and to bring together BBMRI researchers focusing on integrative omics studies in Dutch Biobanks.

  The advent of the genome-wide association study (GWAS) led to the successful identification of thousands of variants that are robustly associated with complex disease phenotypes. Dutch biobanks played a substantial role in these discoveries. For most of these variants, however, the mechanisms through which they contribute to these phenotypes remain unknown. The BIOS Consortium applies a functional genomics approach that integrates genome-wide genetic data with data on the epigenome and transcriptome to elucidate these mechanisms. Over 4000 samples from BBMRI-NL biobanks with in-depth information on disease phenotypes and GWAS data are being enriched with RNA-sequencing and genome-wide DNA methylation data. The same is true for samples with whole-genome sequencing data from GoNL. This unique data infrastructure provides a powerful platform to evaluate key questions in integrative omics from establishing comprehensive eQTL and meQTL catalogues to linking molecular pathways across omics levels to phenotypic outcomes.

  Study EGAS00001001077

• Evolutionary analysis of primary tumors and metastatic lesions from 20 breast cancer patients (99 samples in total) using exome sequencing data.

  Metastatic breast cancers are still incurable. Characterizing their evolutionary landscape including the role of metastatic axillary lymph nodes to seed distant organ metastasis can provide rational basis for effective treatments. Here, we describe the genomic analyses of the primary tumors and metastatic lesions from 20 breast cancer patients (99 samples). Our evolutionary analyses revealed diverse spreading and seeding patterns governing tumor progression. Although linear evolution to successive metastatic sites was common, parallel evolution from the primary tumor to multiple distant sites was also evident. Metastatic spreading was frequently coupled with polyclonal seeding, where multiple metastatic subclones originated from primary tumor and/or other distant metastases. Synchronous axillary lymph node metastasis, a well-established prognosticator of breast cancer, was not involved in seeding distant metastasis, suggesting haematogenous route for cancer dissemination. Clonal evolution coincided frequently with emerging driver alterations and evolving mutational processes, notably a significant increase in apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) associated mutagenesis. Our data provide the first genomic evidence regarding the role of axillary lymph node metastasis in seeding distant organ metastasis and elucidates the evolving mutational landscape during cancer progression.

  Study EGAS00001002737

• Low and variable tumor reactivity of the intratumoral TCR repertoire in human cancers

  Infiltration of human cancers by T cells is generally interpreted as a sign of immune recognition, and there is a growing effort to reactivate dysfunctional T cells at such tumor sites. However, these efforts only have value if the intratumoral T cell receptor (TCR) repertoire of such cells is intrinsically tumor-reactive, and this has not been established in an unbiased manner for most human cancers. To address this issue, we analyzed the intrinsic tumor-reactivity of the intratumoral TCR repertoire of CD8+ T cells in ovarian and colorectal cancer – two tumor types for which T cell infiltrates form a positive prognostic marker. Data obtained demonstrate that a capacity to recognize autologous tumor is limited to approximately 10% of intratumoral CD8+ T cells. Furthermore, in two out of four patient samples tested, no tumor-reactive TCRs were identified, despite infiltration of their tumors by T cells. These data indicate that the intrinsic capacity of intratumoral T cells to recognize adjacent tumor tissue can be rare and variable, and suggest that clinical efforts to reactivate intratumoral T cells will benefit from approaches that simultaneously increase the quality of the intratumoral TCR repertoire.

  Study EGAS00001003119

• FASTQ files of total RNA-Seq data of POPS control samples

  Placental biopsies (n = 64 female placentas, n = 67 male placentas) were selected from healthy pregnancies from the POPs cohort. These patients had no evidence of hypertension at booking and during pregnancy, did not experience pre-eclampsia, Hemolysis, Elevated Liver enzymes, and Low Platelets (HELLP) syndrome, gestational diabetes, or diabetes mellitus type I or type II and other obstetric complications. They delivered live babies with a birth weight percentile in the normal range (20-80th percentile), with no evidence of slowing in fetal growth trajectory. Chorionic villi from the corresponding placentas (free from decidua, visible infarction, calcification, hematoma, or damage) were collected and processed within 30 minutes of separation from the uterus. After repeated washes in chilled phosphate buffered saline, the samples were placed in RNA later (Applied Biosystems) and stored at -80°C. Total placental RNA was extracted using mirVana Isolation Kit (Ambion). For each placenta, approximately 5 mg of tissue were homogenized in the Lysis/Binding solution for 20 sec at 6 m/s using a bead beater (FastPrep24) and Lysing Matrix D Tubes (MP Biomedicals). The samples were then spun at 13,000 rpm for 5 min at 4°C and the supernatants recovered. Afterwards, the manufacturer's instructions were followed. Immediately after the RNA extraction, placental RNA samples were DNase-treated using DNA-free DNA Removal Kit (Ambion), aliquoted, and stored in -80°C. Quantity and quality of the RNA samples were assessed using the Agilent 2100 Bioanalyzer, the Agilent RNA 6000 Nano Kit (Agilent Technologies), and Qubit fluorometer. Libraries were prepared starting with 300-500 ng of good quality total RNA (RIN ≥7.5) using the TruSeq Stranded Total RNA Library Prep Kit with Ribo-Zero Human/Mouse/Rat (Illumina), according to the manufacturer's instructions. The kit contains 96 uniquely indexed adapter combinations in order to allow pooling of multiple samples prior to sequencing. After determining their size (with the Agilent 2100 Bioanalyzer and the Agilent High Sensitivity DNA Kit by Agilent Technologies) and concentration (by qPCR with the KAPA Illumina ABI Prism Library Quantification Kit, Kapa Biosystems), libraries have been pooled and sequenced (single-end, 125 bp) using a Single End V4 Cluster Kit and an Illumina HiSeq2500 or HiSeq4000 instrument.

  Dataset EGAD00001003457

• Study on the Genetics of Alcoholism (COGA): African American Family GWAS

  COGA is a family study of alcoholism, in which the subjects have been drawn from the Collaborative Study on the Genetics of Alcoholism (COGA), a large, ongoing family-based study that includes subjects from seven sites around the US. COGA has gathered detailed, standardized data on study participants, including diagnostic and neurophysiological assessments. This project has already proved successful in identifying several genes that influence the risk for alcoholism and neurophysiological endophenotypes, which have been independently replicated. COGA data were included as part of two Genetic Analysis Workshops, and the phenotypes are familiar to the genetics community. Alcoholic probands were recruited from treatment facilities, assessed by personal interview, and after securing permission, other family members were also assessed. A set of comparison families was drawn from the same communities as the families recruited through an alcoholic proband. Assessment involved a detailed personal interview developed for this project, the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA), which gathers detailed information on alcoholism related symptoms along with other drugs and psychiatric symptoms. Many participants also came to the laboratories for electroencephalographic studies. Neurophysiological features that have been shown to be useful endophenotypes for which we have linkage and in some cases association results are included on a subset of the case-control sample: the beta power of the resting electroencephalogram (EEG), the P3(00) amplitude of the visual event-related potential (ERP), and the theta and delta event-related oscillations (EROs) underlying the P3. As part of COGA, a set of informative African American families were selected to have Genome-Wide Association data obtained within families. Genotyping was performed using the Illumina Omni2.5_080814_1 chip to genotype 3,438 subjects selected from densely affected families. Genotyping was performed at CIDR. This sample complements a set of densely affected European American families previously made available under dbGaP study accession phs000763. In addition, exome sequencing data on a subset of individuals with GWAS were added in version 2.For version 3, a subset had 30X Whole Genome Sequencing (WGS) as part of the NIDA Sequencing Initiative. The subset contained two distinct sets: Sibling pairs where one sibling had at least two dependence diagnoses in the set (alcohol, cannabis, cocaine, and opioid), and the other had none, and non-related Case-Control pairs matched for age and ethnicity where the cases had alcohol and at least 2 other dependence diagnoses and controls had none. After sequencing, some sibling pairs are re-classified as half siblings, Three VCF files (small variants, structural variants, and copy number variations) are provided. Additional substance abuse variables are made available in version 3. We note that the full sample data are deposited in four dbGaP submissions and the sequenced samples are split across all four: CIDR: Collaborative Study on the Genetics of Alcoholism Case Control Study (phs000125). GWAS data on cases (primarily probands) and controls drawn from the families. Families with highest density of alcohol dependence and/or extreme event-related oscillation data (phs000763). GWAS data on 119 extended families of European descent are available here, along with extensive documentation. Study on the Genetics of Alcoholism (COGA): African American Family GWAS (phs000976). GWAS data on all available COGA families of African descent are available. COGA: Smokescreen GWAS (phs001208). GWAS data on all remaining COGA DNA samples, primarily of other racial background, were genotyped on the Smoke Screen array. A listing of all sequenced pairs is provided in the documentation to facilitate the merging of these samples.

  Study phs000976

• Acute Respiratory Distress Network Early Versus Delayed Enteral Feeding to Treat People with Acute Lung Injury or Acute Respiratory Distress Syndrome (ARDSNet EDEN-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Biospecimens: Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from ARDSNet-EDEN include bronchial lavage, plasma, DNA, and urine. Please note that use of biospecimens in genetic and non-genetic research is subject to a tiered consent. Objectives: To determine if initial lower-volume trophic enteral feeding would increase ventilator-free days (VFDs) and decrease gastrointestinal intolerances compared with initial full enteral feeding. Background: Mechanically ventilated patients cannot eat normally and if not fed for long periods become malnourished. Because malnutrition is associated with poor outcomes in critically ill patients, artificial nutrition is often provided, especially in those with acute lung injury (ALI) and with expected longer duration of mechanical ventilation. When feasible, enteral nutrition targeting full caloric needs has been advocated over parenteral nutrition. However, feeding intolerance and common care practices often serve as practical barriers to reaching recommended goals. Although confounded by indication and severity of illness, several observational studies have shown improved clinical outcomes, including fewer infections, shorter duration of mechanical ventilation, and lower mortality for patients receiving a higher percentage of calculated caloric needs. Nonetheless, the best timing, formulation, and amount of enteral nutrition remain unknown. Participants: A total of 1,000 participants were enrolled. Design: Participants were randomized, stratified by site and presence of shock at enrollment, to receive either trophic or full enteral feeding for the first 6 days of mechanical ventilation. The initial 272 patients were also simultaneously randomized to a separate trial (the OMEGA study) comparing a nutritional supplement containing omega-3 fatty acids and antioxidants with an isocaloric, isovolemic control in a 2 × 2 factorial design.The designated feeding strategy was initiated within 6 hours of randomization and continued until death, extubation, or day 6. The care of mechanically ventilated patients still receiving enteral feedings after day 6 was managed according to the full feeding strategy in both groups. In extubated patients who then required reintubation, enteral nutrition was restarted and managed according to the study protocol.In the full-feeding group, enteral nutrition was initiated at 25 mL/h and advanced to goal rates as quickly as possible. Gastric residual volumes were checked every 6 hours while enteral feeding was increased. Patients randomized to the initial trophic-feeding group had enteral nutrition initiated at 10 mL/h (10-20 kcal/h) for the first 272 patients who also received the omega-3 or control supplement (240 mL volume per day). After the data and safety monitoring board stopped the OMEGA portion of the factorial design, the initial trophic feeding rate was changed to 20 kcal/h to approximate the calories that had been delivered in the OMEGA study. Gastric Residual Volumes (GRVs) were checked every 12 hours during trophic feeding. In patients randomized to trophic feeding, enteral nutrition was advanced to full-energy feeding rates following the same protocol used for the full-feeding group if they were still receiving mechanical ventilation at 144 hours. Conclusions: There was no difference between groups with regard to the primary end point, VFDs to day 28. There also were no differences in 60-day mortality, organ failure−free days, ICU-free days, or the incidence of infection between groups. Similarly, there were no differences between groups in VFDs or survival when analyzed by body mass index category or when subsets of patients with shock or more severe lung injury (acute respiratory distress syndrome) were examined.JAMA. 2012 Feb 22;307(8):795-803

  Study phs004168

• Transcriptome of CD4+ T cells and CD8+ T cells in glioblastoma multiforme

  Patients included in this study were over 18 years of age and had a histology-confirmed diagnosis of glioblastoma multiforme (GBM). Exclusion criteria were the previous administration of any anti-tumor therapy including radiation therapy. All patients gave written informed consent. The study was approved by the local ethics committee (TUM Medical school) and conducted following the Declaration of Helsinki. During resection of the tumors, tumor tissue and tissue from normal appearing brain within the operative channel was collected. Blood was drawn during the surgical procedure. Single cell suspensions were prepared from the tumor tissue, the normal appearing brain, and the blood. CD4+ T cells and CD8+ T cells were sorted by flow cytometry. Only patients with a complete set of specimens (CD4+ tumor infiltrating lymphocytes (TIL), CD8+ TIL, CD4+ T cells from normal appearing brain, CD8+ T cells from normal appearing brain, blood-derived CD4+ and CD8+ T cells) containing a minimum of 1000 cells in each sorted sample were further analyzed (n=9). Total RNA was isolated from sorted cell populations using the RNAeasy Plus micro kit (Qiagen, 74034). Quality and integrity of total RNA was controlled on a Bioanalyzer 2100 (Agilent Technologies). Library preparation for bulk-sequencing of poly(A)-RNA was done as described previously (Parekh et al., 2016). Briefly, barcoded cDNA of each sample was generated with a Maxima RT polymerase (ThermoFisher Scientific, EP0742) using oligo-dT primer containing barcodes, unique molecular identifiers (UMIs) and an adaptor. Ends of the cDNAs were extended by a template switch oligo (TSO) and full-length cDNA was amplified with primers binding to the TSO-site and the adaptor. NEB UltraII FS kit was used to fragment cDNA. After end repair and A-tailing, a TruSeq adapter was ligated and 3'-end-fragments were finally amplified using primers with Illumina P5 and P7 overhangs. In comparison to previous descriptions (Parekh et al., 2016), the P5 and P7 sites were exchanged to allow sequencing of the cDNA in read 1 and barcodes and UMIs in read 2 to achieve a better cluster recognition. The library was sequenced on a NextSeq 500 (Illumina) with 59 cycles for the cDNA in read 1 and 16 cycles for the barcodes and UMIs in read 2. Data were processed using the published Drop-seq pipeline (v1.0) to generate sample- and gene-wise UMI tables (Macosko et al., 2015). Reference genome (GRCh38) was used for alignment. Transcript and gene definitions were used according to the Genecode Annotation Version 35.

  Dataset EGAD50000000226

• High Density SNP Association Analysis of Lung Cancer

  This research builds upon an extensive resource of a case-control study that has been ongoing at the UT MD Anderson Cancer Center since 1991. To identify risk variants for lung cancer, we conducted a genome-wide association study. Cases are newly diagnosed, histologically-confirmed patients presenting at MD Anderson Cancer and who had not previously received treatment other than surgery. Controls are healthy individuals seen for routine care at Kelsey-Seybold Clinics, the largest physician group-practice plan in the Houston Metropolitan area. This lung GWAS led to the identification of a susceptibility locus for lung cancer at 15q25.1. We used data from 315,450 tagging SNPs in 1,154 current and former (ever) smoking cases of European ancestry and 1,137 frequency-matched, ever-smoking controls from Houston, Texas in the discovery followed by the replication of the ten SNPs most significantly associated with lung cancer in an additional 711 cases and 632 controls from Texas and 2,013 cases and 3,062 controls from the UK. Two SNPs, rs1051730 and rs8034191, were significantly associated with risk of lung cancer with combined analysis yielded odds ratios of 1.32 (P < 1X10-17) for both SNPs. These two SNPs mapped to a region of strong linkage disequilibrium within 15q25.1 containing PSMA4 and the nicotinic acetylcholine receptor subunit genes CHRNA3 and CHRNA5. (Nat Genet. 2008 May;40(5):616-22. PMID:18385676)

  Study phs000753

• NIMH Human Middle Temporal Gyrus (MTG) Cell Types

  Elucidating the cellular architecture of the human neocortex is central to understanding our cognitive abilities and susceptibility to disease. In this study, we applied single nucleus RNA sequencing to perform a comprehensive analysis of cell types in the middle temporal gyrus of human cerebral cortex. We identify a highly diverse set of excitatory and inhibitory neuronal types, many of which are relatively sparse. Additionally, we found that excitatory types are less layer-restricted than expected based prior knowledge from cell morphologies and from mouse studies. Comparison to a similar mouse cortex single cell RNA-sequencing dataset revealed a surprisingly well-conserved cellular architecture that enables matching of homologous types and predictions of human cell type properties. Despite this general conservation, we also find extensive differences between homologous cell types in human and mouse, including dramatic alterations in proportions, laminar distributions, gene expression, and morphology. These species-specific features emphasize the importance of directly studying human brain. This study conducted by the Allen Institute for Brain Science was supported by the Allen Institute for Brain Science and by US National Institutes of Health grant U01 MH114812-02 to E.S.L. Collaborators request that publications resulting from these data cite their original publication: Hodge RD, Bakken TE, et al. Conserved cell types with divergent features between human and mouse cortex. bioRxiv. 2018 doi: 10.1101/384826.

  Study phs001790

• North Carolina Clinical Genomic Evaluation by NextGen Exome Sequencing (NCGENES)

  North Carolina Clinical Genomic Evaluation by Next-generation Exome Sequencing This study is part of a larger consortium project investigating the validity and best use of next-generation sequencing (in particular, whole exome sequencing, or WES) in clinical care. Participants are patients who were either seen in the UNC Cancer and Adult Genetics Clinic or referred to the study by their physician. They will be approached by their physician or a genetic counselor for recruitment. Once enrolled, a clinical geneticist or genetic counselor will obtain consent and collect blood samples to be analyzed using WES. Results may include information related to a diagnosis and incidental information. Medically actionable incidental findings will be CLIA-certified and returned to participants in a routine genetic counseling session, along with diagnostic findings. Eligible adult participants will be randomized to have the opportunity to choose to get certain types of non-medically actionable incidental findings, as well. Their decisions will be investigated, as will psychosocial and behavioral responses to sequencing and receiving sequencing information. This is a longitudinal, mixed methods study (i.e., multiple assessments pre- and post-return of results, with both quantitative and qualitative methods used to gather data). Because only the quantitative component of the study uses randomization, only measures and procedures associated with that component are included here. The third study release includes data of additional n=189 subjects.

  Study phs000827

• Ischemic Stroke Genetics Study (ISGS)

  The third leading cause of death in the United States, stroke is an acute neurological event leading to death of neural tissues. Although the majority of strokes are ischemic strokes, meaning there is oxygen deprivation to the brain, almost 20% of strokes are hemorrhagic, resulting from bleeding into the brain. Stroke is a complex disorder and likely multigenic in nature, resulting from a combination of genetic and environmental factors. These well characterized risk factors that contribute to the incidence of stroke include hypertension, cardiac disease, sickle cell disease, hyperhomocysteinemia, family history of stroke and smoking. ISGS aim is to perform a prospective genetic association study of ischemic stroke focusing on the hemostatic system. ISGS is a 5-center case-control study of first-ever ischemic stroke cases and concurrent controls individually matched for age, sex and recruitment site. This data includes that from subjects both banked in the NINDS repository with biologicals publicly available, and those whose samples are not banked/not available. Important links to apply for individual-level data Data Use Certification Requirements (DUC) Apply here for controlled access to individual level data Participant Protection Policy FAQ --> This study utilized the NINDS Repository Cerebrovascular/Stroke Study, and neurologically normal controls from the sample population which are banked in the National Institute of Neurological Disorders and Stroke (NINDS Repository) collection for a first stage whole genome analysis.

  Study phs000102

• Natural History, Pathogenesis and Outcome of Melorheostosis

  Melorheostosis is a rare osteosclerotic disease resulting in exuberant excessive bone growth with a characteristic radiographic appearance often described as "dripping candle wax". As a result of these bony formations, patients report mild to moderate pain that interferes with their routine activities. It is usually diagnosed on radiographs but bone biopsy may be performed to exclude other osteosclerotic diseases and/or osteosarcoma. Deformities, limb-length discrepancy, muscle atrophy, neurological deficit have been reported as complications. A subset of patients have somatic mutations in MAP2K1. The cause of this disease is not known in all patients, the natural history poorly described and there is no clearly-defined systemic therapy. We propose a prospective observational study to investigate the natural history and pathogenesis of the disease. Subjects will undergo standardized initial evaluation and medically indicated testing. Skin biopsies may be performed to test for known mutations related to melorheostosis, and if negative affected bone and/or skin may be sent for genetic testing for acquired somatic mutations in genes that control bone homeostasis. Enrolled subjects will be followed every two to three years for assessment of disease progression and receive clinically indicated testing and treatment. The study of this rare bone disease offers the potential to generate new insights, provide answers as well as generate new questions into the biology of the skeletal and mineral metabolism.

  Study phs001976

• Osteosarcoma Genomics

  In this study we attempt to elucidate the genomic characteristics of osteosarcoma. Clinical characteristics 58 tumor / normal pairs from 58 patients were included in the study. Median age at diagnosis was 12 years. 49% of the patients were male and 47% had metastases at diagnosis. 5 year overall survival was 49% for the entire population, 33% for patients with metastatic disease and 64% for patients with localized disease. Patients with metastatic disease at diagnosis had a significantly worse overall survival. All cases except 2 were sporadic and no patients had stigmata of Rothmund-Thomson, Bloom's or Werner's syndromes or Paget's disease. Two familial cases were affected siblings from a family in which there were 2 unaffected parents and 2 unaffected siblings. None of the patients had known Li Fraumeni or hereditary retinoblastoma. Sample Selection and Clinical Data Samples were contributed by hospitals in Brazil, Spain, Mexico and the United States. All patients had histopathology confirmed to be osteosarcoma by a pathologist at the local institution. All but 5 tumor specimens sequenced were obtained pre-chemotherapy from the primary tumor at the time of diagnosis. 2 tumor specimens were obtained pre-chemotherapy from a metastatic tumor at the time of diagnosis. 3 tumor specimens were obtained post-chemotherapy from a metastatic tumor.

  Study phs000699

• The Gene Partnership (TGP) - eMERGE Data

  The Gene Partnership (TGP) is a prospective longitudinal registry at Boston Children's Hospital (BCH) to study the genetic and environmental contributions to childhood health and disease, collect genetic information on a large number of children who have been phenotyped, and implement the Informed Cohort and the Informed Cohort Oversight Board (ICOB). The term "The Gene Partnership" reflects a partnership between researchers and participants. Children seen at BCH are offered enrollment, as are their parents and siblings. DNA is collected on all enrollees. BCH has a comprehensive EMR system, and virtually all inpatient and outpatient data are captured electronically. Clinical data in the BCH EMR is loaded in the i2b2 data warehouse which is available to investigators. Cases, phenotypes, and covariates are ascertained using the i2b2 database. Participants at BCH in TGP have consented to receive any research result and/or incidental finding that arises from studies using TGP that is approved by the Informed Cohort Oversight Board (ICOB) and is in accordance with the participants' preferences; results are returned through the Personally Controlled Health Record (PCHR). BCH and Cincinnati Children's Hospital Medical Center (CCHMC) have partnered as the Pediatric Alliance for Genomic and Electronic Medical Record (EMR) Research (PAGER) site for the eMERGE Phase II network for pediatric institutions, and the cohort for eMERGE at BCH is TGP.

  Study phs000495

• Single-cell RNA-seq of rheumatoid arthritis synovial tissue using low-cost microfluidic instrumentation

  Droplet-based single-cell RNA-seq has emerged as a powerful technique for massively parallel cellular profiling. While these approaches offer the exciting promise to deconvolute cellular heterogeneity in diseased tissues, the lack of cost-effective, reliable, and user-friendly instrumentation has hindered widespread adoption of droplet microfluidic techniques. To address this, we have developed a microfluidic control instrument that can be easily assembled from 3D printed parts and commercially available components costing approximately $575. We adapted this instrument for massively parallel scRNA-seq and deployed it in a clinical environment to perform single-cell transcriptome profiling of disaggregated synovial tissue from 5 rheumatoid arthritis patients. We sequenced 20,387 single cells from synovectomies, revealing 13 transcriptomically distinct clusters. These encompass a comprehensive and unbiased characterization of the autoimmune infiltrate, including inflammatory T and NK subsets that contribute to disease biology. Additionally, we identified fibroblast subpopulations that are demarcated via THY1 (CD90) and CD55 expression. Further experiments confirm that these represent synovial fibroblasts residing within the synovial intimal lining and subintimal lining, respectively, each under the influence of differing microenvironments. We envision that this instrument will have broad utility in basic and clinical settings, enabling low-cost and routine application of microfluidic techniques, and in particular single-cell transcriptome profiling. Reprinted from [Stephenson et al., Nature Communications, 2018], with permission from the Nature Publishing Group.

  Study phs001529

• Genome-Wide Association Study of Heparin-Induced Thrombocytopenia

  Heparin-induced thrombocytopenia (HIT) is an unpredictable, potentially catastrophic adverse effect resulting from an immune response to platelet factor 4 (PF4)/heparin complexes. We performed a genome-wide association study (GWAS) with positive functional assay as the outcome. Genetic associations were investigated in a cohort of functional assay-confirmed HIT cases, antibody-positive (function assay-negative) controls, and antibody negative controls. Both PF4-specific enzyme-linked immunosorbent assay (ELISA) and serotonin release assay (SRA) were positive in every HIT case. GWAS genotyping was performed at the Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences (IMS). All samples in the discovery and replication cohorts were genotyped using the lllumina® Infinium HumanOmniExpressExome BeadChip, which contains 958,497 markers, including 273,000 functional exonic markers. Quality control was accomplished using sample and marker call rate ≥98%, sex mismatch, duplicate concordance, and removal of related samples through identity by descent. Genomic imputation was performed for samples using Minimac4 and the phase3 v5 reference panel data from the 1000 genomes project. The primary GWAS analysis used multivariable logistic regression assuming an additive genetic model with functional assay-confirmed case status as the outcome. Both PF4/heparin antibody negative and antibody positive controls were considered controls in the primary analysis. Logistic regressions were used to generate odds ratios and 95% confidence intervals (95%CIs) after adjustment for age, sex, and first three principal components.

  Study phs002863