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• University of Pennsylvania CAR T Cell Responding and Non-responding Patients

  The adoptive transfer of autologous T cells genetically modified to express a CD19-specific, 4-1BB/CD3zeta-signaling chimeric antigen receptor (CAR; CTL019) has shown remarkable activity in patients with B acute lymphoblastic leukemia. Similar therapy can induce long-term remissions for relapsed/refractory chronic lymphocytic leukemia (CLL) patients, but in only a small subset of subjects. The determinants of response and resistance to CTL019 therapy of CLL are not fully understood. We employed next generation sequencing of RNA (RNA-seq) to identify predictive indicators of response to CTL019 treatment. We performed RNA-seq on leukapheresis and manufactured infusion product T cells from patients with heavily pre-treated and high-risk disease. To characterize potency, we also performed RNA-seq on the cellular infusion product after CAR-specific stimulation. Our findings indicate that durable remission in CLL is associated with gene expression signatures of early memory T cell differentiation (e.g., STAT3), while T cells from poorly- or non-responding patients exhibited elevated expression of key regulators of late memory as well as effector T cell differentiation, apoptosis, aerobic glycolysis, hypoxia and exhaustion. These gene expression signatures, along with additional immunological biomarkers, may be used to identify which patients are most likely to respond to cellular therapies and suggest manufacturing modifications that might potentiate the generation of maximally efficacious infusion products. In a follow-up study, we report multiplex CRISPR-Cas9 gene editing on T cells in humans to test the hypothesis that disrupting genes encoding the endogenous T cell receptor (TCR), TCRα (TRAC) and TCRβ (TRBC), as well as PD-1 (PDCD1) would enhance the efficacy of autologous T cells engineered to express a transgenic NY-ESO TCR. We used single cell RNA-seq to comprehensively characterize the transcriptomic phenotype of this T cell product and its evolution over time in a patient with sarcoma. Notably, this patient's transferred T cells that persisted in vivo demonstrated increases in expression of genes associated with a central memory state (IL7R, TCF7). These findings may guide future trials involving administration of genetically redirected, genome -edited T cells.In this follow-up study, we investigated whether CRISPR-Cas9-mediated disruption of PDCD1 and/or CTLA-4 could restore CART dysfunction in healthy donors and/or CLL patients. We show that depletion of CTLA-4 rescues the function of T cells from leukemia patients that previously failed CART cell treatment. We performed single-cell RNA sequencing and characterized the transcriptomic landscape of CTLA-4 KO CART19 cells that showed higher proliferation and anti-tumor efficacy by permitting unopposed CD28 signaling and maintenance of CAR expression on the T cell surface under stress-test conditions of chronic antigen exposure. Our findings reveal that selective disruption of CTLA-4 invigorates dysfunctional patient T cells, providing a strategy for increasing patient responses to CART cell therapy.

  Study phs001707

• dbGaP Collection: Compilation of Individual-Level Genomic Data for General Research Use

  This dbGaP Collection contains all authorized individual-level genomic datasets currently in dbGaP that are approved for General Research Use (GRU) and have no further limitations beyond those outlined in the model Data Use Certification Agreement. Access to this study will include any additional authorized individual-level GRU datasets that become available. Renewal of this study is required annually. Data Included in this Study Individual-level genomic data designated for general research use with no further use limitations or restrictions, that is, Data use does not require approval by an Institutional Review Board for secondary analyses Data have no publication embargo Data have no other use limitations (e.g., requirement for collaboration or publication; restricted for use by academic or not-for-profit organizations; restricted to health, medical, and/or biomedical research) In response to requests from the scientific community, the NIH implemented a change in the procedures for accessing individual-level GRU genomic data. Under the modified procedures, interested investigators can request GRU individual-level genomic datasets with a single application. However, please note that these data have not been harmonized. Additionally, to help expedite the processing of requests for individual-level GRU genomic datasets, the requests will be reviewed by a single, central Data Access Committee. The process for requesting these datasets is identical to the request process for non-GRU individual-level, controlled-access data, such as the expectation that investigators will abide by the NIH Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies and Data Use Certification Agreement. Effective April 24, 2018, the Data Use Limitations (DUL) for the Genes and Blood Clotting Study (GABC) (phs000304) was updated to Health/Medical/Biomedical, Not-for-profit Use Only (HMB-NPU). Additionally, the submitting institutions have requested the removal of the National Heart, Lung, and Blood Institute (NHLBI) "Grand Opportunity" Exome Sequencing Project (GO-ESP) Lung Cohorts Exome Sequencing Project: Genetic modifiers of Pseudomonas aeruginosa (Pa) lung infection acquisition in cystic fibrosis (phs000254) from the dbGaP Compilation of Individual-Level Genomic Data for General Research Use (dbGaP Compilation) (phs000688). As such, data from studies phs000304 and phs000254 are no longer available as part of the dbGaP Compilation (phs000688). Investigators must submit separate Data Access Requests (DARs) for the two studies and be approved by the NHLBI Data Access Committee.

  Study phs000688

• Pancreatic Cancer Sequencing Initiative

  Pancreatic Cancer Sequencing Initiative for the International Cancer Genome Consortium at the Ontario Institute for Cancer Research.

  Study EGAS00001000343

• Hematopoietic Cell Transplant for Sickle Cell Disease (HCT for SCD)

  The Center for International Blood and Marrow Transplant Research (CIBMTR) is a hematopoietic cell transplant registry that was established in 1972 at the Medical College of Wisconsin. The overarching goal of the registry is to study trends in transplantations and to advance the understanding and application of allogeneic hematopoietic cell transplantation for malignant and non-malignant diseases. Included in this dataset are children, adolescents and young adults with severe sickle cell disease who received an allogeneic hematopoietic cell transplant in the United States and provided written informed consent for research.Hematopoietic cell transplant for sickle cell disease is curative. Offering this treatment for patients with severe disease is challenging as only about 20-25% of patients expected to benefit have an HLA-matched sibling. Consequently, several transplantations have utilized an HLA-matched or mismatched unrelated adult donor and HLA-mismatched relative. Transplantation strategies have also evolved over time that has included transplant conditioning regimens of varying intensity, grafts other than bone marrow and novel approaches to overcome the donor-recipient histocompatibility barrier and limit graft-versus-host disease. The data that is available for sickle cell disease transplants have been utilized to report on outcomes after transplantation and compare outcomes after transplantation of grafts HLA-matched related, HLA-mismatched related, HLA-matched and HLA-mismatched unrelated donors. Collectively, these data have advanced our knowledge and understanding of hematopoietic cell transplant for this disease. These data can also serve as "contemporaneous controls" for comparison with other more recent curative treatments like gene therapy and gene editing.Data available for request include allogeneic hematopoietic cell transplants for sickle cell disease (Hb SS and Hb Sβ thalassemia) in the United States from 1991 to 2019. Follow-up data through December 2020 are available.Instructions for requesting individual-level data are available on BioData Catalyst at https://biodatacatalyst.nhlbi.nih.gov/resources/data/. Apply for data access in dbGaP. Upon approval, users may begin accessing requested data in BioData Catalyst. For questions about availability, you may contact the BioData Catalyst team at https://biodatacatalyst.nhlbi.nih.gov/contact.

  Study phs002385

• Unmatched WGS from bone marrow samples of 5 chr21 amplified blast phase myeloproliferative neoplasm patients

  We describe recurrent chromothripsis of chromosome 21 in a subset of patients in blast phase of a myeloproliferative neoplasm (BP-MPN), which alongside other structural variants leads to amplification of a region of chromosome 21 in ~25% of patients (‘chr21amp’). Chr21amp BP-MPN has a particularly aggressive and treatment-resistant phenotype. Here we provide high-depth whole genome sequencing (WGS) in five chr21amp BP-MPN cases, to a median coverage of 81x [range 77-86] and purity 79% [range 58-88%].

  Dataset EGAD00001011280

• Metaplastic breast cancer in a patient with neurofibromatosis type 1 and somatic loss of heterozygosity

  Targeted genetic sequencing was performed on a 41-year-old female with metaplastic breast cancer (MBC) and neurofibromatosis type I (NF1). A custom panel capturing 279 cancer related genes was used to identify a germline pathogenic SNV in NF1, as well several other somatic alterations.

  Study phs001566

• Bell_activation_timecourse

  We purified human naive and memory B cells from PBMCs. We stimulated them with IgM cross-linker providing BCR stimulation, multimeric CD40L that engages costimulatory receptor CD40 on the B cell, and cytokines IL-2 and IL-21. To comprehensively characterise activation dynamics of naive and memory B cells, we performed single-cell RNA sequencing (scRNA-seq) and B cell receptor sequencing (BCR-seq) in resting cells (day 0), before the first division (day 1), at the time of the first division (day 3) and following the full B cell differentiation (day 6)

  Dataset EGAD50000002115

• Whole scRNA-seq from pre frontal cortex patient biopsy

  The single- cell RNA-seq prefrontal cortex sample was selected from a cohort of patients with hydrocephalus ≥18 years of age planning to undergo CSF diversion surgery either with a ventriculoperitoneal shunt placement (VP) or ventriculocisternostomy (VCS). The tissue was dissociated followed by red cell and debris removal and counting of the cells to be sequenced with (scRNA-seq; 10x Genomics kit v2). After dissociation only non neuronal cells were retrieved.

  Dataset EGAD50000001542

• Somatic L1 retrotransposition mapping in high-grade serous ovarian carcinoma using LDI-PCR/Nanopore-sequencing (part 2)

  Somatic L1 retrotransposition was mapped in high-grade serous carcinoma (HGSC) tumors using LDI-PCR/Nanopore-seq method. This method identifies somatic L1 insertions originating from two active L1 loci at chr22q12.1 and chrXp22.2. Multiple tumors from the same patient were utilised to understand L1-mediated intrapatient heterogeneity. Long-read data generated by LDI-Nanopore sequencing was aligned to the reference genome (GRCh38). This dataset contains the remaining file of this study.

  Dataset EGAD50000001757

• human placenta derived trophoblast organoids expression changes by co-culturing with adipose spheroids

  This dataset includes the Prime-seq raw sequencing data of the 3 replicates of trophoblast organoids co-cultured with adipose spheroids and 3 without adipos spheorids. The libraries were generated according to the published Prime-seq library preparation protocol, and were multiplexed with all the samples from the experiment. The libraries were sequenced on Illumina NovaSeq 6000 at Novogene. The files are paired fastq files.

  Dataset EGAD50000001223

• Transcriptome analysis of human iPSC-derived microglia in a novel human 3D cortical tissue model

  scRNA-seq analysis of human iPSC-derived microglia in a novel, human in vitro 3D cortical tissue model. Samples include three distinct conditions (each as biological duplicates): wild-type microglia extracted from cultures after 1 month (WT_1mo) and 3 months (WT_3mo) of culturing, as well as knock-in microglia extracted from cultures carrying three familial AD mutations in the APP gene (Swedish, Iberian, Arctic; introduced by CRISPR/Cas9-mediated knock-in) after 3 months of culturing (KI_3mo).

  Dataset EGAD50000000677

• Impact of allogeneic umbilical-cord derived mesenchymal stromal cells on B-cell scRNAseq in patients with systemic lupus erythematosus

  The impact of MSC(UC) on peripheral B cells from Systemic Lupus Erythematosus (SLE) patients was studied by 10X scRNAseq. This scRNAseq study encompassed 3 SLE patients at 3 time points: before or after (1 month, and 3 months) MSC injection in order to analyze B cell subsets and their DEG. The aim of this study was to observe the potential changes of B cell subsets after MSC(UC) injection in SLE patients.

  Dataset EGAD50000000471

• Quantitative Exploratory Proteomics Analysis of Glioblastoma in Initial and Recurrent Tumors

  Shotgun Proteomics; Glioblastoma samples from 11 patients were obtained at initial and recurrent tumor stages. Proteins were extracted, identified and quantified via tandem mass spectrometry based on a TMT isobaric labelling approach. Quatitative proteomics reveals 146 differentially abundant proteins using a patient-matched statistical modelling. Analysis of proteolytic processing reveals differential proteolytic patterns in recurrent tumors. Proteogenomics reveals the presense of 30 single-amino acid variants present in glioblastoma tumor and 1 of those as increased in recurrent tumor.

  Dataset EGAD00010002350

• Massive genomic rearrangement acquired in a single catastrophic event during cancer development

  Massive genomic rearrangement acquired in a single catastrophic event during cancer development

  Dataset EGAD00001000002

• Copy number and mutation profiling of Stage 1 epithelial ovarian cancer biopsies

  This project aims at characterizing the genome-wide copy number profile and the variant profile of 139 genes om the five major histotytpes of early-stage (stage I) epithelial ovarian cancer (EOC), to provide insight in the the aethiology and development of the disease.

  Study EGAS00001004961

• Whole genome sequencing of colorectal cancer patients (SG-BULK-1)

  The study was approved by the institutional review board of Singhealth (2018-2795). Ten 5-µm tissue sections were cut using standard microtomy techniques. Each collected cell population was then extracted using the allprep kit. Extracted material was then quantified using a Qubit fluorometer.

  Study EGAS00001006030

• Genome and transcriptome sequence data from a metastatic colorectal carcinoma patient

  Genome and transcriptome sequence data from a metastatic colorectal carcinoma patient, generated as part of the BC Cancer Agency's Personalized OncoGenomics (POG) study

  Dataset EGAD00001001307

• Genome and transcriptome sequence data from a primary unknown cancer patient

  Genome and transcriptome sequence data from a primary unknown cancer patient, generated as part of the BC Cancer Agency's Personalized OncoGenomics (POG) study

  Dataset EGAD00001001308

• Genome and transcriptome sequence data from a breast cancer patient

  Genome and transcriptome sequence data from a breast cancer patient, generated as part of the BC Cancer Agency's Personalized OncoGenomics (POG) study

  Dataset EGAD00001002534

• Genome and transcriptome sequence data from a breast cancer patient

  Genome and transcriptome sequence data from a breast cancer patient, generated as part of the BC Cancer Agency's Personalized OncoGenomics (POG) study

  Dataset EGAD00001002531

• Genome and transcriptome sequence data from an ovarian cancer patient

  Genome and transcriptome sequence data from an ovarian cancer patient, generated as part of the BC Cancer Agency's Personalized OncoGenomics (POG) study

  Dataset EGAD00001002533

• Genome and transcriptome sequence data from a breast cancer patient

  Genome and transcriptome sequence data from a breast cancer patient, generated as part of the BC Cancer Agency's Personalized OncoGenomics (POG) study

  Dataset EGAD00001002532

• Genome and transcriptome sequence data from a uterine sarcoma patient

  Genome and transcriptome sequence data from a uterine sarcoma patient, generated as part of the BC Cancer Agency's Personalized OncoGenomics (POG) study

  Dataset EGAD00001002538

• Genome and transcriptome sequence data from a cholangiocarcinoma patient

  Genome and transcriptome sequence data from a cholangiocarcinoma patient, generated as part of the BC Cancer Agency's Personalized OncoGenomics (POG) study

  Dataset EGAD00001002537

• Genome and transcriptome sequence data from a breast cancer patient

  Genome and transcriptome sequence data from a breast cancer patient, generated as part of the BC Cancer Agency's Personalized OncoGenomics (POG) study

  Dataset EGAD00001002536