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• Mtb infected and uninfected neutrophils after 1 and 6 hrs

  Fastq.gz files for mRNA sequenced from Mtb infected and uninfected neutrophils after 1 and 6 hrs. Samples were sequenced in 2 batched as indicated per experiment. Batch 1 was SE unstranded, 100bp on an Illumina HiSeq4000 sequencer and batch 2 unstranded, 150bp paired-end on an Illumina NovaSeq6000 sequencer. Phenotypic data for the samples is also included.

  Dataset EGAD00001010893

• Gene Characterization in Carbohydrate metabolic alterations (neonatel diabetes & congenital hyperinsulinemic) in early childhood (2018-03-14)

  Whole Exome Sequencing of trios (proband + parents) or probands only with Neonatal Diabetes Mellitus (NDM) or Congenital Hyperinsulinism of Infancy (CHI) of unknown genetic origin. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/ . This dataset contains all the data available for this study on 2018-03-14.

  Dataset EGAD00001004040

• Preclinical Pediatric Molecular Analysis for Therapy Choice (MATCH)

  Purpose: Pediatric solid tumors arise from diverse tissues during development and exhibit a wide range of molecular, cellular and genetic features. This diversity, combined with the low incidence of pediatric cancer makes it increasingly difficult to personalize therapy for individual patients based on the unique features of their tumors. Therefore, well-credentialed preclinical models that capture the diversity and heterogeneity of pediatric solid tumors are essential for identifying molecular targeted therapeutics for precision medicine. Experimental Design: Here, we report 281 orthotopic patient derived xenografts (O-PDXs) from 224 patients representing 24 different types of pediatric solid tumors. We have performed genomic characterization of the O-PDXs and compared them to their corresponding patient tumors. To demonstrate the feasibility and utility of using such a diverse collection of O-PDXs in preclinical studies, we performed a preclinical pediatric precision medicine trial based on the NCI-COG Pediatric MATCH trial enrollment criteria. We also tested molecular targeted therapy for a novel oncogenic fusion recently reported in pediatric melanoma and precision drug delivery using nano-liposomal irinotecan. Results: In the preclinical match study, we identified one specific single agent response to LY3023414 in an osteosarcoma model with a TSC2 variant of unknown significance. Combinations of nano-liposomal irinotecan were effective in treating both Ewing sarcoma and rhabdomyosarcoma xenografts. Conclusion: Our studies demonstrate the value of large, well-credentialed preclinical models for future precision medicine in pediatric oncology using single agents, drug combinations and novel drug formulations.

  Study EGAS00001008011

• WES analysis of a mixed cohort of pituitary tumors

  BACKGROUND: Sporadic pituitary adenomas are the second most common primary brain tumor, but their genetics remains incompletely understood. We performed deep DNA sequencing of 42 pituitary macroadenomas, including hormonally active and atypical adenomas. METHODS: Pituitary adenomas representative of a spectrum of histopathologic subtypes, primary and recurrent tumors, and MIB-1 proliferative indices were profiled. Whole-exome sequencing was performed on tumors and paired blood followed by analysis of somatic copy number alteration and mutation. RESULTS: On the whole, the tumors harbored a low rate of mutations, similar to other benign brain tumors. However, almost one-third (29%) exhibited somatic copy-number alterations across large fractions of the genome (up to 99%). Despite such widespread genomic disruption, these tumors had few focal events, which is atypical among highly-disrupted cancers. The other 71% of tumors formed a distinct molecular class, with somatic copy-number alterations involving less than 6% of the genome. Among the highly-disrupted group, 92% were functional or atypical null-cell adenomas, whereas 87% of the less-disrupted group were clinically non-functional adenomas. The only significantly recurrent events were arm-level losses of chromosomes 1, 2, 11, and 18. No significantly recurrent mutations or insertion/deletion events were identified, suggesting no genes are altered by exomic mutations in >15% of pituitary tumors. CONCLUSIONS: Genomic characterization of a large series of sporadic pituitary adenomas reveals two classes of tumor, based on genomic disruption from arm-level copy-number alterations, which associate with hormonal and histologic subtypes.

  Study EGAS00001001714

• Oncogenic fate conversion by PRDM16s causes acute myeloid leukemia

  Oncogenic mutations confer aberrant replicative capacity to cells with little or no replicative capacity, generating cancer stem cells that perpetuate the tumor through extensive self-replication and differentiation blockade. However, whether oncogenes disrupt the cellular identity ofcancer stem cell by altering the developmental potential is unknown. Fate conversion has been demonstrated by ectopic expression of master transcriptional regulators, such as PU.1 and C/EBP alpha that confers myeloid cell fate to other cell types, and PRDM16 that confers brown adipose fate to white adipocytes or myoblasts. Here we show that a transcriptional regulator overexpressed in human myeloid malignancies, PRDM16s, causes oncogenic fate conversion, by transforming cells fated to form platelets and erythrocytes into myeloid leukemia-initiating cells (LICs). Prdm16s expression in hematopoietic progenitor cells caused a myelodysplastic syndrome (MDS)-like disease that progressed to acute myelogenous leukemia (AML). The myeloid diseases caused by Prdm16s exhibited expansion of megakaryocyte-erythroid progenitors (MEPs) but not granulocyte-macrophage progenitors. MEPs from Prdm16s-induced leukemia possessed LIC potential, and expression of Prdm16s in normal MEPs was sufficient to convert them to myeloid LICs and blocked megakaryocytic/erythroid potential. Prdm16s induced the expression of myeloid master regulators, including PU.1 and C/EBP alpha, by interacting with their super enhancers. Ablation of myeloid master regulators attenuated the myeloid potential and reinstalled the megakaryocytic/erythroid potential of leukemic-MEPs in mouse models and in human AML with PRDM16 rearrangement. Our study demonstrates that oncogenic Prdm16 expression converts the fate of MEPs to a malignant myeloid fate by activating myeloid master transcription factors.

  Study EGAS00001003235

• Dynamics of genome architecture and chromatin function during human B cell differentiation and neoplastic transformation

  Despite recent advances, the dynamics of genome architecture and chromatin function during human cell differentiation and its potential reorganization upon neoplastic transformation remains poorly characterized. Here, we integrate in situ Hi-C and nine additional omic layers to define and biologically characterize the dynamic changes in three-dimensional (3D) genome architecture across normal B cell differentiation and in neoplastic cells from different subtypes of chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) patients. Beyond conventional active (A) and inactive (B) compartments, an integrative analysis of Hi-C data uncovers a highly-dynamic intermediate compartment enriched in poised and polycomb-repressed chromatin. During B cell development, we detect that 28% of the compartments change at defined maturation stages and mostly involve the intermediate compartment. The transition from naive to germinal center B cells is associated with widespread chromatin activation, which mostly reverts into the naive state upon further maturation of germinal center cells into memory B cells. The analysis of CLL and MCL neoplastic cells points both to entity and subtype-specific alterations in chromosome organization. Remarkably, we observe that large chromatin blocks containing key disease-specific genes alter their 3D genome organization. These include the inactivation of a 2Mb region containing the EBF1 gene in CLL and the activation of a 6.1Mb region containing the SOX11 gene in clinically aggressive MCL. This study indicates that 3D genome interactions are extensively modulated during normal B cell differentiation and that the genome of B cell neoplasias acquires a tumor-specific 3D genome architecture.

  Study EGAS00001004763

• Transcriptional_reprogramming_from_innate_immune_functions_to_a_pro_thrombotic_signature_upon_SARS_CoV_2_sensing_by_monocytes_in_COVID_19

  Alterations in the myeloid immune compartment have been observed in COVID-19, but the specific mechanisms underlying these impairments are not completely understood. Here we examined the functionality of classical CD14+ monocytes as a main myeloid cell component in well-defined cohorts of patients with mild and moderate COVID-19 during the acute phase of infection and compared them to that of healthy individuals. We found that ex vivo isolated CD14+ monocytes from mild and moderate COVID-19 patients display specific expression patterns of costimulatory and inhibitory receptors that clearly distinguish them from healthy monocytes, as well as an altered metabolic profile. In addition, decreased NFB activation in COVID-19 monocytes ex vivo is accompanied by an intact type I IFN antiviral response. Secondary pathogen sensing ex vivo led to a state of functional unresponsiveness characterized by a defect in pro-inflammatory cytokine expression, NFB-driven cytokine responses and defective type I IFN response in moderate COVID-19 monocytes, together with defects in the metabolic reprogramming that innate immune cells usually undergo upon pathogen sensing. Transcriptionally and functionally, COVID-19 monocytes switched their gene expression signature from canonical innate immune functions to a pro-thrombotic phenotype characterized by enrichment of pathways involved in hemostasis, immunothrombosis, platelet aggregation and other accessory pathways to platelet activation, accumulation and clot formation, including extracellular matrix reorganization, integrin cell surface interactions and signaling by PDGF. These results provide a potential mechanism by which innate immune dysfunction in COVID-19 may contribute to disease pathology

  Study EGAS00001006788

• Single Cell RNA Sequencing of Tendon Scar Tissue (Tenolysis)

  This human tenolysis sample was collected as a control (non-diabetic sample) as part of larger study described below.The purpose of the larger study is to define the cellular and molecular environment in tendons, pulleys, synovial sheath, tendon scar tissue, and palmar fascia samples. The samples are isolated from discarded tissues from patients who undergo lower limb amputation surgery, dupuytren's disease, trigger finger release, tenolysis surgery, tenosynovitis surgery, distal biceps tendon repair, common extensor debridement and repair, common flexor debridement and repair, or proximal long head of the biceps tenodesis.The dramatic increase in Type 2 Diabetes Mellitus (T2DM) as part of the obesity epidemic is one of the most pressing health challenges facing the U.S. Type II diabetes results in systemic inflammation and is characterized by metabolic dysfunction including elevated plasma glucose levels (hyperglycemia). There is a clear link between T2DM and musculoskeletal pathologies; T2DM accelerates the progression of osteoarthritis, and increases fracture risk. Moreover, T2DM impairs tendon homeostasis and repair, and increases the risk and severity of tenosynovitis (infection of the tendon and sheath), however there remains a paucity of information regarding the molecular mechanisms of diabetes-induced changes in tendon function. Flexor and extensor tendons facilitate digit range of motion (ROM) and movement of the hand. Tendon gliding can be impaired by tendon fibrosis and an inability to fit within the surrounding synovial sheath, or due to the formation of fibrous adhesions between the tendon and synovial sheath during healing. Fibrosis and increased disorganization of the extracellular matrix are hallmarks of the diabetic hand phenotype observed in T2DM patients. T2DM dramatically affects the baseline function of tendons; up to 50% of diabetic patients experience impaired hand function, including increased rates of tenosynovitis, and carpal tunnel syndrome. In addition to decrements in tendon gliding function, deficits in mechanical properties are also observed, rendering diabetic tendons more susceptible to rupture. Considering that the complication rate of primary flexor tendon repairs is as high as 40% in non-diabetic patients, and that T2DM further impairs tendon healing, it is imperative to understand the cellular and molecular components of diabetic tendinopathy. The study will define the overall cellular and molecular environment in tendon pulleys, palmar fascia, synovial sheath tissue, and scar tissue (tenolysis and tenosynovitis samples) as a function of type II diabetes.

  Study phs004076

• 10x Genomics scRNA-seq for 3 samples

  This dataset contains 10x Genomics single-cell RNA-seq data from two primary leukemia samples and their corresponding patient-derived xenograft (PDX) models. All the 3 samples are in bam file type.

  Dataset EGAD50000001788

• The CHOP Pediatric Genetic Sequencing (PediSeq) Project : Applying Genomic Sequencing in Pediatrics

  The purpose of this research study is to learn more about newer types of genetic testing called whole exome sequencing and whole genome sequencing. Current genetic testing usually examines one gene or a few genes at a time. Exome and genome sequencing allow us to test most of a person's genes at one time with a single test. This testing might identify the reason for a person's unexplained condition or diagnosis. We hope this study will help us identify the best methods for: Educating patients and families about exome and genome sequencing Analyzing exome and genome sequencing data to identify results relevant to patients Giving results to families in a clear, appropriate, and informative manner The current data only includes WES for 159 samples. The WGS samples for 20 samples will be uploaded in the near future.

  Study phs000935