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• Myeloid-specific KDM6B inhibition sensitizes Glioblastoma to PD1 blockade

  Glioblastoma (GBM) tumors are enriched in immune-suppressive myeloid cells and are refractory to immune checkpoint therapy (ICT). Targeting epigenetic pathways to reprogram the functional phenotype of immune-suppressive myeloid cells to overcome resistance to ICT remains unexplored. Single-cell and spatial transcriptomic analyses of human GBM tumors demonstrated high expression of an epigenetic enzyme - histone 3 lysine 27 demethylase (KDM6B) in intra-tumoral immune-suppressive myeloid cell subsets. Importantly, myeloid-cell specific Kdm6b deletion enhanced pro-inflammatory pathways and improved survival in GBM tumor-bearing mice. Mechanistic studies elucidated that the absence of Kdm6b enhances antigen-presentation, interferon response and phagocytosis in myeloid cells by inhibiting mediators of immune suppression including Mafb, Socs3 and Sirpa. Further, pharmacological inhibition of KDM6B mirrored the functional phenotype of Kdm6b deleted myeloid cells and enhanced anti-PD1 efficacy. Thus, this study identified KDM6B as an epigenetic regulator of the functional phenotype of myeloid cell subsets and a potential therapeutic target to improve response to ICT.

  Study EGAS00001007002

• Phase II trial of targeted immune-depleting chemotherapy and reduced-intensity allogeneic hematopoietic stem cell transplantation using 8/8 and 7/8 HLA-matched unrelated donors and utilizing two graft-versus-host disease prophylaxis regimens for the treatment of leukemias, lymphomas, and pre-malignant blood disorders

  Background: Major problems with stem cell transplantation (SCT) for cancer treatment are a lack of suitable donors for patients without an HLA tissue-matched sibling and graft-versus-host disease (GVHD), a serious side effects of immune-suppressing chemotherapy that is given to bring the cancer under control before SCT. In GVHD, the patient's immune system attacks the transplanted donor cells. This study will try to improve the results of SCT from unrelated HLA-matched donors using targeted immune-depleting chemotherapy to bring the cancer under control before transplantation and to lower the chance of graft rejection, followed by reduced-intensity transplant chemotherapy to make the procedure less toxic. Objectives: To evaluate the safety and effectiveness of targeted immune-depleting chemotherapy followed by reduced-intensity transplant chemotherapy in patients with advanced cancers of the blood and immune system. To evaluate the safety and effectiveness of two different drug combinations to prevent GVHD. Both regimens have been successful in preventing GVHD, but they work by different mechanisms and affect the rebuilding of the immune system after the transplant. Eligibility: People 18 to 74 years of age with advanced or high-risk cancers of the blood and immune system who do not have a suitable HLA-matched sibling. Design: All patients receive chemotherapy before transplant to treat the cancer and suppress immune function. All patients receive a conditioning regimen of cyclophosphamide for 4 days and fludarabine for 4 days before SCT to prepare for the transplant. Patients are randomly assigned to one of two combination drug treatments to prevent GHVD as follows: Group 1: Tacrolimus starting 3 days before SCT and continuing for 6 months, plus methotrexate on days 1, 3, 6, and 11 post-SCT, plus sirolimus starting 3 days before the SCT and continuing through day 14 following SCT. Group 2: Alemtuzumab for 4 days starting 8 days before SCT, plus cyclosporine starting 1 day before SCT and continuing for 6 months. Patients receive the donor's stem cells and immune cells 2 days after the conditioning regimen. Patients are followed at the clinic regularly for the first 6 months after SCT, and then less often for at least 5 years. Some visits may include bone marrow aspirates and biopsies, blood draws, and other tests to monitor disease status. A skin biopsy, oral mucosa biopsy, and saliva collection are done to study chronic GVHD.

  Study phs002021

• Temptation Resistance Failures: Transdiagnostic Features and Influences

  Multiple forms of psychopathology involve problems with resisting temptations and urges. This study utilizes experience sampling (ES) methodology to assess temptation resistance across different classes of temptations and urges including both common everyday temptations and more disorder-specific temptation classes. The study tests the hypothesis that the broad ability to successfully resist temptations and urges across temptation classes is a common features of the externalizing superspectrum (factor) of psychopathology, particularly the disinhibition spectra as defined by the Hierarchical Taxonomy of Psychopathology (HiTOP). Additional associations are expected to arise between reduced temptation resistance success for specific temptation classes and narrower symptom domains associated with the externalizing and internalizing spectra (e.g., binge eating, and nonsuicidal self-harm among internalizing symptoms). The study further tests genetic and environmental influences on temptation strength and resistance ability with a focus on polygenic scores, adverse childhood experiences and childhood neighborhood deprivation variables that have previously been related to externalizing. To address these issues, we will study up to 1200 subjects (minimum 1000) selected with enrichment for psychopathology. Subjects will be recruited from a combination of ResearchMatch, and targeted contact with Reddit groups, and targeted social media/online advertisements, with targeted recruitment of at least 150 subjects who indicate problems with SUD, alcohol use disorder (AUD) or nicotine dependence, 70 who indicate problems with gambling or other impulse control problems, 70 subjects with criminal/legal problems, and 70 subjects based on binge eating episodes 70 with self-injurious behavior, and 70 with obsessive-compulsive disorder. Subjects will complete the (Externalizing Spectrum Inventory-BF and HiTOP-SR) to measure externalizing and internalizing spectra. Diagnoses in key categories will be confirmed with structured diagnostic interviews. Subjects also complete information on childhood adversity and geocoding is used to assess environment during development. The two-week ES regimen collects data on the strongest types of temptations and urges experienced by the subject, their subjective strength, the goal of the urge (pleasure/relief from negative feelings), the level of conflict with other goals, whether the person attempted to resist the temptation, the resistance strategy, and resistance success, to allow assessment of the extent to which differences in each of these facets (and calculated temptation resistance efficacy) are related to narrow or broad dimensions of psychopathology. Whole genome sequencing with .5x coverage and imputation will be performed to allow generation of polygenic scores for externalizing and addiction in order to test the hypothesis that externalizing polygenic scores are related to poor temptation resistance efficacy across temptation classes.

  Study phs004064

• PAS Pedigrees: Identification of novel genetic variants contributing to cardiovascular disease in pedigrees with premature atherosclerosis.

  The heritability of CVD has been estimated to be between 40 and 55%. Due to the low MAF, PAS-causing mutations cannot be identified by indirect genotyping because their presence cannot be inferred from common haplotypes, as has been done successfully to uncover common risk variants by GWAS. It has been shown by Ng et al that the causative gene for rare syndromes can be unequivocally identified by sequencing the exomes of only four cases and eight controls. We expect exome sequencing to result in a high number of mutations and non-causitive coding variants.

  Study EGAS00001000052

• Comprehensive genomic profiling of matched glioblastoma tumours, cell-lines, and xenografts reveals genomic stability and adaptation to disparate growth environments

  The mandate of this project was to use drug screening to deliver new drugs for glioblastoma (GBM) to clinical trials, and perform genomic assessment of GBM to discover new therapeutic targets and predictors of response. The sequencing data in this set was derived from GBM patient tumor samples, matched brain tumor initiating cells lines (BTICs), and tumor tissue derived from orthotopic implants.

  Study EGAS00001002709

• High-resolution profile of neoantigen-specific TCR activation links moderate stimulation to increased resilience of engineered TCR-T cells

  Neoantigen-specific T cell receptors (neoTCRs) promise safe, personalized anti-tumor immunotherapy. Previously, we identified diverse neoTCRs restricted to different neoantigens in a melanoma patient. In this work, we now combined single-cell TCR- and RNA-sequencing after neoantigen-specific restimulation of peripheral blood-derived CD8+ T cells of this patient. We detected novel neoTCRs with specificity to the previously detected neoantigens and observe a heterogeneous spectrum of TCR-intrinsic activation patterns in response to a shared neoepitope ranging from previously detected higher frequent neoTCRs with moderate activation to rare ones with initially stronger activation.

  Study EGAS50000000600

• SNP genotyping data in genes related to trace element homeostasis

  In this study we provide data regarding sample charactheristics and genotypes in 150 human samples of European origin for SNPs located around genes related to metal homeostasis. SNPs were genotyped with the Illumina VeraCode technology (192-plex format). The genotyped SNPs were used to identify quantitative trait loci in the same samples. Data referring to the quantification of 18 micronutrients, the expression levels of 90 genes and the protein abundances of 40 proteins related to metal homeostasis in the same samples are directly available as supplementary material in the publication of this study.

  Study EGAS00001001292

• Proteomic predictors of individualized nutrient-specific insulin secretion in health and disease

  Population level variation and molecular mechanisms behind insulin secretion in response to carbohydrate, protein, and fat remain uncharacterized despite ramifications for personalized nutrition. We now define prototypical insulin secretion dynamics in response to the three macronutrients in islets from 140 cadaveric donors, including those diagnosed with type 2 diabetes. We leverage the insulin response heterogeneity and use transcriptomics and proteomics to identify molecular pathways of specific nutrient responsiveness. Surprisingly, we find robust insulin secretion to fatty acid stimulus in ~8% of donors, challenging the idea that fat has negligible effects on insulin release. Distinct islet proteomes with differences in metabolic signalling networks convey this hyper-responsiveness to fat relative to carbohydrate. By comparing human islets to human embryonic stem cell-derived islet clusters, we show that, unlike glucose-responsiveness, fat hyper-responsiveness is equivalent and may be a hallmark of functionally immature cells. Our study represents the first comparison of dynamic responses to nutrients and multi-omics analysis in human insulin secreting cells. Responses of different people’s islets to carbohydrate, protein, and fat lay the groundwork for personalized nutrition.

  Dataset EGAD50000000519

• Longitudinal study of whole blood gene expression in Kenyan children exposed to malaria

  We have collected RNA samples from whole blood of Kenyan children exposed to malaria in the Kilifi region of Kenya. Collections were performed each year from 2015 until 2018. This is a follow-up study to that described in Bediako et al. (in preparation). The SIMS consortium is seeking to identifying the underlying reasons why some children are more susceptible to malaria than others. In this study we hope to track changes in children’s immune systems over time which relate to the number of malaria episodes they experience. 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/

  Dataset EGAD00001015405

• A Multiethnic Genome-wide Scan of Prostate Cancer

  Multiple GWA studies of prostate cancer conducted in European White populations are ongoing. These studies will continue to have a dramatic impact on our understanding of the contribution of common genetic variation on inter-individual susceptibility to this common cancer. Important questions that will remain unanswered, however, are whether all common risk alleles for prostate cancer will be revealed in studies limited to populations of European ancestry. A comprehensive examination of common genetic variation in men of Japanese, Latino, and African ancestry will be required to understand population differences in disease risk and to reveal the full spectrum of causal alleles that exist in these populations. Further, genetic and environmental diversity is likely to contribute to ethnic heterogeneity of genetic effects. Elucidating gene x gene and gene x environment interactions is also likely to provide knowledge that may be critical for understanding the contribution of genetic susceptibility to racial/ethnic disparities in prostate cancer incidence and for translating the findings from GWA studies into interventions. In this study we plan to undertake a genome-wide association study (GWAS) of prostate cancer in the Multiethnic Cohort (MEC) Study. We propose the following hypotheses: (a) that inherited DNA variation influences risk of prostate cancer; (b) that many of the causal alleles will be outside known "candidate genes" requiring an agnostic, comprehensive search; and (c) that performing this search in a multi-ethnic cohort is more powerful than a study limited to a single population to reveal the full range of causal alleles relevant to the U.S. population. The version 1 release of this dataset will include genotype data for the Japanese and Latino populations in the study. The version 2 release will include data for the African ancestry population along with the Japanese and Latino subjects. The version 3 release will include fully-cleaned genotype data for all three populations. This study is part of the Gene Environment Association Studies initiative (GENEVA, http://www.genevastudy.org) funded by the trans-NIH Genes, Environment, and Health Initiative (GEI). The overarching goal is to identify novel genetic factors that contribute to prostate cancer through large-scale genome-wide association studies of a well-characterized multi-ethnic cohort. Genotyping was performed at the Broad Institute of MIT and Harvard, a GENEVA genotyping center and at the University of Southern California. Data cleaning and harmonization were performed at the GEI-funded GENEVA Coordinating Center at the University of Washington. As an add-on to this GWAS we performed a targeted re-sequencing of all known prostate cancer risk loci in the samples from the MEC. Sequencing was performed in Dr. Reich's lab at Harvard Medical School.

  Study phs000306