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• M116 CHIP Amplicon Sequencing

  Genomic DNA was obtained from M116 peripheral blood sample and was used for targeted deep sequencing (TDS) studies. Barcoded libraries were prepared according to the manufacturer’s instructions, using a probe-based panel (KAPA HyperCap, Roche®) targeting frequently mutated regions of 50 myeloid-related genes. Samples were run on a MiSeq (Illumina®) sequencer for paired-end 2x75 bp reads with a mean coverage of 1000X.

  Dataset EGAD50000001287

• Whole-exome and RNA sequencing data from a uveal melanoma patient with multi-regional sampling

  This dataset includes whole-exome sequencing (WES) and RNA sequencing (RNA-seq) data from a uveal melanoma patient. Tumor samples were obtained from three distinct regions, each with matched RNA-seq and WES data. Additionally, WES data from the patient’s peripheral blood mononuclear cells (PBMCs) is provided as a germline reference.

  Dataset EGAD50000001422

• Whole-genome sequencing with complement C1s deficiency linked to systemic lupus erythematosus

  This dataset includes two FASTQ files (R1 and R2) from an Illumina germline nuclear DNA whole-genome sequencing run of a single sample. The sample corresponds to a 34-year-old male with a rare deficiency in complement component C1s, linked to systemic lupus erythematosus (SLE). Genomic analysis revealed two novel mutations in the C1S gene.

  Dataset EGAD50000000988

• Heterogeneity and evolution of DNA mutation rates in microsatellite-stable colorectal cancer

  A mutation accumulation experiment in colorectal cancer (CRC) derived tumoroids. A sequential single-cell cloning approach was adopted to measure the mutation rate in eight tumoroids obtained from five patients. WGS was also performed on their matched normal tissue and on standard tumoroids cultures without any cloning step. This is a 150x depth sequencing for 7 samples.

  Dataset EGAD50000000616

• Whole-genome sequencing of tumour, germline and plasma samples from a BRCA1-mutant breast cancer patient

  This data set contains the fastq files from whole-genome sequencing of temporally matched tumour (fresh frozen biopsies), blood germline and plasma samples collected from a BRCA1-mutant breast cancer patient to directly compare mutation signature analysis using gold-standard tumour-germline paired variant calling with a novel ctDNA-based method (MisMatchFinder).

  Dataset EGAD50000000811

• A complex chromosomal rearrangement (CCR) was resolved at the nucleotide level by whole genome long read sequencing using PacBio sequencing platform.

  A complex chromosomal rearrangement (CCR) involving 7 chromosomes and 11 breakpoints was resolved at the nucleotide level by whole genome long read sequencing using PacBio sequencing platform.

  Study EGAS00001008133

• Sharma/Busskamp Retinal Organoid

  DAC controlling a transcriptomic data set from retinal organoids generated with 10x chromium data, part of a publication between Sharma and Busskamp (DOI: 10.1016/j.stem.2025.12.013)

  Dac EGAC50000000487

• USH genes sequencing

  Sequencing of a panel including the whole genomic sequence of Usher genes.

  Study EGAS50000000476

• Kidney_tumour_RNA

  This is a bulk DNA and RNA sequencing study of human renal tumours

  Study EGAS00001002487

• Targeted_NanoSeq___Thyroid

  Targeted NanoSeq in thyroid from a number of donors, both healthy and with pathology.

  Study EGAS00001007647

• A Personalized Neoantigen Vaccine Generates Anti-Tumor Immunity in High-Risk Renal Cell Carcinoma

  Personalized cancer vaccines (PCVs) can generate circulating immune responses against predicted neoantigens. However, whether such responses can target cancer driver mutations, lead to immune recognition of a patient's tumor, and result in clinical activity are largely unknown, particularly in patients with lower mutation burden tumors. We conducted a phase I trial testing a neoantigen-targeting PCV in patients with high-risk, fully resected clear cell renal cell carcinoma (RCC; stage III or IV), with or without ipilimumab administered adjacent to the vaccine. At a median follow-up of 40.2 months from surgery, none of the 9 initial participants experienced a recurrence of RCC. No dose-limiting toxicities were observed. All patients generated T cell immune responses against PCV antigens, including RCC driver mutations in VHL, PBRM1, BAP1, KDM5C, and PIK3CA. Following vaccination, there was a durable expansion of peripheral T cell clones, and T cell reactivity against autologous tumor was detected in 7 of the 9 patients. Our results demonstrate that neoantigen-targeting PCVs in high-risk RCC are highly immunogenic, capable of targeting key driver mutations, and induce anti-tumor immunity. These observations, in conjunction with the absence of recurrence in all 9 vaccinated patients, highlights the promise of PCV as effective adjuvant therapy in RCC. We are submitting WES data from whole blood samples and tumor FFPE samples, and RNA-Seq data from tumor FFPE samples. We are also submitting RNA-Seq data from purified tumor samples. scRNA-seq data will be submitted for skin samples (vaccine site biopsies at Weeks 0, 4, and 13), tumor samples (including resected metastatic tumor samples for two patients), and normal kidney samples. Bulk TCR-seq data will be submitted for blood samples.

  Study phs003710

• New set of services for all users unveiled at the EGA

  The European Genome-phenome Archive (EGA) releases today a brand-new website as well as a set of improved services for users, comprising a revamped Submitter Portal with an improved API and data brokering functionality for submitters, as well as a new DAC Portal for Data Access Committee members to easily manage data access requests. The EGA team has been working hard over the past months on these improvements that will provide a better experience for the users. Discover them below! Visit our new EGA website and check the new functionalities and updated guides Our new website is live, with a fresh look and updated features to discover all the novelties. The homepage now includes three pathways to guide our users, depending on whether they want to deposit, download or manage data within the Archive. One of the most outstanding developments is the introduction of a streamlined process for requesting access to data: EGA Users can now directly request access to their preferred datasets through the website using their EGA accounts. Additionally, users can customise their profile, oversee active sessions, and manage the public keys, essential for our latest array of services, alongside a range of other features. Another major change is our new Help Desk contact method: a built-in website form tailored for user inquiries. This system, called "Need Help?", can be easily located on the top right-hand side of the website. It will encompass both EGA and Federated EGA node users' requests. We will detail its use soon, so stay tuned. Register your metadata to the EGA easily with our new Submitter Portal The new Submitter Portal makes the submission process quicker and more intuitive. The process is currently divided into sections that the user will know beforehand by taking the tour that the EGA team has created to guide users through the Portal before starting the first submission. Do not complete your data submissions alone! Our Submitter Portal now includes a collaboration mode so that every submission can be completed by authorised collaborators with an EGA Profile. There are a lot more features that we will be detailing from now on in incoming posts. A new platform for Data Access Committee Members The new DAC Portal brings novelties for individuals engaged in governance, legal, technical, operational roles, or those acting as data stewards. DAC members will be able to easily manage DACs, policies, and data access requests with the new Portal. Take the tour now to check them out! Help us improve the services completing the EGA Survey As part of our ongoing journey to improve your experience, we have created an EGA User Survey. This questionnaire covers a wide range of aspects such as user experience, support and data accessibility, among others. Participate now and take the opportunity to suggest your own improvements. Help us enhance your experience in this new era for the EGA. Subscribe to the EGA Mailing List and stay tuned In the next weeks we will share more information about the possibilities of the new services. You can easily join the EGA Mailing List to receive all the updates.

  Blog new-set-of-services-at-EGA

• Repotrectinib in NTRK fusion–positive advanced solid tumors: a phase 1/2 trial

  Early-generation TRK tyrosine kinase inhibitors (TKIs) approved for treating NTRK fusion–positive (NTRK+) solid tumors provide clinical benefit; however, resistance emerges. Repotrectinib is a next-generation ROS1/TRK TKI with a compact macrocyclic structure designed to improve durability of response. TRIDENT-1 is a registrational phase 1/2 trial assessing repotrectinib, a next-generation ROS1/TRK TKI, in adults with advanced solid tumors, including NTRK+ disease. The primary endpoint was confirmed objective response; secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival and safety. Median follow-up ranged between 21.3 months and 25.7 months. In the TKI-naive cohort (n = 51; 95% confidence interval (CI)), the response rate was 59% (44–72); the median DOR was not estimable (NE); and the median PFS was 30.3 months (9.0–NE). In the TKI-pretreated cohort (n = 69; 95% CI), the response rate was 48% (36–60); the median DOR was 9.8 months (7.4–13.0); and the median PFS was 7.4 months (3.9–9.7). Of 30 TKI-pretreated patients with NTRK solvent front mutations, 16 had a response (53%; 95% CI: 34–72). Intracranial responses were observed in two of three TKI-naive patients and in four of six TKI-pretreated patients with measurable intracranial disease at baseline. Among all treated patients (n = 565), the most common any-grade treatment-related adverse event (TRAE) was dizziness (57%); most TRAEs were low grade; and 4% discontinued repotrectinib due to a TRAE. Overall, repotrectinib demonstrated durable systemic and intracranial responses with generally low-grade adverse events in patients with NTRK+ solid tumors, including those with previous TRK TKI treatment and solvent front mutations. These results support the use repotrectinib to treat patients with NTRK+ solid tumors. ClinicalTrials.gov identifier: NCT03093116 .

  Study EGAS50000001572

• RNA-seq as a tool for evaluating human embryo competence

  The majority of embryos that are created through IVF do not implant. One possibility for this inefficiency is an incomplete understanding of the molecular factors affecting embryo competence. Currently, the process of selecting an embryo for uterine transfer utilizes an ad-hoc combination of morphological criteria, the kinetics of development, and genetic testing for aneuploidy. However, no single criterion can ensure selection of a viable embryo. In contrast, RNA-sequencing of embryos could yield highly dimensional data, which may provide additional insight and illuminate the discrepancies among current selection criteria. Indeed, recent advances enabling the production of RNA-sequencing (RNA-seq) libraries from single cells have facilitated the application of this technique to the study of some transcriptional events in early human development. However, these studies have not assessed the quality of their constituent embryos relative to commonly used embryological criteria. Here, we perform proof-of-principle advancement to clinical selection procedures by generating high quality RNA-seq libraries from a trophectoderm biopsy as well as the remaining whole embryo. We combine state-of-the-art embryological methods with low-input RNA-seq to develop the first transcriptome-wide approach for use in future predictive embryology studies. Specifically, we demonstrate the capacity of RNA-seq as a promising tool in preimplantation screening by showing that biopsies of an embryo can capture valuable information content available in the whole embryo from which they are derived. Furthermore, we show that this technique can be used to generate a RNA-based digital karyotype, and to develop a foundational dataset for identifying candidate competence-associated genes. Together, these data establish the foundation for a future RNA-based diagnostic in IVF.

  Study EGAS00001003667

• A Multifactorial Tumor and Immune Cell Profile Determines Response to Immune Checkpoint blockade in Melanoma

  The complex crosstalk between tumor and immune cells during immune checkpoint blockade mandates the development of integrated models that interpret the anti-tumor immune response and predict clinical outcome. We have integrated genome-wide sequence and structural alterations with pre and on-therapy transcriptomic and T cell repertoire features for a cohort of 64 immunotherapy-naïve melanomas treated with anti-PD1 monotherapy or combined anti-PD1 and anti-CTLA4 therapy. While tumor mutation burden (TMB) was associated with improved response to therapy, expressed mutation burden was superior to TMB in predicting outcome. An increased pre-existing T cell density differentiated responding from non-responding tumors independent of therapy. Importantly, T cell repertoire reshaping determined by T cell receptor (TCR) clonotypic regressions and expansions reflected response to therapy such that a more dynamic repertoire predicted improved clinical outcome. Through whole-transcriptome analyses, we discovered differential abundance of B cell subsets in responding tumors, which highlights the importance of the interplay between pre-existing T and B cell immunity in shaping therapeutic response. Tumor temporal trajectories during therapy revealed distinct patterns of molecular response related to expressed mutation elimination or retention that accurately interpreted clinical response. High-dimensional genomic, transcriptomic and immune repertoire data were integrated by both a machine learning and a censored regression approach, resulting in a harmonized multi-modal predictor of response to immune checkpoint blockade. B cell abundance, expressed mutation load and tumor aneuploidy were combined to identify patients at high risk for recurrence, such that high risk patients had a significantly shorter progression-free survival (HR=9.18, 95% CI: 3.14-26.85, p=3.4e-06) especially in the anti-PD1/anti-CTLA4 group (HR=20.34, 95% CI: 4.08-101.32, p=1.68e-06).

  Study EGAS00001004548

• Characterization of DLBCL with a PMBL gene expression signature

  Primary mediastinal large B-cell lymphoma (PMBL) is a type of aggressive B-cell lymphoma that typicallyaffects young adults, characterized by presence of a bulky anterior mediastinal mass. Lymphomas withgene expression features of PMBL have been described in non-mediastinal sites, raising questions abouthow these tumors should be classified.Here, we investigated whether these "non-mediastinal PMBLs" are indeed PMBLs or instead represent adistinct group within DLBCL. From a cohort of 325 de novo DLBCL cases, we identified tumors frompatients without evidence of anterior mediastinal involvement that expressed a PMBL expression signature(nm-PMBLsig-pos, n=16, 5%). The majority of these tumors expressed MAL and CD23 – proteins typicallyobserved in bona fide PMBL (bf-PMBL). Evaluation of clinical features of nm-PMBLsig-pos cases revealedclose associations with DLBCL, and the majority displayed a germinal center B-cell-like cell-of-origin(GCB). In contrast to bf-PMBL, nm-PMBLsig-pos patients presented at an older age, did not show pleuraldisease, and bone/bone marrow involvement was observed in three cases. However, while clinicallydistinct from bf-PMBL, nm-PMBL-sig-pos tumors resembled bf-PMBL at the molecular level with upregulationof immune response, JAK-STAT, and NF-kB signatures. Mutational analysis revealed frequent somatic genemutations in SOCS1, IL4R, ITPKB and STAT6, as well as CD83 and BIRC3, with the latter genes beingsignificantly more frequently affected than in GCB-DLBCL and bf-PMBL.Our data establish nm-PMBLsig-pos lymphomas as a group of DLBCL with distinct phenotypic and geneticfeatures, and potential implications for gene expression- and mutation-based subtyping of aggressive Bcell lymphoma and related targeted therapies.

  Study EGAS00001005057

• Prevention and Early Treatment of Acute Lung Injury (PETAL) Acetaminophen in Sepsis: Targeted Therapy to Enhance Recovery (ASTER) (PETAL ASTER-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. Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from PETAL ASTER include plasma, urine and whole blood. Please note that use of biospecimens in genetic research is subject to a tiered consent. Objectives: To determine whether acetaminophen increases days alive and free of organ dysfunction in sepsis participants compared with placebo.Background: Acetaminophen (paracetamol) has many effects that can be beneficial in sepsis treatment, including analgesia, antipyresis, cyclooxygenase-2 inhibition, as well as a potent and specific hemoprotein reduction that can block hemoglobin-induced oxidation of lipids and other substrates. The majority of sepsis participants experience elevated circulating cell-free hemoglobin levels, which is associated with development of organ dysfunction including acute respiratory distress syndrome (ARDS) and death.Acetaminophen has been found in observational studies to be associated with improved survival in critically ill sepsis participants with elevated plasma cell-free hemoglobin, and small clinical trials have had positive sepsis participant outcomes such as reduced plasma biomarkers of lipid peroxidation and improved kidney function. However, a large, randomized trial of acetaminophen administration for treatment of fever in participants with suspected infection did not show a mortality benefit. The NHLBI PETAL Network initiated ASTER as a larger phase trial to examine the utility of plasma cell-free hemoglobin level as a biomarker for future sepsis trials and whether acetaminophen would increase the number of days alive and free of organ support for participants with sepsis and respiratory or circulatory organ dysfunction. Participants: A total of 447 participants were enrolled and randomized, 227 to the acetaminophen arm and 220 to the placebo arm. Data from 40 participants who were randomized to the Vitamin C arm, which was stopped early (see Design section below), is also included.Design: ASTER was a phase 2b multicenter, randomized, double-blind trial. The study originally had a 3-arm platform trial in which participants were randomized 1:1:1 to treatment with intravenous acetaminophen, vitamin C, or a common placebo. The vitamin C arm of the trial was stopped after enrolling 79 participants due to external clinical trial data for vitamin C.Participants randomized to the acetaminophen arm received acetaminophen at the dose of 1 g in 100 mL diluent (or 15 mg/kg if actual body weight was Conclusions: Intravenous acetaminophen was considered to be safe but did not significantly improve days alive and free of organ support in critically ill sepsis participants. There was no significant interaction between cell-free hemoglobin levels and acetaminophen.

  Study phs003900

• Capturing the Genetic Diversity of the Himba Population

  The Himba people are a semi-nomadic, Bantu-speaking pastoralist group from the northwestern Kunene region of Namibia. Because of their limited population size, restricted geographic distribution, and endogamy, founder populations represent an ideal system for genetic analyses due to reduction of the confounding environmental and cultural variables. The original study used genotype data and demographic interview data to understand family dynamics and ancestry in a population of Himba pastoralists. HLA allele calls and genome-wide methylation array data were later generated for a subset of the initial dataset for 2 additional studies. These 3 molecular datasets, available through dbGaP, are relevant to broader studies of ancestry, allele frequencies and the relationship of Himba to other ethnic groups in sub-Saharan Africa. The Himba population provides a unique opportunity to study questions regarding extra-pair paternity and mate selection because Himba culture allows both men and women, married and not, to take multiple partners. Previous estimates of extra-pair paternity rates in human populations have been very low, but these estimates lack global and cultural diversity in population representation. Thus, investigating the rate of extra-pair paternity in the Himba greatly aids in understanding the global variation in non-paternity rates among human populations. Saliva samples were collected from parents and children, and were genotyped on Illumina SNP array platforms (MEGAex and H3Africa). In total, 678 individuals' genotype array data are deposited. Paternity results were de-identified and protected by a double blind protocol (no researcher has full knowledge of individual paternity results). Due to the sensitive nature of this study, paternity assertions are not available for access. For a subset of 360 individuals, HLA class 1 (A, B, C) and class 2 (DPA1, DPB1, DQA1, DQB1, DRB1) genes were targeted for DNA sequencing using a probe-based capture method. HLA alleles at the four field resolution were determined from the sequence capture using the consensus calls obtained from two algorithms: NGSengine® 2.10.0 (GenDX, Utrecht, the Netherlands) and HLA Explore™ (Omixon Biocomputing Ltd. Budapest, Hungary). These data were used to investigate evidence for mate selection based on HLA dissimilarity in the Himba. Himba cultural norms permit concurrent arranged marriages and chosen sexual partnerships allowing us to directly test for evidence of disassortative mate selection based on HLA genotype. Due to the sensitive nature of this study, partnership data are not available for access.For a subset of 51 Himba individuals methylation array data was generated from the saliva-derived DNA. These data were generated in order to investigate the accuracy of epigenetic age predictors in this population and to construct population-specific epigenetic age predictors in a subsequent publication. Chronological ages are available for these 51 individuals.

  Study phs001995

• Beyond BRCA deficiency: Clinical and molecular predictors of survival in patients with BRCA-deficient tubo-ovarian high-grade serous carcinoma

  Homologous recombination DNA repair deficient (HRD) tumors account for about 50% of tubo-ovarian high-grade serous carcinomas (HGSC) and are associated with a high response to platinum-based chemotherapy. However, a subset of patients with HRD tumors have unexpected resistance to chemotherapy and experience short survival. Our study compared BRCA-deficient and proficient HGSC among patients with short (<3 years, the lowest quartile of overall survival (OS)) versus longer-term (>3 year OS) to identify prognostic markers and potential therapeutic opportunities. Primary tumors from a cohort of patients with advanced-stage HGSC (n=154) enriched for those with HRD tumors and short survival (n=42) were analyzed using whole-genome sequencing, bulk RNA-sequencing, and DNA methylation profiling. A subset of HRD tumors (n=143) were characterized for immune cell densities by multiplex immunofluorescence. Clinicopathological features were assessed in 1,389 patients with HGSC, including 282 with pathogenic germline BRCA variants (gBRCApv). Findings were validated in two international HGSC cohorts: the Ovarian Tumor Tissue Analysis consortium (n=5,875) and Multisciplinary Ovarian Cancer Outcome Group (n=895). In gBRCApv-carriers, residual disease following surgical cytoreduction was not associated with shorter OS unlike in non-carriers where it was strongly associated. While most patients with gBRCApv had a more favorable OS compared to non-carriers, a survival advantage was not apparent in those with variants located outside of BRCA1 exon 10/23 and BRCA2 exon 11/27. Patient survival correlated with HRD score, such that those with a score ≥63 had significantly longer OS compared to those with HRD scores of 42-63 and <42. While higher HRD scores were associated with better survival outcomes, most gBRCApv carriers with a short survival had tumor HRD scores that exceeded the threshold typically considered predictive of a good response to carboplatin or PARP inhibitors. BRCA2-deficient HGSC with loss of the tumor suppressor NF1 was associated with exceptionally favorable outcome (median OS 17 years), whereas amplification of both PIK3CA and RAD21, was associated with poor outcome in BRCA2-deficient HGSC (median OS 2.9 years). The density of tumor-infiltrating CD8+ PD-1+ T cells was prognostic for OS in gBRCApv-carriers. In summary, rather than simply the presence or absence of a germline BRCA pathological variant influencing patient survival, the co-occurrence of specific somatic gene alterations, the extent of immune cell infiltration, the level of homologous recombination deficiency, and BRCA-variant location may modify clinical outcomes in patients with BRCA-deficient HGSC. Analysis of exceptional outcome patients, in this case gBRCApv-carriers with an atypically short survival, may identify determinants of outcome applicable to the wider HGSC patient population.

  Study EGAS00001008059

• Genomic and clinical characterization of a familial GIST kindred intolerant to imatinib

  Familial gastrointestinal stromal tumors (GIST) are rare. We present a kindred with multiple family members affected with multifocal GIST who underwent whole genome sequencing of the germline and tumor. Affected individuals with GIST harbored a germline variant found within exon 13 of the KIT gene, (c.1965T>G; p.Asn655Lys, p.N655K) and a variant in the MSR1 gene (c.877C>T; p.Arg293*, pR293X). Multifocal GISTs in the proband and her mother were treated with preoperative imatinib, and resulted in severe intolerance. The clinical features of multifocal GIST, cutaneous mastocytosis, allergies and gut motility disorders seen in the affected individuals may represent manifestations of the multifunctional roles of KIT in interstitial cells of Cajal or mast cells and/or may be suggestive of additional molecular pathways which can contribute to tumorigenesis.

  Study EGAS50000000372

• Exome sequence data for germline, primary tumor, and relapse tumor of a transformed non-Hodgkins lymphoma patient with unexpected long-time remission

  The patient was diagnosed with a transformed high-grade non-Hodgkin lymphoma stage III, and treated with conventional R-CHOP (Rituximab (R), Cyclophosphamide (C), Doxorubicin (H), Vincristine (O) and Prednisone (P)). Unfortunately, she suffered from severe toxicity but recovered during the following six months remission until a biopsy verified relapse. The patient refused second line combination chemotherapy, but accepted a 3 months palliation with R and Chlorambucil. Unexpectedly, she obtained continuous complete remission and is at present >9 years after primary diagnosis.Molecular studies and data evaluation by principal component analysis, mutation screening, and copy number variations of the primary and relapsed tumor, identified patterns of branched lymphoma evolution, most likely diverging from an unknown in situ follicular lymphoma.

  Study EGAS00001001973

• A genetic compendium of human brains from the UK Medical Research Council brain tissue resource

  Common neurodegenerative diseases have a complex genetic architecture. Highly penetrant diseases alleles are found in a significant minority of cases, and common risk alleles are present in a large proportion. Given the central role of genetic factors in the pathogenesis of these disorders, it is critical that mechanistic studies in human subjects and tissue samples are interpreted in an genetically enlightened context. To address this we performed exome sequencing on 1461 human brains accessible through the Medical Research Council (UK) brain banks network. Our findings confirm the complex genetic landscape of neurodegenerative disease. Clinical, pathological and genetic data for the 1461 brains with corresponding exome sequencing data are available within this dataset, enabling the genetic stratification and selection of post-mortem tissue samples for researchers.

  Study EGAS00001001599

• Patient-derived organoids as a novel tool to study cervical cancer

  Cervical cancer is the most prevalent gynecological malignancy worldwide, often caused by infection with a high-risk human papillomavirus. Currently, there are only limited number of human-derived culture systems available that enable to study the viral infection for short-term. Here, we report on establishment of long-term human-derived organoid cultures from both healthy ecto- and endocervical epithelia that closely recapitulate the tissues of origin by maintaining the authentic histological and tissue-specific gene expression profiles. Additionally, using material from patients’ Pap-brush material, a successful panel of long-term patient-derived cancer organoids was established that maintain the causative viral infection in vitro and show differential response to common chemotherapy regimens. This study provides a promising platform for cervical cancer research and studying direct virus-host interactions.

  Study EGAS00001004439

• Cell and Circuit-Specific Exploration of HIV Neurogenomics in Context of Opiate and Cocaine Misuse

  Utilizing frozen postmortem brain tissue from the Manhattan HIV Brain Bank, we performed cell-type-specific, genome-wide sequencing of three different types: 1) single-nucleus RNA-sequencing (snRNA-seq), 2) in situ Hi-C, and 3) HIV integration site sequencing (IS-seq). We assayed tissue from three different donor types: 1) HIV-uninfected control (HIV-), HIV-infected (HIV+), and HIV-infected with HIV encephalitis (HIVE), who served as a positive control for active CNS viral infection. The diagnosis of HIVE was made by a board-certified neuropathologist on routine histopathology, based on the presence of a microglial nodule encephalitis with characteristic multinucleated syncytial cells and staining for HIV p24 antigen. Other HIV-infected individuals (the HIV+ group) did not have this histologic evidence of active HIV brain replication, and were variable with regard to cART status and virologic control prior to death. Donor characteristics, including ante-mortem plasma HIV loads, CD4 counts, and cART status, were documented. Quality controls were used for each assay: For snRNA-seq we applied filters to remove low quality nuclei from analysis and performed experiments in which mouse tissue was mixed with human tissue to determine a reliable HIV read count threshold. For Hi-C, we used paired HIV- and HIVE samples and processed all samples in parallel, at the same time. Correlation analysis was used to ensure biological replicates were aligned. For IS-seq, each time the assay was run, a positive and negative control were included. This allowed us to ensure a lack of contamination in IS-seq libraries and that, when a particular sample failed to yield library, this was due to low levels of HIV rather than a failure of the assay. Altogether, we built an integrative dataset from 79 sequencing files, including snRNA-seq, and cell type specific Hi-C, IS-seq, and ChIP-seq datasets. Human autopsy brain samples were collected by the Manhattan HIV Brain Bank (MHBB, U24MH100931), using protocols under the supervision of the Icahn School of Medicine at Mount Sinai (ISMMS) Institutional Review Board. Written informed consent was obtained either from decedents or their primary next of kin. Major Findings: Reorganization of open/repressive (A/B) compartment structures in HIVE microglia encompassing 6.4% of the genome was linked to transcriptional activation of interferon (IFN) signaling and cell migratory pathways and was partially recapitulated by IFN-gamma stimulation of cultured microglia. In contrast, decreased expression and repressive compartmentalization of genes regulating neuronal health and signaling was seen in both HIVE and HIV+ microglia. IS-seq recovered 1,221 integration sites in the brain that displayed distinct genomic patterns as compared to peripheral lymphocyte integration and were enriched for chromosomal domains newly mobilized into a permissive chromatin environment in HIVE microglia. Viral transcription occurred in a subset of highly activated microglia comprising 0.003% of all nuclei in HIVE brain. Our findings point to a disruption of microglia-neuronal interactions in the HIV infected brain and an interrelation of retroviral integration and expression with interferon-associated remodeling of the microglial 3D genome during progression to HIVE. Search terms: HIV, postmortem brain, microglia, substance abuse, viral integration, chromosomal conformation capture, Hi-C, chromatin, single nuclei RNA-seq, Irf8, NeuN, HIV encephalitis, neuron-microglia interaction, cytokine

  Study phs003080

• Prevention and Early Treatment of Acute Lung Injury Network - Reevaluation of Systemic Early Neuromuscular Blockade (PETAL ROSE-BioLINCC)

  Data Access NOTE: Please refer to the "Authorized Access" section below regarding accessing data through the BioData Catalyst ecosystem. The data from this accession is not available for download through dbGaP. Available Data: The data available for request now include Long Term Outcome data.Biospecimens: Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from PETAL ROSE include Plasma, DNA, Whole Blood, and Urine. Please note that use of biospecimens in genetic research is subject to a tiered consent.Objectives: To determine the efficacy and safety of early neuromuscular blockade with concomitant heavy sedation as compared with a strategy of usual care with lighter sedation targets in patients with moderate-to-severe ARDS.Background: It has been well established that the approaches used for the application of mechanical ventilation in patients with acute respiratory distress syndrome (ARDS) can affect survival and outcomes after discharge from the intensive care unit (ICU). A large, multicenter trial conducted a decade before this study reported that the early administration of a 48-hour infusion of neuromuscular blockade in patients with moderate-to-severe ARDS (defined by a ratio of the partial pressure of arterial oxygen [Pao2] to the fraction of inspired oxygen [Fio2] of Participants: There were 1006 participants.Design: PETAL-ROSE was a multicenter, unblinded, randomized trial of patients with moderate-to-severe ARDS. Participants were randomly assigned in a 1:1 ratio to receive 48 hours of continuous neuromuscular blockade with concomitant deep sedation (intervention group) or to receive usual care without routine neuromuscular blockade and with lighter sedation targets (control group).Patients in the intervention group who were not under deep sedation at baseline were deeply sedated within 4 hours after randomization. Subsequently, patients in this group received an intravenous bolus of 15 mg of cisatracurium, followed by a continuous infusion of 37.5 mg per hour for 48 hours. After the 48-hour trial intervention period, decisions regarding further use of neuromuscular blockade, including the choice of agent, were left to the discretion of the treating clinician. Neuromuscular blockade could be stopped early if the patient met the criteria for freedom from mechanical ventilation (Fio2 ≤0.40 and PEEP ≤8 cm of water) for at least 12 hours. All patients were treated with a strategy of low tidal volume ventilation within 2 hours after randomization and a high PEEP strategy for up to 5 days after randomization. Assessors who were unaware of the group assignment interviewed surviving patients or their proxies at 3, 6, and 12 months after randomization. The primary end point was in-hospital death from any cause at 90 days (in-hospital was defined as the time in the trial hospital plus transfer to another hospital, including the time in long-term acute care facilities). Conclusions: After the second interim analysis, the decision to stop the trial for futility was made independently by the data and safety monitoring board.In critically ill patients identified shortly after the diagnosis of moderate-to-severe ARDS, the addition of early continuous neuromuscular blockade with concomitant deep sedation did not result in lower mortality than a usual-care approach to mechanical ventilation that included lighter sedation targets.

  Study phs003878