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• CONNECTS Master Protocol for Clinical Trials targeting Macro- and Micro-Immuno-Thrombosis, Vascular Hyperinflammation, and Hypercoagulability and Renin-Angiotensin-Aldosterone System (RAAS) in Hospitalized Patients with COVID-19 (ACTIV-4 Host Tissue)

  ACTIV 4 Host Tissue is a shared-placebo clinical trial platform evaluating therapies targeting the host response to COVID-19 in hospitalized patients. The overarching goal of the platform was to find effective strategies for inpatient management of patients with COVID-19. Therapeutic goals for patients hospitalized for COVID-19 include hastening recovery and preventing progression to critical illness, multiorgan failure, or death. Our objective is to determine whether modulating the host tissue response improves clinical outcomes among patients with COVID-19. Three trials were implemented to investigate three agents: TXA-127, TRV-027, and Fostamatinib. These agents all impact the host tissue response in COVID-19 via a number of unique mechanisms, including potential beneficial effects on the RAAS system and formation of neutrophil extracellular traps (NETs). Each trial evaluated the efficacy of these agents' ability to impact the host tissue response and improve outcomes in patients hospitalized with COVID-19. We found no evidence that any of the three agents significantly improved clinical outcomes as measured by the primary outcome, oxygen free days through day 28.

  Study phs003708

• Circulating Genomic Determinants of Treatment Failure in Hodgkin Lymphoma

  In this study, we show that the plasma representation of mutations exceeds the bulk tumor representation in most cases, making classic Hodgkin Lymphoma (cHL) particularly amenable to noninvasive profiling. Leveraging single-cell transcriptional profiles of cHL tumors, we demonstrate hazard ratios (HRs) circulating tumor DNA (ctDNA) shedding to be shaped by DNASE1L3, whose increased tumor microenvironment-derived expression drives high ctDNA concentrations. Using this insight, we comprehensively profile 366 patients, revealing two distinct cHL genomic subtypes with characteristic clinical and prognostic correlates, as well as distinct transcriptional and immunological profiles. Furthermore, we identify a novel class of truncating IL4R-mutations that are dependent on IL13 signaling and therapeutically targetable with IL4R blocking antibodies. Finally, we demonstrate the clinical value of pre- and on-treatment ctDNA levels for longitudinally refining cHL risk prediction, and for detection of radiographically occult minimal residual disease. Collectively, these results support the utility of noninvasive strategies for genotyping and dynamic monitoring of cHL as well as capturing molecularly distinct subtypes with diagnostic, prognostic, and therapeutic potential.Methods utilized include a) targeted genotyping of baseline plasma samples, b) whole exome sequencing (WES) of baseline plasma samples, c) epigenetic expression inference from cell-free DNA-sequencing (EPIC-Seq) to infer gene expression from cell-free DNA (cfDNA) fragmentation profiles, d) ctDNA tracking in on-treatment samples, e) RNA-Sequencing, and f) Phased variant Enrichment and Detection Sequencing (PhasED-Seq).All patients were treated at cancer centers across Europe and North America between 2011 and 2020. The following 3 cancer centers, Stanford (CA, USA), Bellinzona [Confoederatio Helvetica (CH) or Switzerland], and Leuven (Belgium), were included. The 6 clinical trial collectives included in this study are the Phase III trial AHOD1331 trial (NCT02166463) and the Phase II cHOD17 study (NCT03755804) for enrolled pediatric patients, the Phase III AHL2011 (NCT01358747), the Phase II BREACH trial (NCT02292979), a pilot study evaluating concurrent Pembrolizumab with AVD (Doxorubicin, also known as Adriamycin, Vinblastine, and Dacarbazine; NCT03331341), and a Phase II study evaluating PVAB (Prednisone, Vinblastine, Doxorubicin and Bendamustine; NCT02414568) in older patients (61 years and older). In addition, lymph node specimens from a biorepository at St. Jude Children's Research Hospital (TN, USA) were included.

  Study phs003435

• Liquid biopsy-based minimal residual disease monitoring for early risk stratification and decision-making in advanced non-small cell lung cancer

  Circulating tumor DNA (ctDNA)-based minimal residual disease (MRD) monitoring shows promise for risk stratification and decision-making in cancer patients. However, factors like background noise from non-tumor DNA, clonal haematopoiesis, and non-shedding tumors may complicate manual interpretation and limit its clinical application. In this proof-of-concept study in advanced non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs), we developed an algorithm that automatically classifies serial cell-free DNA (cfDNA) samples, thereby enabling reliable and reproducible interpretation, and preventing time-consuming manual interpretation in approximately 75% of patients. Importantly, application of the algorithm allowed early risk stratification and decision-making, specifically identifying approximately 35% of patients with short-term clinical benefit and approximately 25% of patients who may potentially benefit from treatment escalation. Simultaneous serum tumor marker (STM) monitoring further improved risk stratification and decision-making in our study, enabling accurate identification of all patients with a clinical benefit of at least one year.

  Study EGAS50000001554

• A Machine Learning Tool Integrating Circulating Cell-Free DNA Methylation with Clinical Variables for Non-Invasive Diagnosis of Liver Graft Pathology

  Liver Transplant Recipients (LTRs) with elevated liver enzymes can develop graft injury due to various etiologies, such as T-cell mediated rejection (TCMR) and NASH (NASH-LT). While liver biopsy is the gold standard method for diagnosis of graft pathology, it is invasive and is associated with risks. The goal of our study was to develop a Machine Learning (ML) tool integrating clinical variables with methylation patterns on circulating DNA in plasma as a non-invasive diagnostic tool of graft injury. We generated methylation profiles of circulating DNA in a pilot study of 43 LTRs (11 NASH-LT, 19 TCMR, and 13 Control-LT), and developed an L2 multinomial logistic regression ML approach across 101 bootstrapped models to distinguish between the graft conditions. NASH was associated with distinctive methylation patterns on genes involved in fatty acid metabolism, while methylation of platelet-derived growth factors was identified in patients with TCMR. Our ML model achieved a mean multi-classification accuracy of 0.91, with mean specificity and sensitivity of 0.94 and 0.91, respectively. The model was found to be particularly adept at detecting TCMR and Control-LT, with true positive rates (TPRs) of 95% and 90%, and areas under the curve (AUROC) of 0.992 and 0.985, respectively. For NASH-LT, the models achieved a performance with a TPR of 82% and an AUROC of 0.991. These preliminary results suggest that our newly developed ML tool, leveraging cell-free DNA methylation and clinical variables, is a promising non-invasive classifier of graft pathology.

  Study EGAS00001007171

• DPY30 ChIP-seq

  H9 human embryonic stem cells (hESCs) were cultured in feeder-free chemically-defined conditions in medium containing 10ng/ml Activin A and 12ng/ml FGF2 (Vallier L. 2011, Methods in Molecular Biology, 690: 57-66). Chromatin immunoprecipitation was performed as described in Brown S. et al. 2011. Stem Cells 29: 1176-85 by using 5ug of anti-DPY30 antibody (Sigma, cat. number HPA043761). This protocol was performed in control hESCs (expressing a scrambled shRNA) and in hESCs stably expressing an shRNA against DPY30 (Sigma, clone n. TRCN0000131112).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 EGAD00001001268

• NextGen Consortium: Globin Gene Expression in Sickle Cell Genotype-Specific iPS Cells

  Implement an efficient, highly reproducible and 'scalable' system for the production of large numbers of sickle cell anemia-specific iPS cells (iPSC). Derive and characterize a novel, in vitro system for the production of an unlimited supply of erythroid lineage cells from the directed differentiation of 'clinical grade' transgene-free iPS cells; use this system to recapitulate erythroid-lineage ontogeny in vitro with the sequential development of primitive and definitive erythropoiesis, accompanied by the appropriate expression of stage-specific globin genes. Identify developmental gene expression profile differences between erythroid precursors that produce primarily HbF and those that produce primarily HbA or HbS. Determine the effects of the three known HbF major quantitative trait loci (QTL) on globin gene expression in disease-specific iPS cells during in vitro erythropoiesis. Search for novel HbF genetic modifiers associated with markedly elevated HbF levels found in sickle cell anemia patients naturally, or in response to hydroxyurea treatment, by examining gene expression profiles and mRNA sequence of their iPSC-derived erythroid cells. Develop and use a CRISPR-based gene editing platform to study the effect of novel HbF genetic modifiers, explore globin switching, and correct the HbS mutation in sickle iPSC lines.

  Study phs001212

• Comparative transcriptome of CD34+ hematopoietic progenitors from myeloproliferative patients and control donors

  BCR-ABL-negative MPNs are related to mutations activating the JAK2/STAT pathway and occurring in hematopoietic stem cells (HSC). The most prevalent mutation is JAK2V617F. Calreticulin (CALR) and activating MPLW515 mutations are also observed in ET and PMF. Additional non-MPN mutations may be found, particularly in PMF, and can change disease phenotype or accelerate progression to myelofibrosis or leukemia. In this study, we wanted to compare the transcriptome of CD34+ progenitors from JAK2V617F postive MPN patients to the CD34+ progenitors from control donors. The patients were selected for their high JAK2V617F variant allele frequency (from 60 to 100% VAF). Peripheral blood from patients was collected in EDTA tubes. Hematopoietic progenitors (CD34+) were isolated from mononuclear cells (MNCs) by immunomagnetic enrichment (Miltenyi, Biotech) and were amplified for 5 days in serum-free medium in the presence of a cocktail of human recombinant cytokines containing EPO (1 U/mL) (Amgen Thousand Oaks, CA), TPO (20 ng/mL) (Kirin, Japan), SCF (25 ng/mL) (Biovitrum AB, Sweden), IL-3 (10 ng/mL), FLT3-L (10 ng/mL), G-CSF (20 ng/mL) and IL-6 (100 U/mL) (MiltenyiBiotec).

  Study EGAS00001005106

• Prevention and Early Treatment of Acute Lung Injury (PETAL) Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS) (PETAL CLOVERS-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 CLOVERS include plasma, and whole blood. Please note that use of biospecimens in genetic research is subject to a tiered consent. Available Data: The data available for request now include Long Term Outcome data.Objectives: To compare the effects of a restrictive fluid strategy (with early use of vasopressors) to a liberal fluid strategy in participants with sepsis-induced hypotension.Background: Intravenous fluid resuscitation is a common therapy used in the initial treatment of participants with septic shock and sepsis-induced hypotension. The goal of initial fluid therapy is to increase depleted or functionally reduced intravascular volume that occurs in sepsis due to a vasodilated vascular network. However, intravenous fluid resuscitation can create dilutional coagulopathy, fluid overload, and pathogenic edema in the lungs and other organs. Vasopressor agents are also commonly used to treat hypoperfusion by inducing constriction of arterioles and venules and increasing cardiac contractility. Vasopressor therapy also comes with risks that include vasoconstriction resulting in tissue ischemia, increased cardiac workload, and arrhythmias. Clinicians have used these strategies, typically in combination, to provide supportive care for participants with sepsis-induced hypoperfusion. However, at the time of the CLOVERS study, there was limited data to guide specific use of these therapies, including fluid volumes, in the early care of participants with sepsis-induced hypotension. The CLOVERS study hypothesized that a restrictive fluid strategy used during the first 24-hours of resuscitation for sepsis-induced hypotension would lead to lower mortality before discharge home by day 90 than a liberal fluid strategy.Participants: A total of 1,563 participants, from 60 medical centers, of the planned 2,230 participants were enrolled, with 782 assigned to the restrictive fluid group and 781 to the liberal fluid group. Enrollment in the trial was ended after the second interim analysis due to a lack of significant difference observed between the two 24-hour strategies.Design: This study was a multi-center, prospective, phase 3 randomized non-blinded interventional trial of fluid treatment strategies in the first 24 hours for participants with sepsis-induced hypotension. Participants were randomly assigned in a 1:1 ratio to either a restrictive fluid strategy (with early vasopressor use) or a liberal fluid strategy. In each group, the assigned protocol was followed for a period of 24 hours. The restrictive fluid protocol prioritized vasopressors as the primary treatment for sepsis-induced hypotension, with 'rescue fluids' being permitted for prespecified indications that suggested severe intravascular volume depletion. The liberal fluid protocol consisted of a recommended initial 2000-ml intravenous infusion of isotonic crystalloid, followed by fluid boluses administered on the basis of clinical triggers (e.g., tachycardia) with 'rescue vasopressors' permitted for prespecified indications. A protocol amendment implemented in October, 2019, allowed for limiting the initial infusion to 1,000 ml if the participant's blood pressure and heart rate had stabilized and the clinical assessment was that the participant was unlikely to benefit from additional intravenous fluid administration. The clinical team could override the protocol-specified care instructions at any time if it was judged to be in the best interest of the participant.The primary outcome was death from any cause before discharge home by day 90. Secondary outcomes included 28-day measures of the number of days free from ventilator use, days free from renal-replacement therapy, days free from vasopressor use, days out of the ICU, and days out of the hospital. Conclusions: Among participants with sepsis-induced hypotension, the restrictive fluid strategy that was used in this trial did not result in significantly lower (or higher) mortality, or other measures of recovery such as length of hospital stay, before discharge home by day 90 than the liberal fluid strategy.

  Study phs004080

• IMpower133 (GO30081) clinical data and biomarker data

  Relevant clinical data for IMpower133 (GO30081) including treatment arm, overall survival, progression-free survival, best overall response, PD-L1 IHC, molecular subtype, and baseline clinical features.

  Dataset EGAD50000000195

• Clinical data

  Clinical data from AVANT: Clinical data include race, age, sex, baseline ecog, tumor stage, node status, treatment arm, KRAS and BRAF mutation status, tumor location, concensus molecular subtype, overall survival and disease free survival for 797 patients across AVANT.

  Dataset EGAD00001009727