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• Extracellular microRNA Biomarkers for Diagnostic and Prognostic Assessment of Preeclampsia at Triage

  This study is comprised of samples from 123 donors (71 cases and 52 controls) undergoing evaluation for preeclampsia. All samples were collected between 20 and 40 weeks of gestation. Small RNA sequencing was done on serum RNA obtained from donors. We were able to identify 3 bivariate extracellular miRNA biomarkers that can enable early diagnosis of preeclampsia. The raw fastq small-RNA sequencing fastq files will be submitted to dbGaP.

  Study phs003169

• The light chain IgLV3-21 defines a new poor prognostic subgroup in Chronic Lymphocytic Leukemia: results from a multicenter study

  Purpose: Unmutated (UM) immunoglobulin heavy chain region (IgHV) status or IgHV3-21 gene usage is associated with poor prognosis in chronic lymphocytic leukemia (CLL). Interestingly, IgHV3-21 is often co-expressed with light chain IgLV3-21 which is potentially able to trigger cell-autonomous BCR-mediated signaling. However this light chain has never been characterized independently of the heavy chain IgHV3-21.Experimental Design: we performed total RNA sequencing to characterize IgLV3-21 patients (n=32) and investigated IgLV3-21 prognostic impact in terms of treatment-free (TFS) and overall (OS) survival in 3 other independent cohorts for a total of 813 patients where IgLV3-21 presence was tested by real-time PCR and confirmed by Sanger sequencing.Results: Using total RNA sequencing to characterize 32 patients with high-risk CLL, we found a high frequency (28%) of IgLV3-21 rearrangements. Gene set enrichment analysis revealed that these patients present higher expression of genes responsible for ribosome biogenesis and translation initiation (P<0.0001) and MYC target genes (P=0.0003). Patients with IgLV3-21 rearrangements displayed a significantly shorter TFS and OS (P<0.05), in particular in IgHV mutated patients. In each of the 3 independent validation cohorts (n=813), we showed that IgLV3-21 rearrangements -similar to UM IgHV status- conferred poor prognosis compared to mutated IgHV (P<0.0001). Importantly, we confirmed in multivariate analysis that this was independent of IgHV mutational status or subset #2 stereotyped receptor (P<0.0001). Conclusions: We therefore demonstrate for the first time that a light chain can impact on CLL prognosis and that IgLV3-21 light chain usage defines a new poor prognostic subgroup in CLL.

  Study EGAS00001002894

• Single-Cell and Spatial Multi-Omics Highlight Effects of Anti-Integrin Therapy Across Cellular Compartments in Ulcerative Colitis

  This is a focused, nested case-control study within our larger cohort "Immunoprofiling of the Blood and Intestine and Creation of a Gut Cell Atlas". This sub-study is titled as "Single-cell and spatial multi-omics highlight effects of anti-integrin therapy across cellular compartments in ulcerative colitis”. We examined the impact of Vedolizumab (VDZ), an anti-integrin antibody therapy, on the cellular landscape of ulcerative colitis (UC). While VDZ is primarily recognized for its role in preventing lymphocyte migration to the gut, the extent of its influence on other cellular populations has not been fully characterized. We used single-cell RNA sequencing (scRNA-seq) and cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) to profile cells from both the blood and colon tissue samples. We pooled single-cell suspensions together before running scRNA-seq and CITE-seq, and subsequently deconvoluted the samples using the freemuxlet and demuxlet algorithms and variant call files (vcf) from bulk RNA-seq. This allowed us to assign cells to individual study subjects. We compared the cellular compositions of healthy individuals to those of UC patients undergoing treatment with VDZ or mesalamine (5-aminosalicylic acid/5-ASA). Our results revealed that VDZ induces significant changes in the variety and dynamics of mononuclear phagocytes within both the bloodstream and intestinal tissue, accompanied by subtle variations in lymphocyte populations. The dbGaP submission will provide raw sequencing data and participant phenotype data regarding disease and treatment status.

  Study phs003502

• Transcriptome profiling of patient derived neural stem cells highlights the importance of CTNND2 and WNT signaling in early neuralization

  Loss of CTNND2/δ-catenin function is implicated in neurodevelopmental disorders, including Cri-du-chat syndrome, autism spectrum disorder and attention deficit hyperactivity disorder. CTNND2, the encoded protein, is crucial for the cadherin-catenin cell adhesion complex in the brain. However, the specific impact on neurodevelopment remains unclear. To investigate, we used neuroepithelial stem cells (NESCs) derived from patient-specific induced pluripotent stem cells (iPSCs) with loss of CTNND2. In monolayer cultures, we observed abnormal neural rosette formation and failure to establish stable neural stem cells. 3D organoid cultures confirmed delayed neurogenesis and slower growth in patient-derived iPSC lines. We have built a transcriptomic catalog and observed a dysregulation of the WNT signaling pathway linked to our observed cellular phenotypes. To validate we excluded the WNT activator CHIR99021 from the media, which partially rescued the transcriptomic and morphological phenotype of the patient neural induction. This study enhances our understanding of how CTNND2 loss affects early neurogenesis and neuronal maturation in patient specific cells.

  Study EGAS50000000323

• QUANTitative Chest Computed Tomography UnMasking Emphysema Progression in Alpha-1 Antitrypsin Deficiency

  AAT deficiency is a genetic disorder associated with emphysema. Spirometry, the lung function test that measures how well the lungs exhale air, is used to diagnose and track the progression of emphysema. Some studies have suggested that forced expiratory volume in 1 second (FEV1) measurements, a type of spirometry test, may lack accuracy in detecting disease progression in cases of severe AAT deficiency. Another method, high resolution chest CT scans, may be more accurate at measuring the progression of emphysema. The purpose of this study is to determine if high resolution CT scans are better at detecting the progression of emphysema than lung function tests. Results from this study may lead to the development of a more accurate way to assess lung tissue loss and may improve the understanding of lung destruction in AAT deficiency. This study will last 4 years and will enroll people with AAT deficiency who have nearly normal lung function test results. Study visits, each lasting about 4 hours, will occur at baseline and months 6, 12, 18, 24, and 36. At each visit, participants will undergo lung function tests, a CT scan, blood collection, and a physical exam. Female participants will have urine collected for a pregnancy test. All participants will also complete questionnaires to assess health status and lung function. Study researchers will call participants every 2 months to collect information on lung disease symptoms and medication changes.

  Study phs000698

• Health Information National Trends Survey-SEER (HINTS-SEER)

  HINTS-SEER is a cross-sectional survey that sampled cancer survivors from three different SEER cancer registries. Sampling frames of survivors from each registry were stratified by time since diagnosis and race/ethnicity, with non-malignant tumors and non-melanoma skin cancers excluded. Respondents who consented completed a self-administered questionnaire sent through the mail and resulted in a total sample of 1,234 respondents. The goal of HINTS-SEER was to better understand the communication needs and practices, information preferences, risk behaviors and cancer knowledge of cancer survivors using a modified version of the Health Information National Trends Survey (HINTS) specifically designed for cancers survivors. Demographic information on the survivors showed that over 60% of the sample was 10 or more years since diagnosis with the most common cancers being male reproductive (24.6%), female breast (23%) and melanoma (9.6%) and gastrointestinal (8.6%). De-identified data is available in SAS, SPSS, and STATA formats, as part of a data package that also includes a history document, methodology report, data analysis recommendations, and a codebook.

  Study phs004065

• Heart Failure Network - Xanthine Oxidase Inhibition for Hyperuricemic Heart Failure Patients (HFN EXACT-BioLINCC)

  ObjectivesTo determine the effect of allopurinol after 24 weeks on a composite clinical endpoint that classifies subject's clinical status (improved, worsened, unchanged) in patients with heart failure and high uric acid levels.BackgroundMorbidity and mortality rates for patients with heart failure are high, despite guideline-recommended therapy. Heart failure is characterized by an imbalance between left ventricular (LV) performance and myocardial energy consumption. There is a growing body of evidence that suggests oxidative stress contributes to ventricular and vascular remodeling, and disease progression in heart failure. Targeting potential source(s) of oxidative stress, e.g. Xanthine oxidase (XO), was the focus of recent clinical trials and epidemiological studies. Increased XO activity has been shown to lead to production of superoxide and uric acid (UA). Serum uric acid levels are included in heart failure risk scores, and hyperuricemia is present in about 25% of patients with heart failure. Hyperuricemia is associated with exercise intolerance, reduced survival, and worsening symptoms. The EXACT-HF trial tested allopurinol, an inhibitor of XO, as a potential target therapy for hyperuricemic heart failure patients.Subjects253 subjects were enrolled in the EXACT-HF study. 128 participants were randomized to the allopurinol arm, and of those participants, 119 completed the trial and 9 did not. 125 participants were randomized to the placebo arm, and of those participants, 116 completed the trial and 9 did not.DesignEXACT-HF was a multi-center, double-blind, placebo controlled, 24-week trial of allopurinol. Eligible participants had to be receiving a stable regimen for at least two weeks (3 months for beta-blockers) prior to randomization. Participants were randomized by an automated system to either the allopurinol or placebo arm, and started treatment within 12 hours of completing the baseline visit. During the first week, participants in both treatment arms received 300mg daily of the respective medications. For the following 23 weeks, participants in both treatment arms received 600mg daily of the respective medications. Patients unable to tolerate 600 mg were maintained on 300 mg.The primary endpoint was a composite clinical endpoint (CCE) that classified a subject's clinical status as improved, worsened, or unchanged at 24 weeks. The CCE was determined based on the following: death; hospitalization, emergency room visit or emergent clinic visit for worsening HF; medication change for worsening HF; and Patient Global Assessment using a 7-point scale. Secondary endpoints at 12 and 24 weeks included changes in quality of life as assessed by the Kansas City Cardiomyopathy Questionnaire, and submaximal exercise capacity as assessed by a 6-minute walk test.ConclusionsParticipants who received allopurinol had significantly less serum uric acid laboratory levels after 24 weeks; however, no significant difference was observed in the primary and secondary endpoints between the allopurinol and placebo-treated patients. Therefore, in high-risk HF patients with reduced ejection fraction and elevated uric acid levels, xanthine oxidase inhibition with allopurinol failed to improve clinical status, exercise capacity, quality of life, or LVEF at 24 weeks (Circulation. 2015 May 19; 131(20):1763-71).

  Study phs003533

• MINCR is a MYC-induced lncRNA able to modulate MYC’s transcriptional network in Burkitt lymphoma cells

  Despite the established role of the transcription factor MYC in cancer, little is known about the impact of a new class of transcriptional regulators, the long non-coding RNAs (lncRNAs), on the way MYC is able to influence cellular transcriptome. To this aim we have intersected RNA-sequencing data from two MYC-inducible cell lines and from a cohort of 91 mature B-cell lymphomas carrying, or not carrying, genetic variants resulting in MYC over-expression. By this approach, we identified 13 lncRNAs differentially expressed in IG-MYC-positive Burkitt lymphoma and regulated in the same direction by MYC in the model cell lines. Among them we focused on a lncRNA that we named MINCR, for MYC-Induced long Non-Coding RNA, showing a strong correlation with MYC expression in MYC-positive lymphomas and also in pancreatic ductal adenocarcinomas. To understand its cellular role we performed RNA interference (RNAi) experiments and found that MINCR knock-down is associated with a reduction in cellular viability, due to an impairment in cell cycle progression. Differential gene expression analysis following RNAi showed a strongly significant enrichment of cell cycle genes among the genes down-regulate following MINCR knock-down. Interestingly these genes are enriched in MYC binding sites in their promoters, suggesting that MINCR acts as a modulator of MYC transcriptional program. Accordingly, following MINCR knock-down, we observed a reduction in the binding of MYC to the promoters of selected cell cycle genes. Finally we provide evidences that down-regulation of AURKA, AURKB and CTD1 may explain the reduction in cellular proliferation observed upon MINCR knock-down. We therefore suggest that MINCR is a newly identified player in the MYC transcriptional network able to control the expression of cell cycle genes.

  Dataset EGAD00001001441

• Sequencing data (BAM files) from - A mutation in VPS15 (PIK3R4) causes a ciliopathy and affects IFT20 release from the cis-Golgi. The Data Access Committee (DAC) is responsible for sequencing data release to external requestors based on consent and/or National Research Ethics terms.

  Dac EGAC00001000552

• PEVOsq

  The PEVOData PEVOsq basket trial is an open-label, multi-center, phase II trial investigating the combination of pembrolizumab (an immune checkpoint inhibitor) with vorinostat (a histone deacetylase inhibitor). This trial focuses on treating patients with recurrent or metastatic squamous carcinomas, including cancers of the cervix, head and neck, anus, vulva/vagina, penis, and lung. The aim is to evaluate the efficacy and safety of this combination, with pembrolizumab administered every 3 weeks and vorinostat daily. Outcomes include overall response rate and progression-free survival.

  Study EGAS50000000731