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• Whole genome sequencing of tumor samples from advanced pre-treated NSCLC patients recruited in a phase I/II single-arm trial utilising CVA21, an oncolytic coxsackie virus, in combination with pembrolizumab.

  Acquired or de novo resistance to immune checkpoint inhibitors occurs in the majority of advanced non-small cell lung cancers (NSCLC). There is an unmet need to improve outcomes for patients with this condition. Oncolytic viruses represent an attractive treatment approach due to their dual activity in inducing tumor cell lysis directly and potentially augmenting anti-tumor immunity. Here, we present the safety, efficacy and translational findings from a phase I/II single-arm trial utilising CVA21, an oncolytic coxsackie virus, in combination with pembrolizumab in patients with advanced pre-treated NSCLC. We performed paired biopsies pre- and post-treatment in 10 patients who received intravenous CVA21 and pembrolizumab, 8 of whom had prior treatment with immune checkpoint inhibitor (ICI) therapy. Whole genome sequencing and spatial proteomics were performed to comprehensively characterise the response to CVA21. Combination CVA21/pembrolizumab (anti PD-1) therapy was well tolerated with no serious treatment-related adverse events. Partial responses were seen in two patients with prior acquired anti-PD-1 resistance and disease stabilisation in 6 patients, giving a clinical benefit rate of 80%. High baseline tumor mutational burden and PD-L1 expression were observed in patients with better response to treatment. Interestingly, an increase in antigen presentation and CD8+ T cell infiltration was observed on treatment compared with baseline in patients with better progression-free survival. This study demonstrates the potential of CVA21 to modulate the immunogenicity of tumor cells and remodelling the tumor microenvironment, providing novel insights for patient selection for trials involving novel immunotherapeutic approaches.

  Study EGAS00001008258

• Tubulointerstitial fibrosis is the histological hallmark of chronic kidney disease (CKD). Hypoxia and inflammation (i.e., interleukin (IL)-1β signalling) are independent mediators of tubulointerstitial fibrosis. However, the physiological response of human kidney tubular cells to IL-1β/IL-1RI signalling under the hypoxic conditions of CKD is poorly understood and remains a clinical imperative for therapeutic targeting. This study reports that hypoxia and IL-1β act in synergy to trigger cell cycle arrest/cellular senescence of ex vivo patient-derived primary proximal tubular epithelial cells (PTECs).

  Hypoxia and interleukin (IL)-1β are independent mediators of tubulointerstitial fibrosis, the histological hallmark of chronic kidney disease (CKD). Here, we examine how hypoxia and IL-1β act in synergy to augment maladaptive proximal tubular epithelial cell (PTEC) repair in human CKD. Ex vivo patient-derived PTECs were cultured under normoxic (21% O2) or hypoxic (1% O2) conditions in the absence or presence of IL-1β and examined for maladaptive repair signatures. Hypoxic PTECs incubated with IL-1β displayed a discrete transcriptomic profile distinct from PTECs cultured under hypoxia alone, IL-1β alone or under normoxia. Hypoxia+IL-1β-treated PTECs had 692 ‘unique’ differentially expressed genes (DEGs) compared to normoxic PTECs, with ‘cell cycle’ the most significantly enriched KEGG pathway based on ‘unique’ down-regulated DEGs (including CCNA2, CCNB1 and CCNB2). Hypoxia+IL-1β-treated PTECs displayed signatures of cellular senescence, with reduced proliferation, G2/M cell cycle arrest, elevated senescence-associated β-galactosidase (SA-β-gal) activity and increased production of pro-inflammatory/fibrotic senescence-associated secretory phenotype (SASP) factors compared to normoxic conditions. Treatment of Hypoxia+IL-1β-treated PTECs with either a senolytic drug combination, quercetin+dasatinib, or a type I IL-1 receptor (IL-1RI) neutralizing antibody attenuated senescent cell burden. Our data identify a mechanism whereby hypoxia in combination with IL-1β/IL-1RI signalling trigger PTEC senescence, providing novel therapeutic and diagnostic check-points for restoring tubular regeneration in human CKD.

  Study EGAS00001007904

• Cerebrospinal Fluid Analysis of HIV-1 Viral Burden in HIV-1 Infected Subjects: Response to Antiretroviral Therapy

  The purpose of this study is to provide a reference profile of small extracellular RNAs in body fluids. These samples were originally obtained in a study that had a different purpose. The purpose of the original study was to collect information on the changes in cerebrospinal fluid (CSF) related to HIV infection, including the viral burden (amount of virus) and the body responses of the infected individual, such as the number and types of lymphocytes in the CSF. In addition to looking at the number and types of lymphocytes in the CSF, this original study also examined the presence of markers of inflammation and other chemical changes, and the relationship of those changes to nervous system dysfunction in AIDS.

  Study phs001694

• Translational Research Investigating Underlying disparities in acute Myocardial infarction Patients' Health status (TRIUMPH)

  The Translational Research Investigating Underlying disparities in acute Myocardial infarction Patients' Health status (TRIUMPH) cohort is a cohort of 4340 patients prospectively enrolled after hospitalization for acute myocardial infarction (AMI) between June 1, 2005, and December 31, 2008 from 24 U.S. hospitals. Consenting patients had detailed chart abstractions of their medical history and processes of inpatient care, supplemented with a detailed baseline interview. Detailed genetic and metabolic data were obtained at hospital discharge in 2979 (69%) and 3013 patients (69%), respectively. Centralized follow-up interviews sought to quantify patients' post-discharge care and outcomes, with a focus on their health status (symptoms, function, and quality of life). Reprinted from [Article Citation], with permission from [Publisher].

  Study phs001518

• NIDDK IBD Genetics Consortium Repository Exome Chip

  The Illumina Infinium HumanExome+ BeadChip contains putative functional exonic variants selected from individual exome and whole-genome sequences from diverse populations. It includes nonsynonymous variants, splice variants and stop-altering variants. It also includes tags for previous GWAS-identified loci, ancestry informative markers, markers designed for identity by descent analyses, synonymous variants, fingerprint SNPs common to major genotyping platforms, mitochondrial SNPs, chromosome Y SNPs, and HLA tag SNPs. For more information as well as a detailed description of the variant calling and QC procedures, see Li et al. (2016). Li, D., et al. (2016) A pleiotropic missense variant in SLC39A8 is associated with Crohn's disease and human gut microbiome composition. Gastroenterology, 151, 1-9. PMID: 27492617.

  Study phs001723

• Urothelial Cancer - Genomic Analysis to Improve Patient Outcomes and Research (UC-GENOME): A Bladder Cancer Advocacy Network (BCAN)-Led Collaborative Research Pilot Study

  UC-GENOME is a real-world cohort of patients with metastatic urothelial carcinoma (UC). The study consisted of two co-equal aims: 1) to provide targeted DNA sequencing for clinical decision making at no cost to patients; and 2) to create a resource for collaborative translational science including a clinically annotated biobank. The submitted data represents the foundational analysis of 218 patients accrued at 7 academic medical centers. The analysis includes 176 patients with both targeted DNA sequencing and RNA sequencing. The genomic data was combined with clinical variables to model response to chemotherapy and immune checkpoint inhibitors (ICI). Due to additional sharing restrictions, data from one site can be found in phs003094.

  Study phs003066

• Therapeutic Targeting of ATR Yields Durable Regressions in High Replication Stress Tumors

  Patients with relapsed or recurrent small cell lung cancer or extra-pulmonary small cell cancers were enrolled on an investigator-initiated, single-arm, phase 2 trial (NCT02487095) combining an ATR inhibitor M6620 (VX-970, berzosertib) administered at 210 mg/m2 intravenously over 60 minutes on day 2 and day 5, and topotecan 1.25 mg/m2 intravenously over 30 minutes every 23 hours on days 1 through 5, with a support of pegfilgrastim 6mg subcutaneously on day 6 in 21-day cycles. Tumor samples were collected either just before starting the treatment or before starting treatment prior to be enrolled in the trial. Whole exome and RNA were sequenced to evaluate genomic and transcriptomic characteristics associated with the response to the combination treatment.

  Study phs002327

• Urothelial Cancer - Genomic Analysis to Improve Patient Outcomes and Research (UC-GENOME): a Bladder Cancer Advocacy Network (BCAN)-Led Collaborative Research Pilot Study - for Samples Collected at Johns Hopkins

  UC-GENOME is a real-world cohort of patients with metastatic urothelial carcinoma (UC). The study consisted of two co-equal aims: 1) to provide targeted DNA sequencing for clinical decision making at no cost to patients; and 2) to create a resource for collaborative translational science including a clinically annotated biobank. The submitted data represents the foundational analysis of 218 patients accrued at 7 academic medical centers. The analysis includes 176 patients with both targeted DNA sequencing and RNA sequencing. The genomic data was combined with clinical variables to model response to chemotherapy and immune checkpoint inhibitors (ICI).The larger dataset for this study can be found in dbGaP study phs003066.

  Study phs003094

• Next Generation Mendelian Genetics: Malignant Hyperthermia

  Malignant hyperthermia (MH) is a genetic disorder that causes a profound metabolic derangement following exposure to certain anesthetics. While approximately half of all cases are associated with ryanodine receptor-1 gene (RYR1) mutations, many cases have an unknown genetic cause. We sought to identify rare variants in novel MH candidate genes by sequencing the protein-coding regions of the genomes of individuals whose disease was either ruled in or out by the gold-standard diagnostic test. We also carefully selected individuals from well-characterized families to use gene-sharing information and maximize efficiency in the study design. Exome sequencing has helped identify the causes of over a dozen Mendelian disorders, has high power at low sample sizes, and is cost-efficient compared to whole-genome sequencing.

  Study phs000405

• GWAS for Membranous Nephropathy

  Primary membranous nephropathy (MN) is a rare autoimmune cause of kidney failure. This dataset is from a genome-wide association study (GWAS) designed to identify novel genetic risk loci for MN. The provided cohort (named as European-1 Cohort) is composed of 611 cases of primary MN and 1,246 healthy controls of European ancestry. This cohort was used in the GWAS meta-analysis, as described in the manuscript entitled "Genetic architecture of membranous nephropathy and its potential diagnostic implications" (Nature Communications 2020, in press).The genome-wide summary statistics, including trans-ethnic meta-analysis across 8 GWAS cohorts of European and East Asian ancestry and ethnicity specific meta-analyses, are freely available for download on the Kiryluk lab website: http://www.columbiamedicine.org/divisions/kiryluk/resources.php.

  Study phs001984