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• The PRIME-AIR Study: Positive End-Expiratory Pressure, Recruitment, Incentive Spirometry, Muscle Relaxant Optimization, Preoperative Education, Postoperative Early Ambulation, Individualized, and Reinforced

  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.The PRIME-AIR study ("Positive end-expiratory pressure, Recruitment, Incentive spirometry, Muscle relaxant optimization, preoperative Education, postoperative early Ambulation, Individualized, and Reinforced") was a prospective multi-center randomized controlled pragmatic trial, with a blinded assessor, to compare post-operative pulmonary complications (PPCs) in patients with an individualized anesthetic-centered intervention (including individualized mechanical ventilation positive end-expiratory pressure (PEEP) management to maximize respiratory system compliance and minimize driving pressures, a neuromuscular agent and subsequent reversal, and post-operative lung expansion and early mobilization) versus usual care.

  Study phs003926

• Profiling the genomic landscape and evolutionary history of polyploid giant cancer cells in undifferentiated pleomorphic sarcomas

  Polyploid giant cancer cells (PGCCs), characterised by multi-nucleation and atypical nuclear morphology, are a common feature of undifferentiated pleomorphic sarcomas. While PGCCs may be a critical substrate for cancer evolution, their formation pathways and the genomic consequences of PGCCs remain relatively under explored. In this study, we characterise PGCCs in undifferentiated pleomorphic sarcomas, as well as their histological mimics, and use topographic single-cell DNA sequencing (scDNA-seq) to investigate their genomic landscape. We selected PGCCs based on their nuclear morphology, including mono-nucleated or multi-nucleated bizarre, misshapen nuclei and analysed them at single-cell resolution. Our findings highlight PGCCs as a highly heterogeneous and evolutionarily dynamic component of undifferentiated pleomorphic sarcomas.

  Study EGAS50000001445

• Single cell transcriptome and TCR sequencing of EBNA1, ANO2 and CRYAB-reactive T cells in multiple sclerosis.

  Molecular mimicry between Epstein-Barr virus (EBV) and self antigens in the brain has been suggested as a mechanism for how adaptive immune responses to EBV may contribute to multiple sclerosis (MS) disease pathogenesis. Anoctamin-2 (ANO2) and ɑ-crystallin B (CRYAB) have been identified as having homologous peptide sequences with the EBV antigen EBNA1. To explore T cell cross-reactivity, we stimulated PBMC from four natalizumab-treated persons with MS with full-length bead-coupled antigens and sorted proliferating CD4+ T cells by flow cytometry after 8 days. Single cell RNA sequencing was performed on T cells reacting to EBV EBNA1, ANO2, CRYAB, albumin binding domain (ABD, irrelevant protein control) and anti-CD3.

  Study EGAS50000001531

• Targeted next-generation sequencing detects novel gene-phenotype associations and expands the mutational spectrum in cardiomyopathie

  Cardiomyopathies are a heterogeneous group of primary diseases of the myocardium,including hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), andarrhythmogenic right ventricular cardiomyopathy (ARVC), with higher morbidity andmortality. These diseases are genetically diverse and associated with rare mutations ina large number of genes, many of which overlap among the phenotypes. To betterinvestigate the genetic overlap between these three phenotypes and to identify newgenotype-phenotype correlations, we designed a custom gene panel consisting of 115genes known to be associated with cardiomyopathic phenotypes and channelopathies.A cohort of 38 unrelated patients, 16 affected by DCM, 14 by HCM and 8 by ARVC,was recruited for the study on the basis of more severe phenotypes and family historyof cardiomyopathy and/or sudden death.

  Study EGAS00001002506

• 16 Year Life History and Genomic Evolution of an ER+ HER2- Breast Cancer

  We reconstructed the genomic evolution through the sixteen year history of an ER+ HER2- breast cancer patient to investigate molecular mechanisms of disease relapse and treatment resistance after long term exposure to hormonal therapy. Genomic and transcriptomic profiling was performed on primary breast tumor (2002), initial recurrence (2012) and liver metastasis (2015) tumor samples. Cell free DNA analysis was performed at eleven timepoints (2015-2017).This phylogenetic reconstruction of the life history of a single patient's cancer as well as monitoring tumor progression through liquid biopsies with the detection of a resistant clone harboring a de-novo ESR1 E380Q mutation allowed for uncovering the molecular mechanisms leading to initial relapse, metastatic spread and treatment resistance.

  Study EGAS00001004624

• Aberrant ERBB4-SRC Signaling as a Hallmark of Group 4 Medulloblastoma Revealed by Integrative Phosphoproteomic Profiling

  The four main medulloblastoma subgroups are characterized by distinct biology, clinicopathological features and clinical outcomes. While the WNT and SHH subgroups are characterized by clearly defined aberrant signaling of developmental pathways, the underlying biology of Group 3 and 4 remains poorly understood. Here, we delineate distinct post-translational regulation orchestrating active oncogenic signaling networks in Groups 3 and 4. Specifically, aberrant ERBB4-SRC signaling constitutes a novel hallmark feature of Group 4, with great promise as a novel oncogenic mechanism and potential vulnerability for therapeutic intervention in the most common subgroup. Altogether, this novel integrative proteogenomic landscape demonstrates the added value of proteomics and phosphoproteomics analysis to discover and exploit unexpected oncogenic mechanisms in medulloblastoma and beyond.

  Study EGAS00001002757

• Genome Asia 100K Project

  The underrepresentation of non-European individuals in human genetic studies so far has limited the diversity of individuals in genomic datasets and led to reduced medical relevance for a large proportion of the world’s population. Population-specific reference genome datasets as well as genome-wide association studies in diverse populations are needed to address this issue. Here we describe the pilot phase of the GenomeAsia 100K Project. This includes a whole-genome sequencing reference dataset from 1,739 individuals of 219 population groups and 64 countries across Asia. We catalogue genetic variation, population structure, disease associations and founder effects. We also explore the use of this dataset in imputation, to facilitate genetic studies in populations across Asia and worldwide.

  Study EGAS00001002921

• Temporal stability of circulating microRNAs in human serum

  Circulating microRNA biomarkers for disease have been subject to extensive research. However, insufficient consideration of variability in the healthy population has led to few markers achieving the performance necessary in independent follow-up studies to be taken forward to clinical practice. To investigate the natural variation of circulating microRNA over time, we performed small RNA sequencing in a longitudinal study of 66 women with no history of cancer, and determined the distribution and dynamics (via intraclass correlation coefficients, ICCs) of the miRNA profile over 3 time points sampled across 2-5 years. We also investigate abundances in circulation, as well as the impact of normalization, age, BMI, and other sample collection factors on microRNA measurements from small RNA sequencing.

  Study EGAS00001003221

• Response to tumor-infiltrating lymphocyte adoptive therapy is associated with preexisting CD8+ T-myeloid cell networks in melanoma

  Adoptive cell therapy (ACT) using ex vivo–expanded tumor-infiltrating lymphocytes (TILs) can eliminate or shrink metastatic melanoma, but its long-term efficacy remains limited to a fraction of patients. Using longitudinal samples from 13 patients with metastatic melanoma treated with TIL-ACT in a phase 1 clinical study, we interrogated cellular states within the tumor microenvironment (TME) and their interactions. We performed bulk and single-cell RNA sequencing, whole-exome sequencing, and spatial proteomic analyses in pre- and post-ACT tumor tissues, finding that ACT responders exhibited higher basal tumor cell–intrinsic immunogenicity and mutational burden. Compared with nonresponders, CD8+ TILs exhibited increased cytotoxicity, exhaustion, and costimulation, whereas myeloid cells had increased type I interferon signaling in responders. Cell-cell interaction prediction analyses corroborated by spatial neighborhood analyses revealed that responders had rich baseline intratumoral and stromal tumor–reactive T cell networks with activated myeloid populations. Successful TIL-ACT therapy further reprogrammed the myeloid compartment and increased TIL-myeloid networks. Our systematic target discovery study identifies potential T-myeloid cell network–based biomarkers that could improve patient selection and guide the design of ACT clinical trials.

  Study EGAS50000001217

• WXS and RNA-seq for 22 patients treated with radiation + immunotherapy

  Over 500 active clinical trials are investigating combination radiation (RT) and immune checkpoint blockade (ICB) as a cancer treatment; however, the majority of trials have found no positive interaction. We performed a comprehensive molecular analysis of a randomized phase I clinical trial of patients with non-small cell lung cancer (NSCLC) treated with concurrent or sequential ablative RT and ICB. Concurrent treatment was superior to sequential treatment in augmenting local and distant tumor responses and improving overall survival in a subset of patients with highly aneuploid tumors, but not in those with less aneuploid tumors. Our analysis suggested that concurrent treatment eliminated immunologically cold aneuploid tumors better than sequential treatment and improved patient outcomes. In addition, we report that RT alone decreased intratumoral cytotoxic effector T cell and adaptive immune gene expression signatures, in contrast to upregulation of key immune pathways after concurrent administration of RT and ICB. Our findings distinguish the differential genomic and transcriptomic effects of RT versus RT and ICB and challenge the prevailing paradigm that local ablative RT beneficially stimulates the immune response. We propose the use of tumor aneuploidy as a novel biomarker and therapeutic target in personalizing treatment approaches for patients with NSCLC treated with RT and ICB.

  Study EGAS00001006212