14 research outputs found

    Whole-genome characterization of myoepithelial carcinomas of the soft tissue

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    Myoepithelial carcinomas (MECs) of soft tissue are rare and aggressive tumors affecting young adults and children, but their molecular landscape has not been comprehensively explored through genome sequencing. Here, we present the whole-exome sequencing (WES), whole-genome sequencing (WGS), and RNA sequencing findings of two MECs. Patients 1 and 2 (P1, P2), both male, were diagnosed at 27 and 37 yr of age, respectively, with shoulder (P1) and inguinal (P2) soft tissue tumors. Both patients developed metastatic disease, and P2 died of disease. P1 tumor showed a rhabdoid cytomorphology and a complete loss of INI1 (SMARCB1) expression, associated with a homozygous SMARCB1 deletion. The tumor from P2 showed a clear cell/small cell morphology, retained INI1 expression and strong S100 positivity. By WES and WGS, tumors from both patients displayed low tumor mutation burdens, and no targetable alterations in cancer genes were detected. P2's tumor harbored an EWSR1::KLF15 rearrangement, whereas the tumor from P1 showed a novel ASCC2::GGNBP2 fusion. WGS evidenced a complex genomic event involving mainly Chromosomes 17 and 22 in the tumor from P1, which was consistent with chromoplexy. These findings are consistent with previous reports of EWSR1 rearrangements (50% of cases) in MECs and provide a genetic basis for the loss of SMARCB1 protein expression observed through immunohistochemistry in 10% of 40% of MEC cases. The lack of additional driver mutations in these tumors supports the hypothesis that these alterations are the key molecular events in MEC evolution. Furthermore, the presence of complex structural variant patterns, invisible to WES, highlights the novel biological insights that can be gained through the application of WGS to rare cancers

    A Novel Quantification Method for Determining Previously Undetected Silent Infarcts on MR-perfusion in Patients Following Carotid Endarterectomy

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    The purpose of this paper is to evaluate the post-operative Magnetic Resonance Perfusion (MRP) scans of patients undergoing carotid endarterectomy (CEA), using a novel image-analysis algorithm, to determine if post-operative neurocognitive decline is associated with cerebral blood flow changes. CEA procedure reduces the risk of stroke in appropriately selected patients with significant carotid artery stenosis. However, 25% of patients experience subtle cognitive deficits after CEA compared to a control group. It was hypothesized that abnormalities in cerebral blood flow (CBF) are responsible for these cognitive deficits. A novel algorithm for analyzing MRperfusion (MRP) scans to identify and quantify the amount of CBF asymmetry in each hemisphere was developed and to quantify the degree of relative difference between three corresponding vascular regions in the ipsilateral and contralateral hemispheres, the Relative Difference Map (RDM). Patients undergoing CEA and spine surgery (controls) were examined preoperatively, and one day postoperatively with a battery of neuropsychometric (NPM) tests, and labeled “injured” patients with significant cognitive deficits, and “normal” if they demonstrated no decline in neurocognitive function. There are apparently significant RDM differences with MRP scans between the two hemispheres in patients with cognitive deficits which can be used to guide expert reviews of the imagery. The proposed methodology aids in the analysis of MRP parameters in patients with cognitive impairment

    System-wide transcriptome damage and tissue identity loss in COVID-19 patients

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    The molecular mechanisms underlying the clinical manifestations of coronavirus disease 2019 (COVID-19), and what distinguishes them from common seasonal influenza virus and other lung injury states such as acute respiratory distress syndrome, remain poorly understood. To address these challenges, we combine transcriptional profiling of 646 clinical nasopharyngeal swabs and 39 patient autopsy tissues to define body-wide transcriptome changes in response to COVID-19. We then match these data with spatial protein and expression profiling across 357 tissue sections from 16 representative patient lung samples and identify tissue-compartment-specific damage wrought by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, evident as a function of varying viral loads during the clinical course of infection and tissue-type-specific expression states. Overall, our findings reveal a systemic disruption of canonical cellular and transcriptional pathways across all tissues, which can inform subsequent studies to combat the mortality of COVID-19 and to better understand the molecular dynamics of lethal SARS-CoV-2 and other respiratory infections., • Across all organs, fibroblast, and immune cell populations increase in COVID-19 patients • Organ-specific cell types and functional markers are lost in all COVID-19 tissue types • Lung compartment identity loss correlates with SARS-CoV-2 viral loads • COVID-19 uniquely disrupts co-occurrence cell type clusters (different from IAV/ARDS) , Park et al. report system-wide transcriptome damage and tissue identity loss wrought by SARS-CoV-2, influenza, and bacterial infection across multiple organs (heart, liver, lung, kidney, and lymph nodes) and provide a spatiotemporal landscape of COVID-19 in the lung

    Astrocytic Expansion in a Model of Neurofibromatosis 1 (NF1) Deficiency

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    Neurofibramatosis type 1 is an autosomal dominant disorder characterized by the development of both benign and malignant neoplasms of glial origin, as well as learning deficits and, less frequently, macrocephaly. Essential to the understanding of NF1 is the observation that the peripheral neoplasms (neurofibroma) which develop are composed primarily of NF1 negative glia which have undergone a loss of NF1 heterozygosity. The etiology of this loss of heterozygosity remains unclear, but a better characterization of these mutation events would provide insight into the cellular origins of the NF1 phenotype. CRISPR/Cas9 systems for genome editing have been, since 2013, a significant technique of interest by which precise mutagenesis may be achieved. Here we demonstrate a use of this system in conjunction with a Piggybac transposon lineage labelling approach by which the clonal identity of modified cell populations and the influence on cortical phenotype of a CRISPR/Cas9 induced model of NF1 deficiency may be investigated. Characterization of the induced NF1 phenotype is performed, and the CRISPR/Cas9 system is shown to be an effective method by which loss of cellular heterozygosity by somatic mutation may be modelled, exhibiting a monoallelic mutation rate of between 42.2% and 48.5. NF1 condition glia are not found to exhibit abnormal proliferation in the adult brain, and evidence supporting a model of neural progenitor fate switching to a glial phenotype in the form of CAG-TDTomato positive astrocyte populations derived from neuronal precursors is presented
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