👤 Adwait Amod Sathe

Vascular dysfunction and capillary leak are common in critically ill COVID-19 patients, but identification of endothelial pathways involved in COVID-19 pathogenesis has been limited. Angiopoietin-like 4 (ANGPTL4) is a protein secreted in response to hypoxic and nutrient-poor conditions that has a variety of biological effects including vascular injury and capillary leak. To assess the role of ANGPTL4 in COVID-19-related outcomes. Two hundred twenty-five COVID-19 ICU patients were enrolled from April 2020 to May 2021 in a prospective, multicenter cohort study from three different medical centers, University of Washington, University of Southern California and New York University. Plasma ANGPTL4 was measured on days 1, 7, and 14 after ICU admission. We used previously published tissue proteomic data and lung single nucleus RNA (snRNA) sequencing data from specimens collected from COVID-19 patients to determine the tissues and cells that produce ANGPTL4. Higher plasma ANGPTL4 concentrations were significantly associated with worse hospital mortality (adjusted odds ratio per log ANGPTL4 is expressed in pulmonary epithelial cells and fibroblasts and is associated with clinical prognosis in critically ill COVID-19 patients. Show less

Gastric intestinal metaplasia ( This study was based on clinical and genomic data from four cohorts: 1) GAPS, a GIM cohort with detailed OLGIM severity scoring (N=303 samples); 2) the Cancer Genome Atlas (N=198); 3) a collation of in-house and publicly available scRNA-seq data (N=40), and 4) a spatial validation cohort (N=5) consisting of annotated histology slides of patients with either GC or advanced GIM. We used a multi-omics pipeline to identify, validate and sequentially parse a highly-refined signature of 26 genes which characterize high-risk GIM. Using standard RNA-seq, we analyzed two separate, non-overlapping discovery (N=88) and validation (N=215) sets of GIM. In the discovery phase, we identified 105 upregulated genes specific for high-risk GIM (defined as OLGIM III-IV), of which 100 genes were independently confirmed in the validation set. Spatial transcriptomic profiling revealed 36 of these 100 genes to be expressed in metaplastic foci in GIM. Comparison with bulk GC sequencing data revealed 26 of these genes to be expressed in intestinal-type GC. Single-cell profiling resolved the 26-gene signature to both mature intestinal lineages (goblet cells, enterocytes) and immature intestinal lineages (stem-like cells). A subset of these genes was further validated using single-molecule multiplex fluorescence using an integrated multi-omics approach, we identified a novel 26-gene expression signature for high-OLGIM precursors at increased risk for GC. We found this signature localizes to aberrant intestinal stem-like cells within the metaplastic microenvironment. These findings hold important translational significance for future prevention and early detection efforts. Show less

The composition, sequence, length and type of glycosidic linkage of polysaccharides profoundly affect their biological and physical properties. However, investigation of the structure-function relationship of polysaccharides is hampered by difficulties in accessing well-defined polysaccharides in sufficient quantities. Here we report a chemical approach to precision polysaccharides with native glycosidic linkages via living cationic ring-opening polymerization of 1,6-anhydrosugars. We synthesized well-defined polysaccharides with tunable molecular weight, low dispersity and excellent regio- and stereo-selectivity using a boron trifluoride etherate catalyst and glycosyl fluoride initiators. Computational studies revealed that the reaction propagated through the monomer α-addition to the oxocarbenium and was controlled by the reversible deactivation of the propagating oxocarbenium to form the glycosyl fluoride dormant species. Our method afforded a facile and scalable pathway to multiple biologically relevant precision polysaccharides, including D-glucan, D-mannan and an unusual L-glucan. We demonstrated that catalytic depolymerization of precision polysaccharides efficiently regenerated monomers, suggesting their potential utility as a class of chemically recyclable materials with tailored thermal and mechanical properties. Show less

The epidermal growth factor receptor (EGFR) is a prime oncogene that is frequently amplified in glioblastomas. Here we demonstrate a new tumour-suppressive function of EGFR in EGFR-amplified glioblastomas regulated by EGFR ligands. Constitutive EGFR signalling promotes invasion via activation of a TAB1-TAK1-NF-κB-EMP1 pathway, resulting in large tumours and decreased survival in orthotopic models. Ligand-activated EGFR promotes proliferation and surprisingly suppresses invasion by upregulating BIN3, which inhibits a DOCK7-regulated Rho GTPase pathway, resulting in small hyperproliferating non-invasive tumours and improved survival. Data from The Cancer Genome Atlas reveal that in EGFR-amplified glioblastomas, a low level of EGFR ligands confers a worse prognosis, whereas a high level of EGFR ligands confers an improved prognosis. Thus, increased EGFR ligand levels shift the role of EGFR from oncogene to tumour suppressor in EGFR-amplified glioblastomas by suppressing invasion. The tumour-suppressive function of EGFR can be activated therapeutically using tofacitinib, which suppresses invasion by increasing EGFR ligand levels and upregulating BIN3. Show less