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The aim of the study was to compare the results of ultrasonography (US) and laparoscopy in a series of 210 patients referred to our institution for the diagnosis of widespread liver diseases. Among 205 patients, laparoscopy revealed cirrhosis in 114, chronic widespread disease in 70 (chronic persistent hepatitis in 21, chronic active hepatitis in 28, steatosis in 14, acute hepatitis in 5, fibrosis in 2), and absence of liver disease in 21. Four of these cases had minor complications. A corroborative diagnosis was obtained in 122 patients (59.5%). Overall sensitivity of US was 84% with a low specificity due to the high rate of false negatives. From the results of this study we conclude that laparoscopy is a safe and essential diagnostic tool in the final diagnosis of widespread liver diseases and that US is not a reliable screening method because of its incidence of false negatives. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitor (ICI) therapies can increase the risk of cardiovascular events in survivors of cancer by worsening atherosclerosis. Here we map the expression of immune checkpoints (ICs) within human carotid and coronary atherosclerotic plaques, revealing a network of immune cell interactions that ICI treatments can unintentionally target in arteries. We identify a population of mature, regulatory CCR7 + FSCN1 + dendritic cells, similar to those described in tumors, as a hub of IC-mediated signaling within plaques. Additionally, we show that type 2 diabetes and lipid-lowering therapies alter immune cell interactions through PD-1, CTLA4, LAG3 and other IC targets in clinical development, impacting plaque inflammation. This comprehensive map of the IC interactome in healthy and cardiometabolic disease states provides a framework for understanding the potential adverse and beneficial impacts of approved and investigational ICIs on atherosclerosis, setting the stage for designing ICI strategies that minimize cardiovascular disease risk in cancer survivors., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Patients with coronavirus disease 2019 (COVID-19) present increased risk for ischemic cardiovascular complications up to 1 year after infection. Although the systemic inflammatory response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection likely contributes to this increased cardiovascular risk, whether SARS-CoV-2 directly infects the coronary vasculature and attendant atherosclerotic plaques remains unknown. Here we report that SARS-CoV-2 viral RNA is detectable and replicates in coronary lesions taken at autopsy from severe COVID-19 cases. SARS-CoV-2 targeted plaque macrophages and exhibited a stronger tropism for arterial lesions than adjacent perivascular fat, correlating with macrophage infiltration levels. SARS-CoV-2 entry was increased in cholesterol-loaded primary macrophages and dependent, in part, on neuropilin-1. SARS-CoV-2 induced a robust inflammatory response in cultured macrophages and human atherosclerotic vascular explants with secretion of cytokines known to trigger cardiovascular events. Our data establish that SARS-CoV-2 infects coronary vessels, inducing plaque inflammation that could trigger acute cardiovascular complications and increase the long-term cardiovascular risk., Competing Interests: The M.S. laboratory has received unrelated research funding in sponsored research agreements from ArgenX N.V., Moderna and Phio Pharmaceuticals which has no competing interest with this work. The authors declare no other competing interests.

The development of new immunotherapies to treat the inflammatory mechanisms that sustain atherosclerotic cardiovascular disease (ASCVD) is urgently needed. Herein, we present a path to drug repurposing to identify immunotherapies for ASCVD. The integration of time-of-flight mass cytometry and RNA sequencing identified unique inflammatory signatures in peripheral blood mononuclear cells stimulated with ASCVD plasma. By comparing these inflammatory signatures to large-scale gene expression data from the LINCS L1000 dataset, we identified drugs that could reverse this inflammatory response. Ex vivo screens, using human samples, showed that saracatinib-a phase 2a-ready SRC and ABL inhibitor-reversed the inflammatory responses induced by ASCVD plasma. In Apoe -/- mice, saracatinib reduced atherosclerosis progression by reprogramming reparative macrophages. In a rabbit model of advanced atherosclerosis, saracatinib reduced plaque inflammation measured by [ 18 F] fluorodeoxyglucose positron emission tomography-magnetic resonance imaging. Here we show a systems immunology-driven drug repurposing with a preclinical validation strategy to aid the development of cardiovascular immunotherapies., Competing Interests: Competing Interests statement C.G. is listed as an inventor on patent application Tech 160808G PCT/US2022/017777, filed by the Icahn School of Medicine at Mount Sinai (patent applicant), that is directly related to the method used in this manuscript to identify saracatinib as an antiatherosclerotic agent. The remaining authors declare no competing interests.

Coronary atherosclerosis results from the delicate interplay of genetic and exogenous risk factors, principally taking place in metabolic organs and the arterial wall. Here we show that 224 gene-regulatory coexpression networks (GRNs) identified by integrating genetic and clinical data from patients with ( n = 600) and without ( n = 250) coronary artery disease (CAD) with RNA-seq data from seven disease-relevant tissues in the Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) study largely capture this delicate interplay, explaining >54% of CAD heritability. Within 89 cross-tissue GRNs associated with clinical severity of CAD, 374 endocrine factors facilitated inter-organ interactions, primarily along an axis from adipose tissue to the liver ( n = 152). This axis was independently replicated in genetically diverse mouse strains and by injection of recombinant forms of adipose endocrine factors (EPDR1, FCN2, FSTL3 and LBP) that markedly altered blood lipid and glucose levels in mice. Altogether, the STARNET database and the associated GRN browser (http://starnet.mssm.edu) provide a multiorgan framework for exploration of the molecular interplay between cardiometabolic disorders and CAD., Competing Interests: Competing interests J.L.M.B. is the founder of Clinical Gene Networks (CGN). J.L.M.B. (chair) and A.R. are on CGN’s board of directors. J.L.M.B., A.R. and T.M. are shareholders in CGN. J.L.M.B. receives financial compensation as a consultant for CGN. CGN has an invested interest in STARNET that is regulated in an agreement with the Icahn School of Medicine at Mount Sinai. Neither the Icahn School of Medicine at Mount Sinai nor CGN have made claims to results presented in this study. E.E.S. is the CEO of Sema4. C.W. and L.-M.G. are employees of AstraZeneca. No funding for this study was received from Sema4. AstraZeneca supported this study through independent grants to J.L.M.B. at the Karolinska Institutet (ICMC). The remaining authors declare no competing interests.