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Vaccines and first-generation antiviral therapeutics have provided important protection against COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there remains a need for additional therapeutic options that provide enhanced efficacy and protection against potential viral resistance. The SARS-CoV-2 papain-like protease (PL pro ) is one of the two essential cysteine proteases involved in viral replication. While inhibitors of the SARS-CoV-2 main protease have demonstrated clinical efficacy, known PL pro inhibitors have, to date, lacked the inhibitory potency and requisite pharmacokinetics to demonstrate that targeting PL pro translates to in vivo efficacy in a preclinical setting. Here, we report the machine learning-driven discovery of potent, selective, and orally available SARS-CoV-2 PL pro inhibitors, with lead compound PF-07957472 ( 4 ) providing robust efficacy in a mouse-adapted model of COVID-19 infection.

Background: Neoangiogenesis plays a crucial role in the progression of hepatocellular carcinoma (HCC), and concerns have been raised about the role of neoangiogenesis on the effectiveness of transarterial chemoembolization (TACE)., Aim: In this study, we aimed to evaluate Vascular Endothelial Growth Factor (VEGF) and Hypoxia-Inducible Factor-1α (HIF-1α) as circulating prognostic biomarkers in HCC patients treated with TACE., Methods: Blood samples were collected from 163 patients before (t 0 ) and four weeks after TACE (t 1 )., Results: Higher levels of VEGF after TACE were demonstrated (264.0 [78.7-450.8] vs. 278.6 [95.0-576.6] pg/mL; p < 0.0001). Responders to TACE had lower levels of VEGF than non-responders both at t 0 (200.0 [58.9-415.8] vs. 406.6 [181.4-558.6] pg/mL; p = 0.006) and at t 1 (257.3 [68.5-528.6] vs. 425.9 [245.2-808.3] pg/mL; p = 0.003), and in both groups there was an increase in VEGF compared to measurements before treatment (p = 0.001 and p = 0.005, respectively). VEGF was not associated with overall survival (OS), while patients with HIF-1α ≤ 0.49 ng/mL showed better prognosis (median OS 28.0 months [95% CI 19.7-36.3] vs. 17.0 months [95% CI 11.1-22.9]; p = 0.01). Moreover, HIF-1α was identified as an independent prognostic parameter., Conclusions: VEGF and HIF-1α can be considered useful prognostic biomarkers in HCC patients treated with TACE., Competing Interests: Conflict of Interest The Authors declare no potential conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

MicroRNAs (miRNAs) are small, non-coding RNA molecules involved in regulating gene expression. Many studies, mostly conducted on pediatric patients, suggested that oxidative stress and several miRNAs may play an important role in coeliac disease (CeD) pathogenesis. However, the interplay between oxidative stress and miRNA regulatory functions in CeD remains to be clarified. In this review, we aimed to perform a literature review on the role of miRNAs and oxidative stress in adult CeD patients and to analyze their potential interactions. In this direction, we also reported the preliminary results of a pilot study we recently performed., Competing Interests: Matteo Fassan has a consulting or advisory role for Astellas Pharma, GlaxoSmithKline, Roche, MSD Oncology, Amgen, Lilly, Incyte, Novartis, AstraZeneca, and Pierre Fabre, and research funding for Astellas Pharma, QED Therapeutics, Macrophage Pharma, and Diaceutics. Fabiana Zingone has served as a speaker for Werfen, EG Stada Group, Fresenius Kabi, Kedrion, Janssen, Pfizer, Takeda, Unifarco, Malesci, and Galapagos and has served as a consultant for Galapagos and Takeda. Filippo Pelizzaro served as a consultant for EISAI and MSD. Romilda Cardin, Giulia Sarasini, Milena Minotto, Chiara Carlotto, Michela Palo, and Fabio Farinati have no conflicts of interest to declare., (© 2024 The Author(s). Published by S. Karger AG, Basel.)