In vitro antiviral activity of SCH446211 (SCH6), a novel inhibitor of the hepatitis C virus NS3 serine protease

Background: Current hepatitis C virus (HCV) therapies may cure ∼60% of infections. They are often contraindicated or poorly tolerated, underscoring the need for safer and more effective drugs. A novel, α-ketoamide-derived, substrate-based inhibitor of the HCV serine protease (SCH446211) was developed. Compared with earlier reported inhibitors of similar chemical class, it has a P1′-P2′ extension which provides extended interaction with the protease active site. The aim of this study was to evaluate the in vitro antiviral activity of SCH446211. Methods: Binding constant of SCH446211 to HCV NS3 protease was measured with the chromogenic substrate in vitro cleavage assay. Cell-based activity of SCH446211 was evaluated in replicon cells, which are Huh-7 hepatoma cells stably transfected with a subgenomic HCV RNA as reported previously. After 72 h of incubation with SCH446211, viral transcription and protein expression were measured by real-time RT-PCR (TaqMan), quantitative in situ hybridization, immunoblot and indirect immunofluorescence. Results: The binding constant of SCH446211 to HCV NS3 protease was 3.8 ± 0.4 nM. HCV replication and protein expression were inhibited by SCH446211 in replicon cells as consistently shown by four techniques. In particular, based on quantitative real-time RT-PCR measurements, the IC50 and IC90 of SCH446211 were estimated to be 40 ± 20 and 100 ± 20 nM (n = 17), respectively. Long-term culture of replicon cells with SCH446211 reduced replicon RNA to <0.1 copy per cell. SCH446211 did not show cellular toxicity at concentrations up to 50 μM. Conclusions: SCH446211 is a potent inhibitor of HCV protease in vitro. Its extended interaction with the HCV NS3 protease active site is associated with potent in vitro antiviral activity. This observation is potentially a useful guide for development of future potent inhibitors against HCV NS3 proteas

A Western single-center experience with endoscopic submucosal dissection for early gastrointestinal cancers

Endoscopic submucosal dissection (ESD) has gained worldwide acceptance as a treatment for early gastrointestinal cancers (EGICs). However, the management of these tumors in the Western world is still mainly surgical. Our aim was to evaluate the safety and feasibility of ESD at a European center. Based on the knowledge transferred by one of the most experienced Japanese institutions, we conducted a pilot study on 25 consecutive patients with EGICs located in the esophagus (n = 3), stomach (n = 7), duodenum (n = 1), and colon (n = 14) at our tertiary center over a 2-year-period. The main outcome measurements were complete (R0) resection, as well as en-bloc resection and the management of complications. The R0 and en-bloc resection rates were 100% and 84%, respectively. There were three cases of bleeding and five cases of perforation. With a median follow up of 18 months, two recurrences were observed. We conclude that ESD for early esophageal and gastric cancers is feasible and effective, while colonic ESD requires more expertise

The 2020 Italian Society of Arterial Hypertension (SIIA) practical guidelines for the management of primary aldosteronism

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Constraints on the χ_(c1) versus χ_(c2) polarizations in proton-proton collisions at √s = 8 TeV

The polarizations of promptly produced χ_(c1) and χ_(c2) mesons are studied using data collected by the CMS experiment at the LHC, in proton-proton collisions at √s=8  TeV. The χ_c states are reconstructed via their radiative decays χ_c → J/ψγ, with the photons being measured through conversions to e⁺e⁻, which allows the two states to be well resolved. The polarizations are measured in the helicity frame, through the analysis of the χ_(c2) to χ_(c1) yield ratio as a function of the polar or azimuthal angle of the positive muon emitted in the J/ψ → μ⁺μ⁻ decay, in three bins of J/ψ transverse momentum. While no differences are seen between the two states in terms of azimuthal decay angle distributions, they are observed to have significantly different polar anisotropies. The measurement favors a scenario where at least one of the two states is strongly polarized along the helicity quantization axis, in agreement with nonrelativistic quantum chromodynamics predictions. This is the first measurement of significantly polarized quarkonia produced at high transverse momentum