HBV DNA Integration into Telomerase or MLL4 Genes and TERT Promoter Point Mutation as Three Independent Signatures in Subgrouping HBV-Related HCC with Distinct Features.

Introduction: A set of genetic mutations to classify hepatocellular carcinoma (HCC) useful to clinical studies is an unmet need. Hepatitis B virus-related HCC (HBV-HCC) harbors a unique genetic mutation, namely, the HBV integration, among other somatic endogenous gene mutations. We explored a combination of HBV DNA integrations and common somatic mutations to classify HBV-HCC by using a capture-sequencing platform. Methods: A total of 153 HBV-HCCs after surgical resection were subjected to capture sequencing to identify HBV integrations and three common somatic mutations in genomes. Three mutually exclusive mutations, HBV DNA integration into the TERT promoter, HBV DNA integration into MLL4, or TERT promoter point mutation, were identified in HBV-HCC. Results: They were used to classify HBV-HCCs into four groups: G1 with HBV-TERT integration (25.5%); G2 with HBV-MLL4 integration (10.5%); G3 with TERT promoter mutation (30.1%); and G4 without these three mutations (34.0%). Clinically, G3 has the highest male-to-female ratio, cirrhosis rate, and associated with higher early recurrence and mortality after resection, but G4 has the best outcome. Transcriptomic analysis revealed a grouping different from the published ones and G2 with an active immune profile related to immune checkpoint inhibitor response. Analysis of integrated HBV DNA provided clues for HBV genotype and variants in carcinogenesis of different HCC subgroup. This new classification was also validated in another independent cohort. Conclusion: A simple and robust genetic classification was developed to aid in understanding HBV-HCC and in harmonizing clinical studies.

Reduced Risk of Atrial Fibrillation Following Cholecystectomy: A Nationwide Population-Based Study.

Background: Gallstone disease (GD) is associated with a high risk of cardiovascular disease. However, it is unknown whether GD contributes to atrial fibrillation (AF). We aimed to investigate the association between GD and AF. Methods: We performed a population-based cohort study using data from the Taiwan National Health Insurance Research Database between 2001 and 2011. A GD cohort of 230,076 patients was compared with a control cohort consisting of an equal number of patients matched for age, sex, cardiovascular and gastrointestinal comorbidities. Results: In total, 5,992 (49.8/10,000 person-years) patients with GD and 5,804 (44.5/10,000 person-years) controls developed AF. GD increased AF risk with a hazard ratio (HR) of 1.20 [95% confidence interval (CI), 1.16-1.25]. In patients with GD but without cholecystectomy, the HR of AF reached 1.57 (95% CI = 1.50-1.63). After cholecystectomy, the HR of AF significantly decreased to 0.85 (95% CI = 0.81-0.90). Among the three age groups with GD (<45, 45-64, and ≥65 years), the adjusted HRs of AF were 1.59 (95% CI = 1.08-2.33), 1.31 (95% CI = 1.18-1.45), and 1.18 (95% CI = 1.13-1.22), respectively. Compared with patients with a CHA2DS2-VASc score equal to 0, the HRs of AF risk among total cohort patients and a score equal to 1, 2, 3, and ≥ 4 were 1.28 (95% CI = 1.15-1.43), 2.26 (95% CI = 2.00-2.56), 3.81 (95% CI = 3.35-4.34), and 5.09 (95% CI = 4.42-5.87), respectively. Conclusion: This population-based longitudinal follow-up study showed that patients with GD had an increased AF risk. Moreover, cholecystectomy was related to reduced AF risk. Cardiovascular checkups may be necessary for patients with GD, especially those who are young and have other typical risk factors.

Furin Inhibitors Block SARS-CoV-2 Spike Protein Cleavage to Suppress Virus Production and Cytopathic Effects.

Development of specific antiviral agents is an urgent unmet need for SARS-coronavirus 2 (SARS-CoV-2) infection. This study focuses on host proteases that proteolytically activate the SARS-CoV-2 spike protein, critical for its fusion after binding to angiotensin-converting enzyme 2 (ACE2), as antiviral targets. We first validate cleavage at a putative furin substrate motif at SARS-CoV-2 spikes by expressing it in VeroE6 cells and find prominent syncytium formation. Cleavage and the syncytium are abolished by treatment with the furin inhibitors decanoyl-RVKR-chloromethylketone (CMK) and naphthofluorescein, but not by the transmembrane protease serine 2 (TMPRSS2) inhibitor camostat. CMK and naphthofluorescein show antiviral effects on SARS-CoV-2-infected cells by decreasing virus production and cytopathic effects. Further analysis reveals that, similar to camostat, CMK blocks virus entry, but it further suppresses cleavage of spikes and the syncytium. Naphthofluorescein acts primarily by suppressing viral RNA transcription. Therefore, furin inhibitors may be promising antiviral agents for prevention and treatment of SARS-CoV-2 infection.

Complement C1q mediates the expansion of periportal hepatic progenitor cells in senescence-associated inflammatory liver.

Most hepatocellular carcinomas (HCCs) develop in patients with chronic hepatitis, which creates a microenvironment for the growth of hepatic progenitor cells (HPCs) at the periportal area and subsequent development of HCCs. We investigated the signal from the inflammatory liver for this pathogenic process in the hepatic conditional ß-catenin knockout mouse model. Senescent ß-catenin-depleted hepatocytes in aged mice create an inflammatory microenvironment that stimulates periportal HPC expansion but arrests differentiation, which predisposes mice to the development of liver tumors. The release of complement C1q from macrophages in the inflammatory niche was identified as the unorthodox signal that activated the ß-catenin pathway in periportal HPCs and was responsible for their expansion and de-differentiation. C1q inhibitors blocked the ß-catenin pathway in both the expanding HPCs and the liver tumors but spared its orthodox pathway in pericentral normal hepatocytes. This mechanism has been validated in human liver specimens from patients with chronic hepatitis. Taken together, these results demonstrate that C1q- mediated activation of ß-catenin pathway in periportal HPCs is a previously unrecognized mechanism for replenishing hepatocytes in the inflammatory liver and, if unchecked, for promoting hepatocarcinogenesis. C1q may become a new target for blocking carcinogenesis in patients with chronic hepatitis.

Percutaneous coronary revascularization improves the prognosis of patients with cardiogenic shock in acute coronary syndrome: a chronological study.

BACKGROUND: Cardiogenic shock complicating acute coronary syndrome (ACS) implies grim prognosis with conventional management. Previous studies of coronary intervention yielded controversial results and were rarely analyzed chronologically. This study was to determine the impact of percutaneous coronary revascularization on outcome by studying two time periods 5 years apart in which the revascularization was more frequent and techniques more refined in the later period. METHODS AND MATERIALS: All patients admitted to the intensive or coronary care unit for ACS in two 1.5-year study periods (Period I: Jan 1994-Jun 1995, Period II: Oct 1999-Apr 2000) were retrospectively screened. Patients who met strict criteria of cardiogenic shock within 24 h of ACS were enrolled. The demographics, management and in-hospital/3-month outcomes were analyzed. RESULTS: Thirty-seven patients (33M/4F, aged 65+/-8 years) were enrolled in Period I and 32 patients (25M/7F, aged 68+/-13 years) in Period II. The incidence of cardiogenic shock was 11.8 and 9.3%, respectively. The demographics were similar except patients in Period II were older. Significantly more coronary angiography and interventions were done in the later period. The in-hospital (68 vs. 44%, P=0.047) and 3-month mortalities (70 vs. 44%, P=0.03) were significantly reduced in Period II. The in-hospital survivors in two study periods differed only in use of coronary angiography (94 vs. 50%, P=0.005) and interventions (83 vs. 33%, P=0.005) but not others. CONCLUSIONS: Percutaneous coronary revascularization does improve the clinical outcome of cardiogenic shock when analyzed chronologically. This treatment is warranted in every such patient in the interventional era.