NK-cell-elicited gasdermin-D-dependent hepatocyte pyroptosis induces neutrophil extracellular traps that facilitate HBV-related acute-on-chronic liver failure.

BACKGROUND AND AIMS: HBV infection is a major etiology of acute-on-chronic liver failure (ACLF). At present, the pattern and regulation of hepatocyte death during HBV-ACLF progression are still undefined. Evaluating the mode of cell death and its inducers will provide new insights for developing therapeutic strategies targeting cell death. In this study, we aimed to elucidate whether and how immune landscapes trigger hepatocyte death and lead to the progression of HBV-related ACLF. APPROACH AND RESULTS: We identified that pyroptosis represented the main cell death pattern in the liver of patients with HBV-related ACLF. Deficiency of MHC-I in HBV-reactivated hepatocytes activated cytotoxic NK cells, which in turn operated in a perforin/granzyme-dependent manner to trigger GSDMD/caspase-8-dependent pyroptosis of hepatocytes. Neutrophils selectively accumulated in the pyroptotic liver, and HMGB1 derived from the pyroptotic liver constituted an important factor triggering the generation of pathogenic extracellular traps in neutrophils (NETs). Clinically, elevated plasma levels of myeloperoxidase-DNA complexes were a promising prognostic biomarker for HBV-related ACLF. More importantly, targeting GSDMD pyroptosis-HMGB1 release in the liver abrogates NETs that intercept the development of HBV-related ACLF. CONCLUSIONS: Studying the mechanisms that selectively modulate GSDMD-dependent pyroptosis, as well as its immune landscapes, will provide a novel strategy for restoring the liver function of patients with HBV-related ACLF.

Entecavir Combined With Adefovir Ameliorates Patients With Chronic Hepatitis B Who Fail to Respond to Nucleotide (Acid) Analog Monotherapy.

The aim of this study was to evaluate the efficacy and safety of entecavir (ETV) combined treatment with adefovir (ADV) on chronic hepatitic B (CHB) patients who failed to respond to nucleotide (acid) analog (NA) treatment. On this basis, the possible factors in the combined treatment of these patients will be analyzed. The safety, biochemical index, and the possible factors that might affect the ETV and ADV combined treatment at different points in time were retrospectively analyzed. The biochemical index included the following: virological response, hepatitis B virus (HBV) DNA decline, primary nonresponse, biochemical response, and the hepatitis B virus E antigen/hepatitis B virus E antibody seroconversion rate. There were 94 CHB patients and compensated liver cirrhosis patients who received ETV plus ADV treatment for over 12 weeks after failure of treatment with NAs. The authors have also investigated 76 CHB patients (80.9%) and 18 hepatitis B cirrhosis patients (19.1%) in this study. The HBV DNA baseline was 4.4 ± 1.4 log10 IU/mL, and the positive rate of HBeAg before salvage treatment was 78.7% (74/94). The sample sizes were 94, 78, 42, 10, 6, and 1 for follow-up of 24, 48, 96, 144, 192, and 240 weeks, respectively. The virological responses (HBV DNA < 2 log10 IU/mL) and biochemical responses were 52.1%, 74.3%, and 90.4% and 63.1%, 61.6%, and 81.1%, respectively, at 24, 48, and 96 weeks, which showed significant differences (P < 0.001 and P < 0.005, respectively). The HBV DNA decline was presented as mean ± SEM, which were 1.53 ± 1.23, 1.75 ± 1.37, 2.07 ± 1.54, and 2.39 ± 1.77 log10 IU/mL at 12, 24, 48, and 96 weeks, respectively. They showed significant differences compared with the baseline (χ = 8.084, P < 0.05). The rate of primary nonresponse was 30.9% (29/94), and the primary treatment failure rates were 26.6% (25/94), 24.4% (19/78), and 4.8% (2/42) at 24, 48, and 96 weeks, respectively. They all have statistical difference (P = 0.011 < 0.05). There were 23 patients who experienced virological breakthrough after the HBV DNA levels were undetectable, whereas after follow-up for 12-24 weeks, the HBV DNA levels were back to undetectable again. ETV plus ADV treatment is an efficient and safe treatment for CHB and compensated liver cirrhosis patients who experienced NA treatment failure. The high quantity of baseline HBV DNA level is a risk factor for poor efficacy of salvage treatment.

Clinicopathological, Immunohistochemical, and Molecular Characteristics of Pigmented Microcystic Chromophobe Renal Cell Carcinoma with Favorable Prognosis.

Background. Pigmented microcystic chromophobe renal cell carcinoma (RCC) is a subtype of chromophobe RCC. Its distinct histopathologic features are microcystic and microtubular pattern, pigmentation, and microcalcifications. Pigmented microcystic chromophobe RCC has ultrastructure, immunophenotypic structure, and molecular results similar to chromophobe RCC. Methods. We report five tumors of pigmented microcystic chromophobe RCC. Morphological observation and immunohistochemical examination were performed, and clinical and molecular features were analyzed. Results. Microscopically, all five tumors showed brown pigmentation, microcystic, and tubular cystic structures, one tumor presented microscopic calcifications. All tumors were positive for EMA, AE1/AE3, PAX8, KRT7, KIT (CD117), claudin 7, KRT8, and E-cadherin, and three tumors expressed P504S. All tumors were negative for vimentin, CA9, KRT20, TFE3, TFEB, Melan-A, HMB45, FH, SDHB, and GATA3. Ki-67 index varied from less than 1% to 2%. In three tumors, next-generation sequencing of the 688 gene was performed, the results found gene variants with potential clinical significance such as JMJD1C, MYCL, TP53, PI3KCA, KRAS, APC, GLI1, LRRK2, and gene variants with unclear clinical significance such as NTRK1 and RAD50; All patients remained alive over a follow-up period of 8-46 months without tumor recurrence and sarcomatoid transformation. Conclusions. Pigmented microcystic chromophobe RCC has a relatively benign biological behavior, and distant metastases and sarcomatoid transformation are rare. This overview of five additional tumors of pigmented microcystic chromophobe RCC offers further insight into this special subtype of chromophobe RCC.

[Dynamic change of hepatitis B surface antigen expression in chronic hepatitis B patients during the natural recovery course and the short-term antivirus treatment].

OBJECTIVE: To investigate the dynamic quantitative changes in expression of hepatitis B virus (HBV) surface antigen (HBsAg) that occurs during the natural recovery course and the short-term antivirus treatment period of patients suffering from flares in chronic hepatitis B (CHB). METHODS: CHB patients presenting for treatment of flare-ups were randomly assigned to receive treatment with Entecavir antiviral (group A, n = 39) or to naturally resolve the acute condition (group B, n = 22). All patients MELD scores were calculated and HBsAg levels and HBV DNA loads were measured upon admission (baseline), at worst-condition stage, and end of treatment/flare-up (discharge). Pairwise comparisons of intergroup differences were made to evaluate the change in the three disease parameters over time in response to the management approach. RESULTS: The levels of HBsAg were not significantly different between the two groups at baseline, worst-condition stage and discharge (group A: (3.68+/-0.45), (3.84+/-0.19) and (3.69+/-0.58) log10 cut-off index (COI) respectively; group B: (3.59+/-0.54), (3.47+/-0.76) and (3.43+/-0.68) log10 COI respectively; all P more than 0.05). However, the HBV DNA loads were significantly lower in group A than in group B at the worst-condition stage and at discharge (all P less than 0.05). In group A, the MELD scores were significantly higher at baseline and at worst-condition stage than at discharge (all P = 0.000), but the difference between baseline and worst-condition stage was not significant. Also in group A, the HBV DNA load showed a gradually decreasing trend over time (baseline more than worst-condition stage more than discharge, all P less than 0.05). No significant differences were observed over time in the HBsAg levels of group A. In group B, the MELD scores were significantly higher at baseline and at worst-condition stage than at discharge (all P = 0.000), but the difference between baseline and worst-condition stage was not significant (P = 0.619). Also in group B, the HBV DNA loads were significantly higher at baseline and worst-condition stage than at discharge (P = 0.000 and P = 0.003 respectively), but the difference between baseline and worst-condition stage was not significant. Finally, no significant differences were observed over time in the HBsAg levels of group B. CONCLUSION: Natural recovery from an acute flare-up of CHB is not accompanied by a change in HBsAg levels. In addition, short-term antiviral treatment to resolve the flare-up has no influence on HBsAg level.

[A five-year follow-up of one hundred and thirty-six patients of hepatitis C].

OBJECTIVE: To investigate the clinical outcome and effect of interferon treatment on patients with chronic hepatitis C. METHODS: 136 cases of patients with chronic hepatitis C were followed up by methods of retrospective survey combined with prospective study. SPSS16. 0 was used to perform chi-square test and multiple logistic regression. RESULTS: 136 cases of patients were infected with HCV virus mainly through blood and blood products transfusion. They were diagnosed mainly between 2000 and 2005. 98 cases of them had anti-viral treatment with interferon and ribavirin, while the rest did not; 12 new cases developed HCV-related cirrhosis or liver carcinoma in five years, which accounted for 8.8% of the total. Among 76 cases once treated with interferon, 46 cases (60.5%) relapsed in five years. For patients with age < 40, the rates of cirrhosis and liver cancer were 0, and patients with age ≥ 40 but < 60 years, the rates of cirrhosis and liver cancer were 12.5% (7/56 cases), while for those ≥ 60 years old the rates were 35.7% (10/28 cases). The difference was significant ( B = 0.111, Wald = 4.324, P = 0.038) as analysed by logistic regression. The rates of cirrhosis and liver cancer were zero for those with normal or within twice the upper normal AST limit in five years, 43.5% (10/23 cases) for those with AST ranging from 2 to 4 fold the upper normal limit, and 58.3% (7/12 cases) for those with AST higher than four times the upper normal limit. The difference was also significant ( B = 2.184, Wald = 5.443, P = 0.02) by logistic regression analysis. The rate of relapse was 29.7% (11/37 cases) for those using pegylated interferon and 89.7% (35/39 cases) for those using interferon. The difference was significant ( Result of logistic regression showed-B = -2.077, Wald = 4.352, P = 0.037). The rate of relapse was 100% (15/15 cases) for those with treatment less than 24 weeks, 76.2% (16/21 cases) for those with treatment more than 24 weeks but less than 48 weeks, and 37.5% (14/40 cases) for those with treatment more than 48 weeks. The difference was significant (Result of logistic regression showed-B = -1.632, Wald = 6.651, P = 0.01). 42 cases of the relapsed (91.3%) were administrated with interferon once again with ideal effect. CONCLUSION: Hepatitis C virus infection increases the risk of liver cirrhosis and liver cancer. Interferon combined with ribavirin therapy could effectively control the virus and improve outcomes. We can reduce the incidence of relapse by choosing the treatment of pegylated interferon instead of interferon and by completing the full treatment.

Efficacy and Safety of Sofosbuvir-Based Direct-Acting Antiviral Agents Treatment for Patients with Genotype 3/6 Hepatitis C Virus Infection.

Aims: The aim is to evaluate the efficacy and safety of Sofosbuvir- (SOF-) based direct-acting antiviral agents (DAAs) treatment for patients with genotype (GT) 3/6 hepatitis C virus (HCV) infection. Methods: Patients infected with GT 3/6 HCV and treated with SOF-based DAAs were enrolled in this prospective, open, single-center, and real-world study. Drugs included Sofosbuvir (SOF), Velpatasvir (VEL), Daclatasvir (DCV), and Ribavirin (RBV). The treatment regimens included SOF + RBV for 24 weeks, SOF + DCV ± RBV for 12/24 weeks, and SOF/VEL ± RBV for 12 weeks. Results: A total of 54 patients were included. Age was 42.5 ± 10.4 years. Baseline HCV RNA was 6.29 ± 0.89log10 IU/mL. The numbers of GT 3a, 3b, and 6a patients were 10, 12, and 32, respectively. The numbers of chronic hepatitis, compensated cirrhosis, and decompensated cirrhosis patients were 39, 9, and 6, respectively. In patients with chronic hepatitis C and liver cirrhosis, sustained virological response 12 weeks after the end of treatment (SVR12) was 97.4% and 96.7%, respectively, and rapid virological response (RVR) was 75.0% and 57.1%, respectively. SVR12 of GT3a, GT3b, and GT6a was 100%, 83.3%, and 97%, respectively. ALT normality rate in chronic hepatitis group is higher than that in cirrhosis group at 4 weeks of treatment (89.7% versus 60.0%, p = 0.033) and at 12 weeks after EOT (94.9% versus 66.7%, p = 0.021). The overall incidence rate of adverse events was 44.4%, with fatigue being the most common (13.0%). Conclusion: SOF-based DAAs regimen can achieve ideal SVR12 for Chinese patients with both GT3a and GT6a HCV infection. The tolerance and safety of SOF-based DAAs regimen are good.