Serum levels of mi RNA in patients with hepatitis B virus-associated acute-on-chronic liver failure

Background: Hepatitis B virus(HBV)-associated acute-on-chronic liver failure(HBV-ACLF) is a lifethreatening condition and its exact pathophysiology and progression remain unclear. The present study aimed to assess the role of serum mi RNAs in the evaluation of HBV-ACLF and to develop a model to predict the outcomes for ACLF.Methods: Serum was collected from 41 chronic hepatitis B and 55 HBV-ACLF patients in addition to30 chronic asymptomatic HBV carriers as controls. The mi RNAs expressions were measured by real-time quantitative PCR(q-PCR). Statistical analyses were conducted to assess the ability of differentially expressed mi RNAs and other prognostic factors in identifying ACLF prognosis and to develop a new predictive model.Results: Real-time q-PCR indicated that serum miR-146 a-5 p, mi R-122-3 p and mi R-328-3 p levels were significantly upregulated in ACLF patients compared to chronic hepatitis B and chronic asymptomatic HBV carriers patients. In addition, multivariate regression analyses indicated that Na+, INR, gastrointestinal bleeding and mi R-122-3 p are all independent factors that are reliable and sensitive to the prognosis of HBV-ACLF. Therefore, we developed a new model for the prediction of HBV-ACLF disease state: Y = 0.402 × Na+-1.72 × INR-4.963 × gastrointestinal bleeding(Yes = 0; No = 1)-0.278 ×(mi R-122-3 p) + 50.449. The predictive accuracy of the model was 95.3% and the area under the receiver operating characteristic curve(AUROC) was 0.847.Conclusions: Expression levels of these mi RNAs(miR-146 a-5 p, mi R-122-3 p and mi R-328-3 p) positively correlate with the severity of liver inflammation in patients with ACLF and may be useful to predict HBV-ACLF severity.

Early hepatitis B viral DNA clearance predicts treatment response at week 96

AIM To investigate whether hepatitis viral DNA load at 24 wk of treatment predicts response at 96 wk in patients with chronic hepatitis B.METHODS A total of 172 hepatitis B envelope antigen(HBe Ag)-positive chronic hepatitis B patients who received initial treatment at 16 tertiary hospitals in Hunan Province, China were enrolled in this study. All patients received conventional doses of lamivudine and adefovir dipivoxil, telbivudine, entecavir dispersible tablets, or entecavir tablets for 96 wk. Patients who used other antiviral drugs or antitumor and immune regulation therapy were excluded. Patients were stratified into three groups according to their viral DNA load at 24 wk: < 10 IU/m L(group 1), 10-103 IU/m L(group 2), and > 103 IU/m L(group 3). Correlations of 24-wk DNA load with HBe Ag negative status and HBe Ag seroconversion at 96 wk were analyzed. Receiver operating characteristic curve analysis was used to test the predictive value of the HBV DNA load at 24 wk for long-term response.RESULTS The rates of conversion to HBe Ag negative status and HBe Ag seroconversion rates were 53.7% and 51.9%, respectively, in group 1; 35.21% and 32.39% in group 2; and 6.38% and 6.38% in group 3. The receiver operating characteristic curves for the three subgroups revealed that the lowest DNA load(< 10 IU/m L) was better correlated with response at 96 wk than a higher DNA load(10-103 IU/m L). Nested PCR was used for amplifying and sequencing viral DNA in patients with a viral DNA load > 200 IU/m L at 96 wk; resistance mutations involving different loci were present in 26 patients, and three of these patients had a viral DNA load 10-103 IU/m L at 96 wk. CONCLUSION Hepatitis B viral DNA load at 24 wk of antiviral treatment in patients with chronic hepatitis B is a predictor of the viral load and response rate at 96 wk.

Novel HBV mutations and their value in predicting efficacy of conventional interferon

BACKGROUND： Accumulating studies assessing the impacts of hot spot mutations on conventional interferon（IFN） efficacy come to discrepant conclusions; studies regarding the mutations in S and RT regions are also unclear. The present study aimed to evaluate the impacts of HBV mutations on the efficacy of conventional IFN. METHODS： A total of 126 patients who received conventional IFN treatment for 48 weeks were enrolled. Biochemical and serological parameters were routinely tested. The sequences of HBV from 78 serum samples were amplified by nested-PCR; mutations were identified with sequence scanner V1.0 after ABI 3730 xl direct sequencing, HBV genotypes were determined according to RT gene sequences utilizing NCBI Genotyping Tool which was based on phylogenetic analysis.RESULTS： The baseline DNA levels of virological response（VR） group were significantly lower than those of no VR group [7.13±0.76 vs 7.69±0.56 lg（copies/m L）, P=0.001]. The baseline ALT levels were significantly higher in the HBe Ag clearance group（204.72±88.65 vs 162.80±85.81 IU/L, P〈0.05） andHBe Ag seroconversion group（204.89 ±95.68 vs 166.75±84.43 IU/L, P〈0.05）. Females and lower BMI levels（20.01±2.33 vs 21.65±3.66 kg/m^2, P〈0.05） were prone to acquired biochemical response（BR）. PC-W28STOP（ntG 1896A） was significantly higher in the combined response（CR） group than that in the no CR group（91.7% vs 39.7%, P=0.001）. Multivariate logistic regression analysis showed that baseline DNA, PC-P159T（ntC2288A）, BCP-N118T（ntA 1726C） and BCP-L134L（ntA 1775C/G/T） influenced VR independently. PC-G182C（nt G2357T）, PC-S64A/T（nt T2003G/A） and BMI were independent influence factors for HBe Ag clearance, HBe Ag seroconversion and BR, respectively. The new predicting model concluded that baseline DNA and new mutations for VR were established successfully, and ROC analysis showed that AUC was 0.842（P〈0.001） with a sensitivity of 0.652 and a specificity of 0.933.CONCLUSIONS： PC-P159T（ntC 2288A）, BCP-N118T（ntA 1726C）, BCP-L134L（nt A1775C/G/T）, PC-G182C（nt G2357T） and PCS64A/T（nt T2003G/A） were novel identified mutations that impacted IFN therapeutic efficacy. These novel mutations could serve as important predictors before conventional IFN treatment.

PTEN Lipid Phosphatase Activity Enhances Dengue Virus Production through Akt/FoxO1/Maf1 Signaling

Dengue virus(DENV) is an arthropod-borne viral pathogen and a global health burden. Knowledge of the DENV-host interactions that mediate virus pathogenicity remains limited. Host lipid metabolism is hijacked by DENV for virus replication in which lipid droplets(LDs) play a key role during the virus lifecycle. In this study, we reveal a novel role for phosphatase and tensin homolog deleted on chromosome 10(PTEN) in LDs-mediated DENV infection. We demonstrate that PTEN expression is downregulated upon DENV infection through post-transcriptional regulation and, in turn, PTEN overexpression enhances DENV replication. PTEN lipid phosphatase activity was found to decrease cellular LDs area and number through Akt/FoxO1/Maf1 signaling, which, together with autophagy, enhanced DENV replication and virus production. We therefore provide mechanistic insight into the interaction between lipid metabolism and the DENV replication cycle.