Relationship Between Platelets and the Clinical Efficacy of Umbilical Cord Mesenchymal Stem Cells for HBV-Related Acute-on-Chronic Liver Failure and Liver Cirrhosis: A Preliminary Clinical Study.

BACKGROUND: Previous studies have found that the production of platelets could enhance the therapeutic effects of stem cells. Nevertheless, there are still no articles reporting on the relationship between platelets and the clinical efficacy of umbilical cord mesenchymal stem cells (UCMSCs) for HBV-related acute-on-chronic liver failure (ACLF) and liver cirrhosis (LC). METHODS: In this retrospective observational study, patients who met the criteria were included. Patients were divided into subgroups according to the aims of this study. In the first part, the platelet count changes of ACLF and patients with LC after UCMSC therapy were compared and analyzed. Subgroup analysis based on UCMSC infusion times and patient age was also performed. In the second part, patients in the ACLF group and LC group were further divided into subgroups according to their platelet levels. Their clinical characteristics, demographics, and biochemical factors were compared. RESULTS: This study enrolled 64 patients with ACLF and 59 patients with LC. In both groups, platelet levels declined similarly. Compared with the short-course UCMSC treatment group (≤4 times), patients with ACLF and patients with LC with long-course UCMSC treatment (>4 times) showed an overall increasing trend. Younger patients with LC (<45 years) had significantly higher platelet levels than older patients with LC (≥45 years). However, this age difference was not present in the ACLF group. The median TBIL decrease and cumulative TBIL decrease were not significantly different between patients with high PLT and patients with low PLT after UCMSC transfusions. For patients with ACLF, the cumulative TBIL decrease and the median TBIL decrease were significantly greater than those of patients with LC at the same platelet level after UCMSC treatment. However, this difference was not observed at all time points. CONCLUSION: Trend of the platelet levels for HBV-related patients with ACLF and LC after UCMSC treatment did not parallel and varied according to treatment times and patients' age. Platelet levels did not affect the efficacy of MSCs for patients with ACLF or LC.

Interferon add-on therapy increased clinical cure significantly for interferon-experienced chronic hepatitis B patients with low HBsAg.

Currently, interferon add-on therapy brings hope for clinical cure of chronic hepatitis B patients with low HBsAg. However, in clinical practice patients with poor responses to their first interferon therapy were often switched to nucleos(t)ide analog therapy and then labeled as unsuitable patients for interferon therapy. Even if their HBsAg levels dropped to a low level, they were reluctant or not recommended to take interferon again, which caused them to miss out on interferon add-on therapy and clinical cure. Therefore, it is urgent to elucidate the effectiveness of interferon add-on therapy to get clinical cure for these interferon-experienced patients with low HBsAg. The purpose of this study was to investigate whether interferon-experienced patients could achieve the same HBsAg clearance and HBsAg seroconversion rates as interferon-naive patients. Also, the associated factor of HBsAg clearance and seroconversion were aimed to be clarified. 292 patients, including 85 interferon-experienced patients, were enrolled with HBsAg< 1500 IU/ml, HBeAg negative and HBV-DNA negative. And then, peg-interferon α-2b add-on therapy was performed. The results showed that the week 48 HBsAg clearance and seroconversion rates of all patients were 29.8% and 22.0%. There was no statistically significant difference between interferon-experienced and interferon-naive patients in week 48 HBsAg clearance and seroconversion rates, suggesting satisfactory clinical cure of the interferon add-on therapy for interferon-experienced patients. The age, baseline HBsAg, and week 12 HBsAg were negative correlated factors for week 48 HBsAg clearance and seroconversion. Furthermore, the age, baseline HBsAg and week 12 HBsAg for predicting the week 48 HBsAg clearance were cut off at 40.5 years, at 152.0 IU/ml and at 34.99 IU/ml, and for predicting seroconversion were cut off at 40.5 years, at 181.9 IU/ml and at 34.99 IU/ml, correspondingly. Significantly, interferon-experienced patients with low HBsAg were suggested with interferon add-on therapy to achieve clinical cure as soon as possible. This research provided evidences and cut-offs for the interferon add-on therapy against chronic hepatitis B.

M2 macrophage-derived exosomal microRNA-411-5p impedes the activation of hepatic stellate cells by targeting CAMSAP1 in NASH model.

Liver fibrosis is a severe stage of nonalcoholic fatty liver disease (NAFLD), which is closely associated with the activation of hepatic stellate cells (HSCs) and their interaction with macrophages. Exosomes can mediate crosstalk between macrophages and HSCs in NAFLD-associated fibrosis. We found that M2 macrophage-derived exosomes significantly inhibit HSCs activation. RNA-seq studies revealed that miRNA-411-5p was decreased in serum exosomes of nonalcoholic steatohepatitis (NASH) patients as compared with that in healthy controls. Besides, miR-411-5p and M2 macrophage markers are decreased in the liver of the NASH model. We further proved that exosomal miR-411-5p from M2 macrophages inhibit HSCs activation and miR-411-5p directly downregulated the expression of Calmodulin-Regulated Spectrin-Associated Protein 1 (CAMSAP1) to inactivate stellate cells. Importantly, knockdown of CAMSAP1 also inhibited HSCs activation. This study contributes to understanding the underlying mechanism of HSCs activation and indicates CAMSAP1 may serve as a potential therapeutic target for NASH.

Relationship of the Circulating Endothelial Progenitor Cells to the Severity of a Coronary Artery Lesion in Unstable Angina.

The number and function of circulating endothelial progenitor cells (EPCs) decreased in stable coronary artery disease. Nevertheless, there were few studies that explored the variation of EPC and the relationship with the severity of coronary artery lesions in unstable angina (UA). Therefore, this leaves an area for the investigation of the difference in the number and activity of circulating EPCs and the relationship with the Gensini score in unstable angina. Fluorescence-activated cell sorter analysis, as well as DiI-acLDL and lectin fluorescent staining measure the number of circulating EPCs. The transwell chamber assay and MTT were evaluated by the migration and proliferation of circulating EPCs. In addition, the flow-mediated dilation (FMD), Gensini score, and IL-6 levels in plasma were determined. We found that UA patients had the higher number and lower function of circulating EPCs. With the increase in severity of coronary artery lesions, the migration and proliferation of EPCs were decreased. Moreover, the function of the circulating EPCs was negatively associated with severity of coronary artery lesions in unstable angina. In addition, UA patients presented elevated IL-6, which was negatively correlated with the function of circulating EPCs and FMD and positively correlated with the severity of coronary artery lesions evaluated by the Gensini score. These findings revealed the decline in the function of circulating EPCs was associated with the severity of coronary artery disease, which may be related to systemic inflammation.

Dynamic microbiome and metabolome analyses reveal the interaction between gut microbiota and anti-PD-1 based immunotherapy in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a severe disease with high mortality and global incidence. However, the interaction between the gut microbiome and combined immunotherapy for HCC is yet unclear. In this prospective clinical study, patients with unresectable HCC who had not received systemic treatment previously were recruited. Fecal and serum samples were collected at the baseline point and before each subsequent administration as specified. Between 20 October 2019 and 2 February 2021, 61 patients were screened for eligibility, of whom 35 patients were finally included in this study. Alpha diversity of fecal samples from patients who responded to immunotherapy was higher than that of nonresponders at baseline. However, the prominent alpha-diversity between responders and nonresponders became similar as early as week 6 after treatment. The beta diversity of intergroup did not show significant difference at the ninth week after treatment. Alpha-d-Glucose was the only serum metabolite that differed between the responders and nonresponders after 3 months. Responder-enriched Ruminococcus showed a positive correlation with serum galactaric acid, while Klebsiella was positively associated with 3-methylindole and lenticin (all P < .01). The machine learning classifier based on serum metabolites were more able to discriminate HCC patients who potentially benefited from immunotherapy at baseline (AUC 0.793, 95% CI: 0.632-0.954) than the classifier of gut microbiome. In conclusion, gut microbiome biomarkers are associated with the response to anti-PD-1 based immunotherapy in HCC patients. Classifiers based on gut microbiota and serum metabolites are feasible.

Follow-Up of 108 Patients with Chronic Hepatitis B Virus Infection Treated with Polyethylene Glycol-Conjugated Derivatives of Interferon-Alpha and Monitoring of Off-Treatment Virological Relapse.

BACKGROUND This single center study, which enrolled 108 patients with chronic hepatitis B virus infection treated with pegylated interferon-alpha (PEG-IFN-alpha), aimed to follow up and monitor off-treatment responses, including virological relapse, and analyze predictors of long-term efficacy of the PEG-IFN-alpha regimen. MATERIAL AND METHODS In total, 108 hepatitis B e antigen (HBeAg)-positive patients with chronic hepatitis B who had completed the PEG-IFN-alpha regimen and achieved virological suppression were enrolled. The patients were followed up for 5 years to monitor off-treatment responses. Twenty-eight relevant factors, including the history of antiviral therapy and HBeAg seroconversion, were analyzed using the Cox proportional hazards regression model. RESULTS The cumulative rates of virological suppression were 75.70%, 68.68%, 65.25%, 63.91%, and 63.91% at 1, 2, 3, 4, and 5 years of the follow-up period, respectively. Compared with the rates of virological suppression, the cumulative rates of clinical suppression were 88.41%, 79.83%, 78.59%, 75.65%, and 75.65%, respectively, for the 5 years. Alanine aminotransferase (ALT) normalization at 24 weeks after off-therapy (relative risk [RR]=3.430, P=0.013) was a potential predictor for sustained virological suppression, and the history of anti-viral therapy (RR=0.164, P=0.004), quantitative value of hepatitis B virus surface antigen (HBsAg) at 48 weeks of anti-viral therapy (RR=2.697, P=0.039), and ALT normalization at 24 weeks after off-therapy (RR=5.467, P=0.004) were potential predictors for sustained clinical suppression. CONCLUSIONS Our results suggested that increased HBsAg levels at 48 weeks and normalization of ALT at 24 weeks after off-therapy might be predictive factors for long-term treatment efficacy.[color=red] [/color].

The Effect of Heat Source Path on Thermal Evolution during Electro-Gas Welding of Thick Steel Plates.

In recent years, the shipbuilding industry has experienced a growing demand for tighter control and higher strength requirements in thick steel plate welding. Electro-gas welding (EGW) is a high heat input welding method, widely used to improve the welding efficiency of thick plates. Modelling the EGW process of thick steel plates has been challenging due to difficulties in accurately depicting the heat source path movement. An EGW experiment on 30 mm thickness E36 steel plates was conducted in this study. A semi-ellipsoid heat source model was implemented, and its movement was mathematically expressed using linear, sinusoidal, or oscillate-stop paths. The geometry of welding joints, process variables, and steel composition are taken from industrial scale experiments. The resulting thermal evolutions across all heat source-path approaches were verified against experimental observations. Practical industrial recommendations are provided and discussed in terms of the fusion quality for E36 steel plates with a heat input of 157 kJ/cm. It was found that the oscillate-stop heat path predicts thermal profile more accurately than the sinusoidal function and linear heat path for EGW welding of 30 mm thickness and above. The linear heat path approach is recommended for E36 steel plate thickness up to 20 mm, whereas maximum thickness up to 30 mm is appropriate for sinusoidal path, and maximum thickness up to 35 mm is appropriate for oscillate-stop path in EGW welding, assuming constant heat input.

The impact of recipient age on the effects of umbilical cord mesenchymal stem cells on HBV-related acute-on-chronic liver failure and liver cirrhosis.

BACKGROUND: The results of a previous study verified that umbilical cord mesenchymal stem cells (UCMSCs) have good therapeutic effects for the treatment of HBV-related acute-on-chronic liver failure (ACLF) and liver cirrhosis (LC). Nevertheless, it is still unknown whether the effects of UCMSCs are affected by recipient age. METHODS: Patients treated with UCMSCs who met the criteria of HBV-related ACLF and liver cirrhosis were identified in this retrospective observational study. Patients were divided into subgroups according to the World Health Organization (WHO) age criteria (< 45 vs. ≥ 45 years). Group A included young ACLF patients (< 45 y), and group B included older ACLF patients (≥ 45 y). Young LC patients (< 45 y) were assigned to group C, and group D included older LC patients (≥ 45 y). Patients' clinical characteristics, demographics, biochemical factors, and model for end-stage liver disease (MELD) scores were compared for 24 weeks. RESULTS: Sixty-four ACLF patients and 59 LC patients were enrolled in this study. Compared with patients in groups B and C, patients in group A did not show significant superiority in terms of the levels of ALT, AST, TBIL, AFP, and PTA and MELD scores. However, the median decrease and cumulative decrease in the TBIL and ALT levels of patients in group C were larger than those of patients in group D after four weeks of UCMSC transfusions. For older patients (≥ 45 y), the cumulative decrease and the median decrease in the TBIL of ACLF patients were significantly greater than those of LC patients after UCMSC treatment. However, the median decrease in ALT levels of ACLF patients was significantly greater than that of LC patients during UCMSC treatment, and the cumulative decrease in ALT levels of ACLF patients was significantly greater than that of LC patients at all time points. CONCLUSION: The therapeutic effects of UCMSCs for HBV-related acute-on-chronic liver failure and liver cirrhosis varied partly by patient age. Assessing patient age is necessary prior to UCMSC clinical use.

A novel panel based on immune infiltration and tumor mutational burden for prognostic prediction in hepatocellular carcinoma.

Tumor mutation burden (TMB) has been associated with prognosis in various malignancies, but it has yet to be elucidated in hepatocellular carcinoma (HCC). We aimed to investigate the prognostic effects of TMB and its relationship with immune infiltration through multiple databases and whole-exome sequencing, so as to establish a panel model capable of predicting prognosis. The results demonstrated that the prognosis of high TMB group was worse than that of low TMB group, with a cutoff TMB value of 4.9. Enrichment analysis demonstrated that differentially expressed genes were mainly related to T cell activation, cell membrane localization and matrix composition. Tumor immune infiltration analysis revealed the infiltrations of Th2, Th17, and Tgd were up-regulated in high TMB group, while those of Tr1, MAIT, and DC were up-regulated in low TMB group. TMB-Infiltration model fit well with the actual survival observation, with a C-index 0.785 (0.700-0.870), which verified in ICGC-LIRI-JP was 0.650 (0.553-0.747). Additionally, these screened immune genes performed well in predicting tumor vascular invasion with a C-index of 0.847 (0.778-0.916). Overall, these results indicated that patients with high mutation frequency of immune-related genes and high TMB were prone to have worse prognosis and relapse after radical treatment.

Research on Mechanism of Superparamagnetic Iron Oxide Nanoparticles in Activating Endoplasmic Reticulum and Prompting Apoptosis of Liver Cells Through Mediation of Tumor Necrosis Factor-α/Tumor Necrosis Factor Receptor 1 (TNF-α/TNFR1) Pathway.

The aim of this study was to assess mechanism of superparamagnetic iron oxide nanoparticles (SPIO-NPs) in activating endoplasmic reticulum (ER) and prompting apoptosis of liver cells through mediating the TNF-α/TNFR1 pathway. The SPIO-NPs were prepared and identified, and HegG2 cells were cultivated in vitro, and their apoptosis was detected. The specific pathogen-free (SPF)-grade rats were divided into several groups; which included blank group, low concentration group, high concentration group and control group. The enzymatic activity of Caspase-3 in liver tissue was tested, and expressions of Caspase-3, Bax, Bcl-2, TNF-α, p-TNFR1, IRE1α, and eIF2α were tested. The size of prepared SPIO-NPs was 7.5 nm and there was no coagulation. There was good dispersity and electric potential, and appearance was stable. The apoptotic rate in the high concentration group was notably higher than in the other groups. There was notable inflammatory cell infiltration in the high concentration group, where quantity of apoptosis was highest. The quantity of apoptosis and fluorocyte in the high concentration group were notably higher than in the other groups. Moreover, there were over expressions of Caspase-3, Bax, Caspase-3, p-TNFR1, IRE1α, and eIF2α in the high concentration group while the expression of TNF-α was lowest. The apoptosis of HegG2 cells was prompted by SPIO-NPs, and quantity of apoptosis was increased with increased adopted concentration. The active expression of p-TNFR1, IRE1α, and eIF2α could be prompted to reduce the expression of TNF-α and increase the expression of Caspase-3 and Bax for prompting the apoptosis.

Rejuvenated Circulating Endothelial Progenitor Cells and Nitric Oxide in Premenopausal Women with Hyperhomocysteinemia.

Hyperhomocysteinemia (HHcy) induced endothelial dysfunction is associated with disturbance in circulating endothelial progenitor cells (EPCs). Nevertheless, whether this unfavorable effect of HHcy on circulating EPCs also exists in premenopausal women is still unknown. Therefore, this leaves an area for the investigation of the difference on the number and activity of circulating EPCs in premenopausal women with hyperhomocysteinemia and its underlying mechanism. The number of circulating EPCs was measured by fluorescence-activated cell sorter analysis, as well as DiI-acLDL and lectin fluorescent staining. The migration and proliferation of circulating were evaluated by the Transwell chamber assay and MTT. Additionally, the endothelial function and levels of nitric oxide (NO), VEGF, and GM-CSF in plasma and culture medium were determined. The number or activity of circulating EPCs and flow-mediated dilatation (FMD) in premenopausal women with or without HHcy were higher than those in postmenopausal women. However, no significant effect of HHcy on the number or activity of circulating EPCs in premenopausal women was observed. A similar alteration in NO level between the four groups was observed. There was a correlation between FMD and the number or activity of EPCs, as well as NO level in plasma or secretion by EPCs. For the first time, our findings illuminated the quantitive or qualitative alterations of circulating EPCs and endothelial function in premenopausal patients with HHcy are preserved, which was associated with retained NO production. The recuperated endothelial repair capacity is possibly the potential mechanism interpreting cardiovascular protection in premenopausal women with HHcy.

Enhanced therapeutic effects of umbilical cord mesenchymal stem cells after prolonged treatment for HBV-related liver failure and liver cirrhosis.

BACKGROUND: Umbilical cord mesenchymal stem cells (UCMSCs) have been demonstrated to have good therapeutic effects in the treatment of HBV-related liver diseases. However, the therapeutic effect of UCMSCs on HBV-related liver failure and liver cirrhosis and the variations in the efficacy of UCMSCs after different treatment courses remain poorly understood. Therefore, this study was designed to answer these two questions. METHODS: This was an observational study that retrospectively considered a 3-year period during which 513 patients who received stem cell infusion and met the criteria of hepatic failure and liver cirrhosis were identified from the databases of the Third Affiliated Hospital of Sun Yat-sen University. The eligible patients were categorized into the liver failure group and liver cirrhosis group. The two groups were divided into different subgroups according to the duration of stem cell therapy. In the liver failure group, group A received more than 4 weeks and group B received less than 4 weeks of stem cell therapy. In the liver cirrhosis group, patients who received more than 4 weeks of stem cell therapy belonged to group C, and the patients in group D received less than 4 weeks of stem cell therapy. The patients were followed up for 24 weeks. The demographics, clinical characteristics, biochemical factors, and model for end-stage liver disease (MELD) scores were recorded and compared among different groups. RESULTS: A total of 64 patients met the criteria for liver failure, and 59 patients met the criteria for liver cirrhosis. After UCMSC treatment, the levels of alanine aminotransferase (ALT), glutamic-oxaloacetic transaminase (AST), and total bilirubin (TBIL) at all postbaseline time points were significantly lower than those at baseline in the liver failure group and liver cirrhosis group; the prothrombin activity (PTA) and MELD scores gradually improved in only the liver failure group. Four weeks after UCMSC treatment, patients who received prolonged treatment with UCMSCs had a larger decrease in TBIL levels than patients who terminated treatment with UCMSCs. After more than 4 weeks of UCMSC treatment, there were no statistically significant differences in the changes in ALT, AST, TBIL, and PTA values and MELD scores between patients with liver failure who received prolonged treatment with UCMSCs and patients with liver cirrhosis who received prolonged treatment with UCMSCs at any time point. However, the median decrease and cumulative decrease in the TBIL level of patients with liver failure with a standard 4-week treatment course were larger than those of patients with liver cirrhosis with a standard 4-week treatment course. CONCLUSION: Peripheral infusion of UCMSCs showed good therapeutic effects for HBV-related liver failure and liver cirrhosis. Prolonging the treatment course can increase the curative effect of UCMSCs for end-stage liver disease, especially for patients with cirrhosis.

HBV promotes the recruitment of IL-17 secreting T cells via chemokines CCL22 and CCL17.

BACKGROUND AND AIMS: Little is known about the mechanisms of IL-17 secreting T cells accumulation in HBV-transfected livers. Here, we investigated the role of the chemokines CCL17, CCL20 and CCL22 in this process. METHODS: Peripheral blood and liver tissues were obtained from 30 chronic hepatitis B (CHB) patients and 15 healthy volunteers and were evaluated by flow cytometric analysis and immunohistochemistry. Chemokine production by monocyte-derived dendritic cells (MoDCs) cocultured with HBV-transfected or untransfected Huh7 cells was measured by quantitative real-time PCR and enzyme-linked immunosorbent assay. The chemotactic activity of the culture supernatants was also tested. RESULTS: The proportions of IL-17 secreting CD4 (Th17) and CD8 (Tc17) T cells were both increased in liver and peripheral blood mononuclear cells of CHB patients compared to those in HVs. CHB patients showed higher intrahepatic levels of CCL17 mRNA, CCL22 mRNA, CCR6 mRNA and CCR4 mRNA than HVs. The expression of CCR6 and CCR4 on the surface of Th17 and Tc17 cells in CHB patients was also significantly higher than that in HVs. Significant correlations existed between the CCR4/CCR6 levels and both the alanine transaminase levels and HBV DNA loads. Contact between MoDCs and pBlue-HBV-transfected Huh7 cells induced the expression of CCL17 and CCL22 dependent on the dose of HBV DNA. However, CCL20 expression was lower in CHB patients than in HVs. Transwell experiments showed that upregulation of CCL17 and CCL22 enhanced the migration of IL-17 secreting T cells. CONCLUSIONS: Contact of HBV-transfected cells with MoDCs induces CCL17 and CCL22 chemokine production, which may favour the recruitment of Th17 and Tc17 cells to liver tissue in CHB. Our results reveal the mechanism of IL-17 secreting T cells recruitment to liver tissue and thus provide new immunotherapy targets for CHB patients.

Relapse rate and associated-factor of recurrence after stopping NUCs therapy with different prolonged consolidation therapy in HBeAg positive CHB patients.

BACKGROUND: Many chronic hepatitis B (CHB) patients recur after off-therapy and have to accept prolonged consolidation therapy with NUCs. We investigated the rate of HBV relapse after stopping NUCs therapy with different time period of prolonged consolidation therapy in HBeAg positive CHB patients, and analyzed the associated-factor of recurrence. METHODS: We recruited 162 HBeAg-positive CHB patients who met the standard of stopping NUCs therapy recommended by the 2005 APASL. Patients in group A, without the prolonged consolidation therapy, were as controls. Patients in group B were divided into 3 subgroups (group B1, 7 (range 3-11) months of the prolonged consolidation therapy; group B2, 17 (range 13-20) months of the prolonged consolidation therapy; group B3, 28 (range 25-34) months of the prolonged consolidation therapy). Virologic relapse was defined as an increase in serum HBV DNA to >10(3)copies/ml after off-therapy. RESULTS: One hundred and thirty-six patients (group A, 40 patients; group B1, 54 patients; group B2, 23 patients; group B3, 19 patients) were eligible for this study. The cumulative rates of relapse in group B at 6 months and 48 months were 29.2%, 41.7% after off-therapy, respectively. The cumulative rates of relapse in group B were statistically lower than that in group A at the same time periods. The cumulative rate of relapse in group B3 or group B2 was statistically lower than that in group B1, respectively. On multivariate analysis by Cox's proportional hazard model, age at off-therapy, baseline ALT and the different time period of the prolonged consolidation therapy were associated with the relapse of HBV after off-therapy. CONCLUSIONS: Consolidation therapy with NUCs after HBeAg seroconversion should be further prolonged. Age at off-therapy, ALT at baseline and the time period of the prolonged consolidation therapy could provide information to direct anti-viral therapy.

[Interleukin-21 expression in serum of patients with acute-on-chronic liver failure and its significance].

OBJECTIVE: To investigate the level of the serum IL-21 and its correlation with serum biochemical indices of liver function test in patients with acute-on-chronic liver failure. METHODS: Sixty patients with acute-on-chronic liver failure (severe hepatitis group) and 18 normal cases (control group) were enrolled in the study. Peripheral blood lymphocytes were isolated and total RNA of lymphocytes was extracted by using Trizol. Real-time PCR was used to assay IL-21 mRNA level. The serum IL-21 expression level was detected by ELISA method. The correlation between IL-21 and ALT, AST, TBiL, ALB was analyzed using Pearson's correlation analysis, respectively. RESULTS: Serum IL-21 expression level in severe hepatitis group was higher than that of control group. Moreover, the difference between them was statistically significant (P < 0.05). Serum IL-21 level was positively correlated with serum ALT, AST, TBil, respectively (P < 0.05), but was negatively correlated with ALB, respectively (P < 0.05). CONCLUSION: Serum IL-21 expression level was increased in patients with acute-on-chronic liver failure and was associated with the severe of inflammation. We, therefore, believe that IL-21 might be involved in the pathogenesis of acute-on-chronic liver failure and might be an index of the severity of liver inflammation.

[Comparative study on the clinical characteristics of HBV/HCV co-infection patients with different HCV contaminnation mode].

OBJECTIVE: The purpose of this study was to compare the epidemiological, biochemical and virological characteristics among patients co-infected with hepatitis B virus (HBV) and hepatitis C virus (HCV) according to the mode of HCV contamination. METHODS: The study included 133 patients with chronic HBV/HCV co-infection. They were studied and subdivided into two groups (drug addicts group and Blood transfusion group) according to the mode of HCV contaminnation. The epidemiological, biochemical and virological characteristics were collected. Univariate analysis was performed with the SPSS 16.0. RESULTS: 78 patients were infected by the mode of drug addicts (IDU), whereas 55 were infected by the mode of blood transfusion( PTCH). Patients in drug addicts group had yonger age, shorter HBV and HCV infection history, and lower cirrhosis percentage than those of patients in PTCH group (P <0.05). However,serum levels of ALT (t =4.760, P =0.000), AST (t = 3.798, P = 0.000), TBil (t = 4.274, P = 0.000) of IDU patients were higher than those of PTCH patients. There was difference of sex composition between two groups (chi2 = 18.706, P = 0.000). CONCLUSIONS: The clinical characteristics of patients with HBV/HCV coinfection were significantly different among different HCV contamination mode. PTCH patients have the characteristics of older age, more cirrhosis and mild degree of liver injury; IDU patients have the characteristics of yonger age,fewer cirrhosis and severe liver injury.

[Adenoviruses mediated BCL-X1 overexpression protects mice from fulminant hepatic failure].

OBJECTIVE: To indentify the relation between hepatic cells apoptosis and the lesion of liver tissue in acute toxic lethal hepatitis. METHODS: 60 Wistar mice were randomly divided into normal control, model group and treatment group. Normal control and model group were pretreated by portal vein injection of normal saline, the treatment group was pretreated by portal vein injection of BCL-X1 adenoviruses. The mice of model group and treatment group were received an injection of D-galn and LPS to establish fulminant hepatic failure models 7 days after pretrement. To observe BCL-X1 expression, serum ALT, AST, hepatocyte apoptosis rate, and mortality rate of the three groups. RESULTS: The BCL-X1 expression was higher in treatment group than in model group; 6 hours after fulminant hepatic failure models were established,the serum ALT, AST level of treatment group was lower than model group;The hepatocyte apoptosis rate of treatment group was lower than model group. The death rate of treatment group was lower than model group. CONCLUSION: In fulminant mice hepatic failure models, the hepatocyte apoptosis rate has a positive correlation with death rate, the overexpression of BCL-X1 can decrease the hepatocyte apoptosis rate and the death rate.

[The levels of HBsAg can predict the efficacy of peglated interferon-alpha 2a combined with adefovir dipivoxil, in HBeAg-positive chronic hepatitis B patients].

OBJECTIVE: To investigate the levels of HBsAg in predicting the efficacy of peglated interferon-alpha 2a combined with adefovir dipivoxil (ADV), in HBeAg-positive chronic hepatitis B patients. METHODS: This trial enrolled 62 HBeAg-positive chronic hepatitis B patients with detectable HBsAg for at least 6 months prior to screening, serum HBV DNA levels of at least 100 000 IU/ml. The efficacy assessment: viral suppression below 100 IU/ml. The patients with HBV DNA < or = 100 IU/ml after 24 weeks therapy were divided into group A, in which monotherapy continued; While the rest were divided into group B, in which ADV was combined until week 48. In group B, at the end-of-treatment, the patients with HBV DNA < or = 100 IU/ml were divided into group B1, the rest were divided into group B2. RESULTS: There was no significant difference on the baseline characteristics of patients between B1 and B2. There was significant difference on the levels of HBsAg at 12-week and 24-week between B1 and B2; while there was no significant difference on the levels of HBeAg. CONCLUSIONS: The levels of HBsAg at 12-week and 24-week would be predictors to evaluate the efficacy of combined therapy in HBeAg-positive chronic hepatitis B patients.

[A clinical study on the efficacy of HBeAg-positive chronic hepatitis B patients treated with adefovir dipivoxil for 4 years].

OBJECTIVE: To observe the efficacy and safety on the efficacy of HBeAg-positive chronic Hepatitis B patients treated with adefovir dipivoxil for 4 years. METHODS: Ninety-five patients with HBeAg-positive chronic hepatitis B were treated with adefovir dipivoxil 10 mg per day orally. The patients were observed before and after treatment for their serum levels of ALT and HBV DNA, the new increasing rates of serum ALT normalization, HBV DNA clearances, HBeAg loss, HBeAg seroconversion and adverse drug events. RESULTS: At 4 years on study, the rates of ALT normalization, HBV DNA clearances, HBeAg loss, HBeAg seroconversion and HBV DNA rebound were 89.5%, 63.2%, 47.4%, 41.1% and 8.0%, respectively. No drug related to renal function impairment was found during the treatment, eight patients had adverse drug events but all were mild. CONCLUSION: Adefovir dipivoxil could effectively inhibit HBV replication, normalize ALT and enhance transformation from HBeAg to HBeAb for cases with naive and treated-first patients. The efficacy were increased with prolongation of the treatment period. It is safe and has a good tolerance.

[Short-term efficacy of adefovir dipivoxil as an add-on therapy in the pegylated IFNalpha-2a treatment for HBeAg positive chronic hepatitis B patients].

OBJECTIVE: To investigate whether the combination therapy of pegylated IFNalpha-2a plus adefovir dipivoxil (ADV) improve the efficacy of the treatment in CHB patients with HBeAg positive or not. METHODS: 57 CHB patients with HBeAg positive received 48-week pegylated IFNalpha-2a therapy were enrolled into this study. If serum HBV DNA levels exceeded 1000 copies/ml at week 24, the patients were assigned to group A (pegylated IFN-alpha2a plus ADV, 21 cases) or group B (pegylated IFNalpha-2a only, 14 cases); otherwise, they received the unceasing monotherapy of pegylated IFNalpha-2a (group C, 22 cases). RESULTS: At week 48, HBeAg seroconversion rates were 23.8%, 28.6% and 63.6% (A vs C,P = 0.014), but rates of aminotransferases normalization and HBV DNA suppression (< 1000 copies/ml) were not statistically significant among three groups. But during week 24 to week 48, rates of HBeAg seroconversion, aminotransferases normalization and HBV DNA suppression were also not statistically significant between group A and B. But amplitude of DNA drop in group A was much more than that in group B (2.60 +/- 1.37 vs 0.86 +/- 2.09, P = 0.005). CONCLUSION: An ADV add-on therapy in pegylated IFNalpha-2a treatment seems able to improve the inhibition of HBV DNA in chronic hepatitis B patients with HBeAg positive. It requires a large, double-blind, randomized clinical trial to further provent.