Risk factors of low-level viremia in chronic hepatitis B patients receiving Entecavir monotherapy: a retrospective cohort study.

BACKGROUND AND AIM: Low-level viremia (LLV), a special case of poor response to antiviral therapy, has become a focus of liver disease research; however, most studies have focused on poor response to antiviral therapy, and little attention has been paid to LLV. Therefore, this study aimed to investigate the factors influencing LLV in patients with chronic hepatitis B (CHB) receiving entecavir (ETV) monotherapy. METHODS: Clinical data of CHB patients receiving ETV treatment for at least 1 year at the outpatient department of the Affiliated Hospital of Xuzhou Medical University from November 2018 to June 2020 were collected. Patients were divided into LLV (180 cases) and sustained virological response (SVR) groups (337 cases) according to the hepatitis B virus (HBV) DNA load at the end of the observation period. Demographic features and laboratory markers were also examined. Univariate and multivariate logistic regression analyses were performed to examine factors influencing LLV in patients receiving long-term ETV monotherapy. RESULTS: Significant differences were noted between the LLV and SVR groups in terms of age, sex, presence or absence of cirrhosis, HBeAg positivity rate, baseline HBV DNA load, and baseline HBsAg level before treatment. Multivariate logistic regression analysis showed that baseline HBeAg status, HBV DNA load, and HBsAg quantification were pretreatment risk factors for LLV in long-term ETV antiviral therapy. CONCLUSIONS: CHB patients with a high HBV DNA load, high HBsAg quantification, and positive HBeAg results tend to have a high risk of LLV despite long-term ETV antiviral treatment and should be dynamically monitored.

Insights into the impact of hepatitis B virus on hepatic stellate cell activation.

During chronic hepatitis B virus (HBV) infection, hepatic fibrosis is a serious pathological condition caused by virus-induced liver damage. The activation of hepatic stellate cells (HSCs) is a central event in the occurrence and progression of liver fibrosis. Although accumulating evidence has shown that HBV directly stimulates HSC activation, whether the virus infects and replicates in HSCs remains controversial. Inflammation is one of the obvious characteristics of chronic HBV infection, and it has been demonstrated that persistent inflammation has a predominant role in triggering and maintaining liver fibrosis. In particular, the regulation of HSC activation by HBV-related hepatocytes via various inflammatory modulators, including TGF-ß and CTGF, in a paracrine manner has been reported. In addition to these inflammation-related molecules, several inflammatory cells are essential for the progression of HBV-associated liver fibrosis. Monocytes, macrophages, Th17 cells, NK cells, as well as NKT cells, participate in the modulation of HBV-related liver fibrosis by interacting with HSCs. This review summarizes current findings on the effects of HBV and the relevant molecular mechanisms involved in HSC activation. Because HSC activation is essential for liver fibrosis, targeting HSCs is an attractive therapeutic strategy to prevent and reverse hepatic fibrosis induced by HBV infection. Video abstract.

Development and validation of a nomogram to predict recompensation in HBV-related cirrhosis with ascites as the single first decompensating event.

BACKGROUND AND OBJECTIVE: Little is known about the influencing factors for recompensation in HBV-related cirrhosis patients with ascites as the single first decompensating event and it's necessary to build a prediction model for these patients. METHODS: Hepatitis B virus-related cirrhosis patients with ascites hospitalized for the first decompensation were included and they were divided into the training cohort (2010.03-2020.03) and the validation cohort (2020.04-2022.04). All patients received antiviral therapy within 3 months before admission or immediately after admission. Recompensation is defined as the patient's ascites disappeared without diuretics, which were maintained for more than 1 year and no other decompensated complications, hepatocellular carcinoma, or liver transplantation occurred. The nomogram was developed from a training cohort of 279 patients and validated in another cohort of 72 patients. RESULTS: Totally, 42.7% of the decompensated patients achieved recompensation. According to the results of logistic regression and competing risk analysis, six independent factors associated with recompensation were found and these factors comprised the nomogram: age, alanine aminotransferase (ALT), albumin (ALB), serum sodium (Na), alpha-fetoprotein (AFP), and maintained virological response (MVR). Through external validation, the area under the receiver operating characteristic curve (AUC) of the nomogram was 0.848 (95% CI: 0.761, 0.936), which was significantly better than CTP, MELD, MELDNa, MELD 3.0, and ALBI grade. CONCLUSIONS: Age, ALT, ALB, Na, AFP, and MVR are closely related to the recompensation. The nomogram developed based on these items can accurately predict the possibility of recompensation in hepatitis B cirrhosis patients with ascites as the single first decompensating event.

Calcium signaling in hepatitis B virus infection and its potential as a therapeutic target.

As a ubiquitous second messenger, calcium (Ca2+) can interact with numerous cellular proteins to regulate multiple physiological processes and participate in a variety of diseases, including hepatitis B virus (HBV) infection, which is a major cause of hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. In recent years, several studies have demonstrated that depends on the distinct Ca2+ channels on the plasma membrane, endoplasmic reticulum, as well as mitochondria, HBV can elevate cytosolic Ca2+ levels. Moreover, within HBV-infected cells, the activation of intracellular Ca2+ signaling contributes to viral replication via multiple molecular mechanisms. Besides, the available evidence indicates that targeting Ca2+ signaling by suitable pharmaceuticals is a potent approach for the treatment of HBV infection. In the present review, we summarized the molecular mechanisms related to the elevation of Ca2+ signaling induced by HBV to modulate viral propagation and the recent advances in Ca2+ signaling as a potential therapeutic target for HBV infection. Video Abstract.

Asymptomatic and Human-to-Human Transmission of SARS-CoV-2 in a 2-Family Cluster, Xuzhou, China.

We report epidemiologic, laboratory, and clinical findings for 7 patients with 2019 novel coronavirus disease in a 2-family cluster. Our study confirms asymptomatic and human-to-human transmission through close contacts in familial and hospital settings. These findings might also serve as a practical reference for clinical diagnosis and medical treatment.

Tim-3 regulates inflammatory cytokine expression and Th17 cell response induced by monocytes from patients with chronic hepatitis B.

Tim-3 is expressed on monocytes/macrophages and is involved in the regulation of inflammatory responses. The aim of this study was to determine the effect of Tim-3 on inflammatory response triggered by peripheral monocytes from patients with chronic hepatitis B (CHB). Tim-3 expression on peripheral monocytes and frequency of Th17 cells in peripheral blood mononuclear cells (PBMCs) derived from CHB patients were detected. Followed by lipopolysaccharides (LPS) activation of circulating monocytes from CHB patients, expression of inflammatory cytokines including TNF-α，IL-1ß and IL-6 were examined in the presence and absence of Galectin-9 which is the ligand for Tim-3. Subsequently, after purified CD4+T cells were cocultured with LPS-activated monocytes from CHB patients in the presence of anti-Tim-3 antibody, percentage of Th17 cells and production of IL-17 were measured. Tim-3 expression was significantly upregulated and closely correlated to the frequency of Th17 cells in patients with CHB. Expression of TNF-α，IL-1ß and IL-6 increased significantly in monocytes stimulated with LPS and Galectin-9, compared to LPS stimulation alone. LPS-activated monocytes from CHB patients could drive differentiation of memory CD4+T cells to Th17 cells. However, under the blockade of Tim-3 signalling by anti-Tim-3 antibody, percentage of Th17 cells and production of IL-17 decreased significantly. Our results demonstrate that upregulated expression of Tim-3 on circulating monocytes accelerates inflammatory response by promoting production of inflammatory cytokines and Th17 responses in CHB.

Liver Injury and Its Impact on Prognosis in Patients with HBV-Related Hepatocellular Carcinoma Undergoing Transarterial Chemoembolization Combined with Tyrosine Kinase Inhibitors Plus Immune Checkpoint Inhibitors.

Purpose: Recently, the triple therapy of transarterial chemoembolization (TACE) combined with tyrosine kinase inhibitors (TKIs) plus immune checkpoint inhibitors (ICIs) has become a new treatment option for advanced or unresectable hepatocellular carcinoma (HCC) patients. We aimed to explore the liver injury and its effect on overall survival (OS) in patients treated with this combination therapy. Patients and Methods: Patients with HBV-related HCC who were treated with TACE-TKIs-ICIs from January 2020 to December 2021 were enrolled. Liver injury and survival time were the main endpoints of the study. Logistic regression analysis was used to analyze the factors associated with liver injury. Cox regression and Kaplan-Meier analysis were used to determine prognostic factors for OS. Results: As of March 2022, 52 of the 119 enrolled patients developed any grade hepatotoxicity: 15 cases with grade 1, 19 cases with grade 2, 16 cases with grade 3 and 2 cases with grade 4. Our analysis indicated that lack of antiviral prevention was a risk factor for liver injury (OR = 0.149; 95% CI: 0.050-0.442; P = 0.001). The findings suggested that liver injury events (HR = 1.912; 95% CI: 1.031-3.546; P = 0.040) was associated with patient death. The median OS of patients without liver injury, grade 1-2 and grade 3-4 liver injury were undefined, 13.7 months and 11.1 months, respectively (log-rank P = 0.034). Conclusion: Liver injury adverse events are common in HBV-related HCC patients treated with TACE-TKIs-ICIs. Patients who developed liver injury had a poor prognosis. For HBV-related HCC patients, effective prophylactic antiviral therapy and regular liver function testing are required before and during this triple therapy.

The Impact of Proton Pump Inhibitors on the Efficacy of Immune Checkpoint Inhibitor Combinations in Patients with HBV-Associated Advanced Hepatocellular Carcinoma.

Purpose: There is limited research on whether Proton Pump Inhibitors (PPIs) will affect the efficacy of immune checkpoint inhibitors (ICIs) in treating hepatocellular carcinoma (HCC).This study aimed to determine whether PPIs affect the survival outcomes of patients with HBV-associated advanced HCC receiving combination therapy based on ICIs. Methods: We retrospectively analyzed patients with hepatitis B virus (HBV)-associated advanced HCC who underwent ICIs combination therapy from January 1, 2020, to December 30, 2022. Patients were stratified into PPI and non-PPI groups based on whether they received PPI treatment within 30 days before or after ICIs therapy. Patients' survival and the risk of PPI-associated mortality was assessed. Adverse events were also evaluated. Results: A total of 183 patients with HBV-associated HCC treated with ICI combination therapy were included. The median survival time (12.5 months vs 13.7 months, P = 0.285) and incidence of adverse events (P = 0.729) did not significantly differ between the PPI and non-PPI groups. Even after propensity score matching, the difference in median overall survival (OS) between the two groups was not significant (10.7 months vs 11.4 months; P = 0.596) and the patient's OS is not significantly related to the dosage of PPI application (P > 0.05).However, according to our subgroup analysis, among HCC patients with a serum HBV DNA concentration ≥ 200 IU/mL, the use of PPIs significantly increased the risk of mortality in patients receiving ICI combination therapy (P = 0.024). Conclusion: PPIs do not notably influence the survival prognosis of patients receiving ICI combination therapy for HBV-associated advanced HCC. However, among patients with high levels of HBV DNA, PPIs increase the risk of mortality. Therefore, antiviral therapy should be intensified in the patients with HBVDNA > 200 IU/mL. Additionally, PPIs do not impact the incidence of adverse reactions in these patients.

Drug repurposing screen identifies vidofludimus calcium and pyrazofurin as novel chemical entities for the development of hepatitis E interventions.

Hepatitis E virus (HEV) infection can cause severe complications and high mortality, particularly in pregnant women, organ transplant recipients, individuals with pre-existing liver disease and immunosuppressed patients. However, there are still unmet needs for treating chronic HEV infections. Herein, we screened a best-in-class drug repurposing library consisting of 262 drugs/compounds. Upon screening, we identified vidofludimus calcium and pyrazofurin as novel anti-HEV entities. Vidofludimus calcium is the next-generation dihydroorotate dehydrogenase (DHODH) inhibitor in the phase 3 pipeline to treat autoimmune diseases or SARS-CoV-2 infection. Pyrazofurin selectively targets uridine monophosphate synthetase (UMPS). Their anti-HEV effects were further investigated in a range of cell culture models and human liver organoids models with wild type HEV strains and ribavirin treatment failure-associated HEV strains. Encouragingly, both drugs exhibited a sizeable therapeutic window against HEV. For instance, the IC50 value of vidofludimus calcium is 4.6-7.6-fold lower than the current therapeutic doses in patients. Mechanistically, their anti-HEV mode of action depends on the blockage of pyrimidine synthesis. Notably, two drugs robustly inhibited ribavirin treatment failure-associated HEV mutants (Y1320H, G1634R). Their combination with IFN-α resulted in synergistic antiviral activity. In conclusion, we identified vidofludimus calcium and pyrazofurin as potent candidates for the treatment of HEV infections. Based on their antiviral potency, and also the favorable safety profile identified in clinical studies, our study supports the initiation of clinical studies to repurpose these drugs for treating chronic hepatitis E.

HBV reactivation and its effect on survival in HBV-related hepatocarcinoma patients undergoing transarterial chemoembolization combined with tyrosine kinase inhibitors plus immune checkpoint inhibitors.

Objective: This study aimed to access hepatitis B virus (HBV) reactivation and its effect on survival in HBV-related hepatocarcinoma (HCC) patients who underwent transarterial chemoembolization (TACE) combined with tyrosine kinase inhibitors (TKIs) plus immune checkpoint inhibitors (ICIs). Methods: In this single-center retrospective study, we enrolled 119 HBV-related unresectable advanced HCC patients receiving TACE combined with TKIs plus ICIs. Risk factors for HBV reactivation were analyzed by logistic regression. Kaplan-Meier method was applied to draw the survival curve, and log-rank test was used to compare survival between patients with and without HBV reactivation. Results: A total of 12 patients (10.1%) encountered HBV reactivation in our study, of which only 4 patients received antiviral prophylaxis. The incidence of HBV reactivation was 1.8% (1/57) in patients with detectable baseline HBV DNA and 4.2% (4/95) in patients with antiviral prophylaxis respectively. Lack of prophylactic antiviral treatment (OR=0.047, 95%CI 0.008-0.273, P=0.001) and undetectable HBV DNA (OR=0.073, 95%CI 0.007-0.727, P=0.026) were independent risk factors for HBV reactivation. The median survival time (MST) for all patients was 22.4 months. No survival difference was observed in patients with or without HBV reactivation. (MST: undefined vs 22.4 months, log-rank test: P=0.614). Conclusion: HBV reactivation could occur in HBV-related HCC patients who treated with TACE in combination with TKIs plus ICIs. Before and during the combination treatment, it is necessary to routinely monitor HBV DNA and to take effective prophylactic antiviral therapy.

Regulation of Pattern-Recognition Receptor Signaling by HBX During Hepatitis B Virus Infection.

As a small DNA virus, hepatitis B virus (HBV) plays a pivotal role in the development of various liver diseases, including hepatitis, cirrhosis, and liver cancer. Among the molecules encoded by this virus, the HBV X protein (HBX) is a viral transactivator that plays a vital role in HBV replication and virus-associated diseases. Accumulating evidence so far indicates that pattern recognition receptors (PRRs) are at the front-line of the host defense responses to restrict the virus by inducing the expression of interferons and various inflammatory factors. However, depending on HBX, the virus can control PRR signaling by modulating the expression and activity of essential molecules involved in the toll-like receptor (TLR), retinoic acid inducible gene I (RIG-I)-like receptor (RLR), and NOD-like receptor (NLR) signaling pathways, to not only facilitate HBV replication, but also promote the development of viral diseases. In this review, we provide an overview of the mechanisms that are linked to the regulation of PRR signaling mediated by HBX to inhibit innate immunity, regulation of viral propagation, virus-induced inflammation, and hepatocarcinogenesis. Given the importance of PRRs in the control of HBV replication, we propose that a comprehensive understanding of the modulation of cellular factors involved in PRR signaling induced by the viral protein may open new avenues for the treatment of HBV infection.

The emerging role of DEAD/H-box helicases in hepatitis B virus infection.

DEAD/H-box helicases are an essential protein family with a conserved motif containing unique amino acid sequences (Asp-Glu-Ala-Asp/His). Current evidence indicates that DEAD/H-box helicases regulate RNA metabolism and innate immune responses. In recent years, DEAD/H-box helicases have been reported to participate in the development of a variety of diseases, including hepatitis B virus (HBV) infection, which is a significant risk factor for hepatic fibrosis, cirrhosis, and liver cancer. Furthermore, emerging evidence suggests that different DEAD/H-box helicases play vital roles in the regulation of viral replication, based on the interaction of DEAD/H-box helicases with HBV and the modulation of innate signaling pathways mediated by DEAD/H-box helicases. Besides these, HBV can alter the expression and activity of DEAD/H-box helicases to facilitate its biosynthesis. More importantly, current investigation suggests that targeting DEAD/H-box helicases with appropriate compounds is an attractive treatment strategy for the virus infection. In this review, we delineate recent advances in molecular mechanisms relevant to the interplay of DEAD/H-box helicase and HBV and the potential of targeting DEAD/H-box helicase to eliminate HBV infection.

Mitochondrial STAT3 exacerbates LPS-induced sepsis by driving CPT1a-mediated fatty acid oxidation.

Rationale: We found that a subset of signal transducer and activator of transcription 3 (STAT3) translocated into mitochondria in phagocytes, including macrophages isolated from individuals with sepsis. However, the role of mitochondrial STAT3 in macrophages remains unclear. Method: To investigate the function of mitochondrial STAT3 in vivo, we generated inducible mitochondrial STAT3 knock-in mice. A cytokine array analysis, a CBA analysis, flow cytometry, immunofluorescence staining and quantification and metabolic analyses in vivo were subsequently performed in an LPS-induced sepsis model. Single-cell RNA sequencing, a microarray analysis, metabolic assays, mass spectrometry and ChIP assays were utilized to gain insight into the mechanisms of mitochondrial STAT3 in metabolic reprogramming in LPS-induced sepsis. Results: We found that mitochondrial STAT3 induced NF-κB nuclear localization and exacerbated LPS-induced sepsis in parallel with a metabolic switch from mainly using glucose to an increased reliance on fatty acid oxidation (FAO). Moreover, mitochondrial STAT3 abrogated carnitine palmitoyl transferase 1a (CPT1a) ubiquitination and degradation in LPS-treated macrophages. Meanwhile, an interaction between CPT1a and ubiquitin-specific peptidase 50 (USP50) was observed. In contrast, knocking down USP50 decreased CPT1a expression and FAO mediated by mitochondrial STAT3. The ChIP assays revealed that NF-κB bound the USP50 promoter. Curcumin alleviated LPS-mediated sepsis by suppressing the activities of mitochondrial STAT3 and NF-κB. Conclusion: Our findings reveal that mitochondrial STAT3 could trigger FAO by inducing CPT1a stabilization mediated by USP50 in macrophages, at least partially.

Sirtuins as Potential Therapeutic Targets for Hepatitis B Virus Infection.

Sirtuins (SIRTs) are well-known histone deacetylases that are capable of modulating various cellular processes in numerous diseases, including the infection of hepatitis B virus (HBV), which is one of the primary pathogenic drivers of liver cirrhosis and hepatocellular carcinoma. Mounting evidence reveals that HBV can alter the expression levels of all SIRT proteins. In turn, all SIRTs regulate HBV replication via a cascade of molecular mechanisms. Furthermore, several studies suggest that targeting SIRTs using suitable drugs is a potential treatment strategy for HBV infection. Here, we discuss the molecular mechanisms associated with SIRT-mediated upregulation of viral propagation and the recent advances in SIRT-targeted therapy as potential therapeutic modalities against HBV infection.

Clinical findings in a group of COVID-19 patients: a single-center retrospective study.

BACKGROUND: The coronavirus disease 2019 (COVID-19) is spreading rapidly across countries and has infected tens of millions of people all over the world. So far, the pandemic is ongoing globally, and the situation is still worsening. METHODS: In this retrospective, single-center cohort analysis, we included 25 adult inpatients with laboratory confirmed COVID-19 disease from the affiliated hospital of Xuzhou Medical University (Xuzhou, China). Epidemiological characterizations, clinical findings, and medical treatments were all reported. In addition, laboratory markers were investigated in terms of course of treatment. RESULTS: Epidemiological features and clinical findings were present for all 25 patients. Laboratory markers were identified due to temporal changes. After medical treatment, all patients were discharged home and recovering from the infection. CONCLUSIONS: This study provides a comprehensive overview of patients with COVID-19 disease in a single hospital. Some of the laboratory markers were statistically different during the course of the disease, which might serve as indicators in identifying patients with COVID-19 disease at an early stage of the infection.

Interleukin-34 mediated by hepatitis B virus X protein via CCAAT/enhancer-binding protein α contributes to the proliferation and migration of hepatoma cells.

OBJECTIVES: Interleukin-34 (IL-34) is associated with hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC). However, the role and associated mechanisms of IL-34 in HBV-related HCC remain unclear. In this study, the expression, biological function and associated mechanisms of IL-34 in HBV-related HCC cells were investigated. METHODS: IL-34 expression induced by HBV and HBV X (HBX) gene was measured in hepatoma cells. The role of CCAAT/enhancer-binding protein α (CEBP/α) in HBX-induced IL-34 expression was examined. The signal pathways involved in the expression of CEBP/α and IL-34 induced by HBX were assessed. The role of IL-34 in the proliferation and migration of HCC cells, and related mechanisms were explored. RESULTS: Dependent on HBX, HBV increased IL-34 expression in hepatoma cells, and HBX upregulated and interacted with CEBP/α to enhance the activity of IL-34 promoters. CEBP/α mediated by HBX was associated with the activation of PI3-K and NF-κB pathways to promote IL-34 expression. Via CSF1-R and CD138, IL-34 promoted the proliferation and migration of hepatoma cells, and contributed to the activation of ERK and STAT3 pathways and the upregulation of Bcl-xl and c-Myc mediated by HBX. CONCLUSION: We demonstrate that IL-34 contributes to HBX-mediated functional abnormality of HCC cells and provides a novel insight into the molecular mechanism of carcinogenesis mediated by HBX.

[The effect of telbivudine on peripheral blood CD4+CD25+ regulatory T cells and its significance in patients with chronic hepatitis B].

OBJECTIVE: To investigate the effect of telbivudine on peripheral blood regulatory T cells and its significance in patients with chronic hepatitis B (CHB). METHODS: Thirty-six HbeAg positive chronic hepatitis B patients were recruited and received telbivudine treatment for 9 months. Before and during the 3, 6, 9 months of treatment, flow cytometry was used to detect the proportion of peripheral blood Tregs; real-time PCR was used to detect the levels of HBV DNA in the serum. Markers of hepatitis B virus infection were detected by ELISA assay and levels of alanine aminotransferase in the serum were measured. RESULTS: The proportion of peripheral blood Tregs in patients with CHB was significantly higher than that in healthy controls and decreased over 6 or 9 months of telbivudine treatment to a level comparable to that of the healthy controls. After 3 months of telbivudine treatment, the rate of undetectable HBV DNA in patients whose proportion of peripheral blood Tregs was decreased was higher than those whose Tregs had been reduced, but the difference was not statistically significant (P more than 0.05). Three, 6 or 9 months of telbivudine treatment resulted in HbeAg negativity in 4 (11.1%) patients, 7 (19.4%) patients or 9 (25.0%) patients respectively. In 7 (19.4%) patients who had seroconversion from HBeAg to anti-HBeAg, after 3 or 6 months of telbivudine treatment, their proportion of peripheral blood Tregs had decreased to a level comparable to that of the healthy controls. CONCLUSION: Telbivudine treatment reduces HBV replication and the proportion of peripheral blood Tregs. In addition, patients who have their proportion of peripheral blood Tregs decreased quickly at the early phase of telbivudine treatment are prone to have HBeAg to anti-HBeAg seroconversion.

[Effect of KLF6 and its splice variant KLF6V on proliferation and differentiation of human hepatocellular carcinoma HepG2 cells].

OBJECTIVE: To investigate the roles of Kruppel-like factor 6 (KLF6) and its splice variant KLF6V on suppressing growth and inducing differentiation of human hepatocellular carcinoma hepG2 cells. METHOD: KLF6V cDNA was amplificated by RT-PCR from human hepatocellular carcinoma (HCC) tissue and then sequenced. The recombinant vectors expressing KLF6 variant (KLF6V) were constructed using molecular clone technology based on established plasmid pcDNA3.1A(-)/wtKLF6. KLF6V or KLF6-transfected HepG2 cells were established after being screened with G418. Growth activity of HepG2/KLF6 or HepG2/KLF6V cells was detected by in vitro MTT assay. Expression of p21WAF1 or cyclin D1 protein was detected by Western blot, and expressions of AFP or ALB protein were measured by radioimmunoassay. RESULTS: A novel alternatively spliced transcript of the human KLF6 gene was found and its sequencing revealed that the variant form of KLF6 lacked 126nt and its encoded protein products had a deletion of 42 aa near the COOH-terminal amino acid in comparison with full-length KLF6. Although KLF6 alternative splicing was present in both normal and cancerous tissues, expression of the KLF6 splice variants seemed to be up-regulated in HCCs tissues. The isoform of KLF6 proteins antagonized the ability of wild-type KLF6 to up-regulate p21 expression or down-regulate cyclin D1 expression and suppress HepG2 cell proliferation. KLF6 gene increased albumin production and decreased alpha fetoprotein production of the cells. CONCLUSION: The isoform of KLF6 protein, present in HCC tissue, antagonizes the ability of wild-type KLF6 to suppress cell proliferation and induce cellular differentiation.

Role of interleukin-21 and interleukin-21 receptor polymorphisms in the treatment of HBeAg-positive chronic hepatitis B patients with peginterferon.

The aim of this study was to evaluate the relationship between interleukin-21 (IL-21) and interleukin-21 receptor (IL-21R) polymorphisms and the response to peginterferon alfa (PEG-IFN α) therapy in HBeAg-positive chronic hepatitis B (CHB) patients.A total of 143 HBeAg-positive CHB patients treated for 48 weeks with PEG-IFN α and followed up for 24 weeks post-treatment were retrospectively evaluated. Genotypes analysis was performed for IL-21 polymorphisms rs907715, rs2221903, and IL-21R polymorphisms rs3093301 and rs2285452. Serum IL-21 levels were measured by enzyme-linked immunosorbent assay.The end of virological response (EVR) rate was 46.9% (67/143) at the end of treatment, the sustained virological response (SVR) rate was 43.4% (62/143) and the complete response (CR) rate was 32.1% (46/143) at 24 weeks post-treatment. Patients who carried IL-21 rs 2221903 genotype AA had a rather higher rate of EVR (response rate: 52.4%, odds ratio [OR] 0.42, 95% confidence interval [CI]: 0.19-0.91, P = .021), SVR (response rate: 47.6%, OR 0.43, 95% CI: 0.19-0.95, P = .028), and CR (response rate: 38.1%, OR 0.31, 95% CI: 0.12-0.79, P = .014) when compared to those had AG genotype. Meanwhile, IL-21rs 2221903 genotype AA was also independently associated with markedly reduced HBsAg levels (>1og10 IU/mL) after 24 weeks treatment and low HBsAg levels (<100 IU/mL) at the end of treatment. IL-21 rs907715 AG/GG genotype was independently associated with SVR (OR: 2.92, 95% CI: 0.98-8.6, P = .039; OR: 3.23, 95% CI: 1.0-10.4, P = .039). Patients with IL-21 rs907715 AG/GG genotype had higher serum IL-21 levels than those with rs907715 AA genotype (P = .021).IL-21 rs2221903 and rs907715 polymorphisms were significantly associated with the treatment response to PEG-IFN α among Chinese HBeAg-positive CHB patients.