Noninvasive Models to Assess Liver Inflammation and Fibrosis in Chronic HBV Infected Patients with Normal or Mildly Elevated Alanine Transaminase Levels: Which One Is Most Suitable?

The prevalence of substantial inflammation or fibrosis in treatment-naïve patients with chronic hepatitis B (CHB) and normal alanine transaminase (ALT) levels is high. A retrospective analysis was conducted on 559 consecutive patients with hepatitis B virus infection, who underwent liver biopsy, to investigate the value of noninvasive models based on routine serum markers for evaluating liver histology in CHB patients with normal or mildly elevated ALT levels and to provide treatment guidance. After comparing 55 models, we identified the top three models that exhibited excellent performance. The APGA model, based on the area under the receiver operating characteristic curve (AUROC), demonstrated a superior ability to evaluate significant (AUROC = 0.750) and advanced fibrosis (AUROC = 0.832) and demonstrated a good performance in assessing liver inflammation (AUROCs = 0.779 and 0.874 for stages G ≥ 2 and G ≥ 3, respectively). APGA also exhibited significant correlations with liver inflammation and fibrosis stage (correlation coefficients, 0.452 and 0.405, respectively (p < 0.001)). When the patients were stratified into groups based on HBeAg status and ALT level, APGA consistently outperformed the other 54 models. The other top two models, GAPI and XIE, also outperformed models based on other chronic hepatitis diseases. APGA may be the most suitable option for detecting liver fibrosis and inflammation in Chinese patients with CHB.

Pan-Cancer Landscape of NEIL3 in Tumor Microenvironment: A Promising Predictor for Chemotherapy and Immunotherapy.

With the aim of enhancing the understanding of NEIL3 in prognosis prediction and therapy administration, we conducted a pan-cancer landscape analysis on NEIL3. The mutation characteristics, survival patterns, and immune features of NEIL3 across cancers were analyzed. Western blotting, qPCR, and immunohistochemistry were conducted to validate the bioinformatics results. The correlation between NEIL3 and chemotherapeutic drugs, as well as immunotherapies, was estimated. NEIL3 was identified as an oncogene with prognostic value in predicting clinical outcomes in multiple cancers. Combined with the neoantigen, tumor mutational burden (TMB), and microsatellite instability (MSI) results, a strong relationship between NEIL3 and the TME was observed. NEIL3 was demonstrated to be closely associated with multiple immune parameters, including infiltrating immunocytes and pro-inflammatory chemokines, which was verified by experiments. More importantly, patients with a higher expression of NEIL3 were revealed to be more sensitive to chemotherapeutic regimens and immune checkpoint inhibitors in selected cancers, implying that NEIL3 may be an indicator for therapeutic administration. Our study indicated NEIL3 has a strong association with the immune microenvironment and phenotypic changes in certain types of cancers, which facilitated the improved understanding of NEIL3 across cancers and highlighted the potential for clinical application of NEIL3 in precision medical stratification.

GTSE1 promotes SNAIL1 degradation by facilitating its nuclear export in hepatocellular carcin oma cells.

Snail family transcriptional repressor 1 (SNAIL1) is a master inducer of the epithelial­to­mesenchymal transition (EMT) process, contributing to tumor metastasis and recurrence. Our previous study reported that G2 and S phase­expressed­1 (GTSE1) served a role in regulating SNAIL1 expression in hepatocellular carcinoma (HCC). However, the underlying mechanism remains unknown. Therefore, the present study aimed to reveal the regulatory mechanism of GTSE1 on SNAIL1 expression using in vitro assays performed in HCC cell models. It was demonstrated that endogenous SNAIL1 expression was downregulated and upregulated by GTSE1 overexpression or small interfering RNA­mediated knockdown, respectively. Via cycloheximide chase experiments, it was identified that GTSE1 overexpression increased the protein turnover of SNAIL1, while knockdown of GTSE1 reduced its degradation rate. Furthermore, it was demonstrated that GTSE1 overexpression induced the cytoplasmic expression of SNAIL1 using immunofluorescence and subcellular fractionation methods. The nuclear export inhibitor leptomycin B was able to decrease the cytoplasmic retention of SNAIL1 caused by GTSE1 overexpression. In addition, TGF­ßI treatment increased both the mRNA and protein expression levels of GTSE1, and decreased the protein expression level of SNAIL1 without affecting its mRNA transcription in Huh7 cells. It was also found that TGF­ß signaling could upregulate the transcription of GTSE1 expression by transactivating the Smad binding elements in the GTSE1 promoter. Moreover, the TGF­ßI­induced decrease in SNAIL1 protein expression was GTSE1­dependent in Huh7 cells. In conclusion, the current study provides a novel mechanism via which GTSE1 affects the stability of SNAIL1 by regulating its subcellular localization in HCC cells.

Association among cytokine profiles of innate and adaptive immune responses and clinical-virological features in untreated patients with chronic hepatitis B.

BACKGROUND: Complete clearance of intracellular viruses depends on effector cells of innate and adaptive immune systems. This study aimed to identify the relationships among antiviral cytokines produced by natural killer (NK) and T cells and clinical-virological characteristics in untreated chronic hepatitis B (CHB) patients. METHODS: We measured antiviral cytokines interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and interleukin-2 (IL-2) produced by T, NK and natural killer T (NKT) cells, respectively, in a cohort with chronic hepatitis B virus (HBV) infection (CHB). We also correlated these cytokines with clinical-virological characteristics using a linear regression model. RESULTS: levels of IFN-γ+ and TNF-α+ CD4+ and CD8+ T cells were significantly higher in immune active (IA) phase than in other phases. Immune tolerant (IT) patients showed the lowest expression of IFN-γ by NK and NKT cells, and TNF-α by NK cells. IFN-γ+, TNF-α+ and IL-2+ CD4+ and CD8+ T cells frequencies were similar between IA and gray zone (GZ) phases. Principal component analysis based on cytokines confirmed that most IT patients significantly differed from inactive carriers (IC) and IA patients, while GZ patients were widely scattered. Multivariate analysis showed both T and NK cells producing IFN-γ and TNF-α, but not IL-2, had significant association with serum alanine aminotransferase (ALT). Moreover, IFN-γ+ NKT cells were associated with HBV DNA, while IFN-γ+ CD4+ and CD8+ T cells were correlated with age. CONCLUSION: HBV clinical phases are characterized by distinct cytokine signatures, which showed relationship to viral features in these untreated CHB patients.

CCL14 is a prognostic biomarker and correlates with immune infiltrates in hepatocellular carcinoma.

C-C motif chemokine ligand 14 (CCL14) is a chemokine promoting the activation of immune cells. However, the relationship between CCL14 expression, tumor immunity, and prognosis in Hepatocellular Carcinoma (HCC) remain unclear. CCL14 expression and its influence on tumor prognosis were analyzed by the ONCOMINE, Tumor Immune Estimation Resource (TIMER) and Kaplan-Meier plotter. The relationship between CCL14 expression and tumor immunity were analyzed by TIMER and Gene Expression Profiling Interactive Analysis (GEPIA). CCL14 expression was significantly lower in several human cancers, including HCC, than in corresponding normal tissues. CCL14 expression in HCC tissues correlated with prognosis. Low CCL14 expression associated with poorer overall survival, disease-specific survival, progression-free survival, and relapse-free survival in multiple cohorts of HCC patients, particularly at early disease stages (stage 1+2 or grade 2). CCL14 showed strong correlation with tumor-infiltrating B cells, CD4+ and CD8+ T cells, macrophages, neutrophils, and dendritic cells. CCL14 expression in HCC negatively correlated with expression of several immune cell markers, including exhausted T cell markers, PD-1, TIM-3 and CTLA-4, suggesting its role in regulating tumor immunity. These findings demonstrate that CCL14 is a potential prognostic biomarker that determines cancer progression and correlated with tumor immune cells infiltration in HCC.

An Immuno-Clinic score model for evaluating T cell immunity and predicting early antiviral therapy effectiveness in chronic hepatitis B.

We generated an Immuno-Clinic score (ICS) model to evaluate T cell immunity based on the clustering of antiviral cytokines and inhibitory molecules in 229 naïve chronic hepatitis B (CHB) patients. 126 patients receiving antiviral therapy were used to validate the model for predicting antiviral therapy effectiveness. Through receiver-operator characteristic curve analysis, the area under the curve, sensitivity, and specificity of the ICS model were 0.801 (95%CI 0.703-0.900), 0.727, and 0.722, respectively. The cut-off value was 0.442. Re-evaluation of T cell immunity in different phases of CHB showed that patients in the immune tolerant phase had the lowest percentage of ICS-high (15%), while patients in the inactive carrier phase had the highest percentage of ICS-high (92%). Patients in the immune active and gray zone phases had 17% and 56% ICS-high, respectively. Elevation of ICS as early as four weeks after treatment could predict the effectiveness of hepatitis B virus (HBV) DNA loss and normalization of alanine aminotransferase, while eight weeks after treatment could predict HBV surface antigen decline. Thus, this ICS model helps clinicians choose an optimal time for initiating antiviral therapy and predicting its efficacy.

Quantative HBsAg level correlates dendritic cells maturation in chronic hepatitis B patients.

BACKGROUND: In order to better understand the role of Dendritic cells (DCs) in Chronic Hepatitis B (CHB), we investigated the frequencies and maturation markers on DCs in CHB patients and its change during entecavir treatment. METHODS: Twenty-six CHB patients on anti-virus treatment for 48 weeks were included in this study. Patients' blood samples were collected on every 3 months since starting treatment. Samples on baseline and after 48 weeks treatment were examined using flow-cytometry to investigate frequencies and maturation markers of DCs. RESULTS: The frequencies of myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) were lower in CHB patients than healthy controls on baseline. pDCs frequencies and mDCs maturation markers expression were increased after entecavir (ETV) treatment. Patients with higher baseline HBsAg levels showed a poorer maturation status than those with low baseline HBsAg levels, regardless of changes in HBsAg levels after treatment. CONCLUSIONS: Entecavir treatment could restore the decreased DCs frequencies in CHB patients and improve DCs maturation levels. Baseline HBsAg level is an important factor that affecting DCs.

Serum HBV pregenomic RNA is correlated with Th1/Th2 immunity in treatment-naïve chronic hepatitis B patients.

BACKGROUND AND AIM: Hepatitis B virus (HBV) load and antigens are related to the innate and adaptive immunity of chronic hepatitis B (CHB) patients. As a new HBV biomarker, the role of pregenomic RNA (pgRNA) in host immunity is not known. This study aimed to identify the relationship between serum HBV pgRNA and host immunity in CHB patients. METHODS: Two hundred twenty-five treatment-naïve CHB patients were enrolled. Serum cytokines were measured by cytokine antibody array (Luminex multiplex platform). Th1 (T-helper cell, Th) and Th2 cells were tested by flow cytometry. Serum HBV pgRNA was detected by a reverse transcription-polymerase chain reaction. RESULTS: Serum HBV pgRNA was significantly different among patients in different disease phases and significantly associated with both HBV antigens and antibodies. Serum HBV pgRNA was positively correlated with the HBsAg level (P < .001) and the presence of HBeAg (P < .001). Patients with higher HBcAb levels showed lower serum HBV pgRNA levels (P = .003). Notably, HBsAb positivity was associated with higher levels of serum HBV pgRNA in HBeAg(-) patients (P = .049). Serum HBV pgRNA was positively associated with ALT level, Th2 cell frequency, and related cytokine sCD30 (P < .001, P < .001, and P = .003, respectively), but negatively associated with Th1-related cytokine interleukin (IL)-12P70 and cytotoxic lymphocytes (CTLs) (P = .017 and P < .001, respectively). CONCLUSION: Our study confirmed the relationship between serum HBV pgRNA and host immunity. The results demonstrated that serum HBV pgRNA is positively correlated with Th2 immunity but negatively correlated with Th1 immunity, indicating that it might have a relationship with HBV antigen conversion and CTL immunodeficiency in CHB patients.

Prognostic roles of the transcriptional expression of exportins in hepatocellular carcinoma.

Aims: A large number of studies have suggested that exportins (XPOs) play a pivotal role in human cancers. In the present study, we analyzed XPO mRNA expression in cancer tissues and explored their prognostic value in hepatocellular carcinoma (HCC).Methods: Transcriptional and survival data related to XPO expression in HCC patients were obtained through the ONCOMINE and UALCAN databases. Survival analysis plots were drawn with Gene Expression Profiling Interactive Analysis (GEPIA). Sequence alteration data for XPOs were obtained from The Cancer Genome Atlas (TCGA) database and c-BioPortal. Gene functional enrichment analyses were performed with Database for Annotation, Visualization and Integrated Discovery (DAVID).Results: Compared with normal liver tissues, significant XPO mRNA overexpression was observed in HCC cancer tissues. There was a trend of higher XPO expression in more advanced clinical stages and lower differentiated pathological grades of HCC. In HCC patients, high expression of XPO1, CSE1L, XPOT, XPO4/5/6 was related to poor overall survival (OS), and XPO1, CSE1L and XPO5/6 were correlated with poor disease-free survival (DFS). The main genetic alterations in XPOs involved mRNA up-regulation, DNA amplification and deletion. General XPO mutations were remarkably associated with worse OS and mostly affected the pathways of RNA transport and oocyte meiosis.Conclusion: High expression of XPOs was associated with a poor prognosis in HCC patients. XPOs may be exploited as good prognostic biomarkers for survival in HCC patients.

Correlations between cytokines produced by T cells and clinical-virological characteristics in untreated chronic hepatitis B patients.

BACKGROUND: Hepatitis B virus (HBV) replicates non-cytopathically in the hepatocytes and HBV-related diseases are caused by immune-mediated inflammatory events. This study aimed to identify the relationship between clinical-virological characteristics and immunity in untreated chronic hepatitis B (CHB) patients. METHODS: A total of 209 CHB patients were categorized into immune tolerant (IT, n = 17), inactive carrier (IC, n = 20), immune active (IA, n = 120), and gray zone (GZ, n = 72) phases. The quantitative hepatitis B surface antigen (qHBsAg), hepatitis B e antigen (HBeAg), anti-HBeAg (HBeAb), HBV genotype, viral mutant and frequencies of interleukin (IL)-4, IL-17, IL-10 and interferon-gamma (IFN-γ) produced by CD4+ and CD8+ T cells were tested. We also correlated these cytokines with clinical-virological characteristics using a linear regression model. RESULTS: CD8+ T cells frequency were significantly decreased in IT patients. Levels of CD4+ T cells IL-4+ or IL-10+ were strongly negatively associated with qHBsAg titers. The frequency of IFN-γ produced by CD4+ and CD8+ T cells showed significant positive association with age and alanine aminotransferase (ALT) level, while that had negative association with qHBsAg titers. Additionally, the ratios of mutations in the HBV precore (PC) stop codon and basal core promoter (BCP) and the combined mutations were 32.5, 27.2, and 11.3%, respectively. The frequency of CD4+ T cells IL-17+ was higher in patients with a PC mutation than that in patients carrying a wild-type sequence. Finally, little associations among T cell derived IL-4, IL-10, IL-17, and IFN-γ was observed in the current untreated CHB cohort. CONCLUSIONS: Several components of the immune system were correlated with HBV factors that influence an inflammatory process during CHB. Of particular relevance are the significant associations of between CD4+ T cells IL-4+ and qHBsAg level, and between CD4+ T cells IL-17+ and the presence of a mutation in PC.

Promising diagnostic and prognostic value of E2Fs in human hepatocellular carcinoma.

BACKGROUND: A growing body of evidence suggests that E2Fs, by regulating gene expression related to cell cycle progression and other cellular processes, play a pivotal role in human cancer. However, the distinct roles of each E2F in the development and treatment of hepatocellular carcinoma (HCC) remain unknown. In the present study, the mRNA expression and prognostic value of different E2Fs in HCC are analyzed. MATERIALS AND METHODS: Transcriptional and survival data related to E2F expression in patients with HCC were obtained through ONCOMINE and UALCAN databases. Survival analysis plots were drawn with Kaplan-Meier Plotter. The sequence alteration data for E2Fs were obtained from The Cancer Genome Atlas and c-BioPortal. Gene functional enrichment analyses were performed in Database for Annotation, Visualization and Integrated Discovery. RESULTS: The mRNA expression levels of E2F1-E2F8 were all significantly upregulated in HCC patients, and high expression of each E2F was obviously related to poor prognosis. Similarly, the expression of E2Fs showed prognostic prediction value in HCC patients with different cancer stages and pathological grades. Moreover, the mutation rate of E2Fs was relatively high in HCC patients, and the DNA sequence alterations primarily occurred in E2F5, E2F3, and E2F6, which were associated with worse overall survival and disease-free survival in HCC patients. Network analysis confirmed that the expression levels of cell cycle-related genes were mostly affected by E2F mutations. CONCLUSION: High expression of individual E2Fs was associated with poor prognosis in all liver cancer patients. E2Fs may be exploited as good prognostic targets for comprehensive management of HCC patients, but this notion should be further evaluated in clinical studies.

A novel T-cell epitope in the transmembrane region of the hepatitis B virus envelope protein responds upon dendritic cell expansion.

Restoring antiviral immunity is a promising immunotherapeutic approach to the treatment of chronic hepatitis B virus (HBV) infection. Dendritic cells play a crucial role in triggering antiviral immunity. In this study, we identified immunodominant epitopes prevalent in CD8+ T cell responses. We characterized the hierarchy of HBV epitopes targeted by CD8+ T cells following autologous monocyte-derived dendritic cell (moDC) expansion in HBV-infected subjects with distinct disease stages: treatment-naïve (TN group, n = 168), treatment with complete virological response (TR group, n = 72), and resolved HBV infection (RS group, n = 28). T cell responses against 32 HBV epitopes were measured upon moDC expansion. Several subdominant epitopes that triggered HBV-specific CD8+ T cell responses were identified. These epitopes' responses varied in individuals with different disease stages. Moreover, the most immunodominant and immunoprevalent epitope included the envelope residues 256-270 (Env256-270), corresponding to amino acid residues 93-107 in the small HBV surface protein (SHBs) across three patient groups. The frequency of Env256-270-specific interferon-γ-producing T cells was the highest in the RS group and the lowest in the TN group. In addition, individuals with HLA-A*02:03/02:06/02:07 were capable of responding to Env256-270. Env256-270-specific CD8+ T cells tolerated amino acid variations within the epitope detected in HBV genotypes B and C. This suggests that Env256-270 in SHBs is crucial in HBV-specific T cell immunity following autologous moDC expansion. It might be a potential target epitope for dendritic-cell-based immunotherapy for CHB patients with complete viral suppression by long-term NAs treatment.

Soluble programmed death-1 is a useful indicator for inflammatory and fibrosis severity in chronic hepatitis B.

Elevated programmed death-1 (PD-1) has been found in immune cells in viral infections and plays an important role in infection persistence. The soluble form of PD-1 (sPD-1) is involved in tumours and viral infections. The aim of this study was to investigate the role of sPD-1 in chronic hepatitis B (CHB). A total of two hundred and eighteen CHB patients and sixty healthy controls (HC) were enrolled. Demographic data and clinical parameters were collected. An ELISA assay was used to measure serum sPD-1 levels, and the relationships between sPD-1 and clinical/virological characteristics was analysed. sPD-1 levels in CHB patients were higher (median 4.409 IQR 3.435-5.306 pg/mL) than those of HC individuals (median 0.3665 IQR 0.2425-0.5010 pg/mL). Among patients at various disease stages, patients with immune activity showed the highest sPD-1 levels (median 5.138 IQR 4.329-5.406 pg/mL). sPD-1 concentration was associated with HBV markers (HBsAg, HBV DNA and HBeAg) and biochemical parameters (serum aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin [TBil] and gamma glutamyl transferase [γ-GT] levels) (all P < 0.05). sPD-1 levels were higher in CHB patients with moderate-to-severe inflammation or fibrosis than in those with mild inflammation or fibrosis, regardless of ALT levels. The association between sPD-1 and disease progression of CHB suggests that sPD-1 could serve as a new indicator in assessing liver fibrosis. These findings may further aid in determining the initiation of antiviral treatment in patients with normal ALT levels.

Co-infection with hepatitis B virus among tuberculosis patients is associated with poor outcomes during anti-tuberculosis treatment.

BACKGROUND: Tuberculosis (TB) and chronic Hepatitis B virus (HBV) infection are common in China. Fist-line anti-TB medications often produce drug-induced liver injury (DILI). This study sought to investigate whether TB patients with chronic HBV co-infection are more susceptible to liver failure and poor outcomes during anti-TB treatment. METHODS: Eighty-four TB patients developed DILI during anti-TB treatment and were enrolled, including 58 with chronic HBV co-infection (TB-HBV group) and 26 with TB mono-infection (TB group). Clinical data and demographic characteristics were reviewed. The severity of DILI and incidences of liver failure and death were compared. Risk factors of clinical outcomes were defined. RESULTS: The patterns of DILI were similar in both groups. Compared with patients in the TB group, patients in the TB-HBV group who did not receive anti-HBV therapy before anti-TB treatment were more susceptible to Grade-4 severity of DILI (36.2% vs. 7.7%, P = 0.005), liver failure (67.2% vs. 38.5%, P = 0.013) and poor outcomes (37.9% vs. 7.7%, P = 0.005). Age > 50 years (48.1% vs. 22.6%, P = 0.049), cirrhosis (50.0% vs. 15.4%, P = 0.046) and total bilirubin > 20 mg/dl (51.6% vs. 14.8%, P = 0.005) were independent risk factors for the rate of death in the TB-HBV group, and HBV DNA > 20,000 IU/ml had borderline significance (44.1% vs. 20.8%, P = 0.081). In the TB-HBV group, nucleos(t)ide analogues as rescue therapy were not able to reduce short-term death (33.3% vs. 36.8%, P = 0.659) once liver failure had occurred. CONCLUSIONS: Patients on anti-TB therapy with chronic HBV co-infection are more susceptible to developing liver failure and having poor outcomes during anti-TB treatment. Regular monitoring of liver function and HBV DNA level is mandatory. Anti-HBV treatment should be considered in those with high viral levels before anti-TB treatment.

Veritable antiviral capacity of natural killer cells in chronic HBV infection: an argument for an earlier anti-virus treatment.

BACKGROUND: There is limited information on innate immunity, especially natural killer (NK) cell function, in different chronic hepatitis B (CHB) stages. Therefore, we examined whether the clinical staging strategy accurately reflects veritable NK cell immunity. METHODS: A total of 237 eligible CHB patients and 22 healthy controls were enrolled in our study. Demographic and clinical data were collected, and the CHB phases (immune active-IA, immune tolerant phase-IT, inactive CHB-IC, and grey zone-GZ) were classified according to the latest American Association for the Study of Liver Disease guidelines. Peripheral blood mononuclear cells from patients and healthy controls were tested for NK cell frequency, phenotype and function using flow cytometry. RESULTS: A significant decrease in activating receptor NKp44 and NKp46 expression and significant increase of exhaustion molecule Tim-3 expression were observed in NK cells from CHB patients. Reduced cytokine secretion and preserved or elevated cytotoxic function were also observed. Patients in the IT group exhibited comparable cytokine secretion and cytolytic capacity as age-matched IA patients. NK cell anti-viral functions were preserved in GZ patients. Some of the NK cell function in patients who were excluded from treatment by the current treatment guidelines was less compromised than patients who qualified for treatment. CONCLUSION: Our findings provide evidence of veritable NK cell immunity during different natural history phases in treatment-naïve patients with chronic HBV Infection. Chronic HBV infection hindered NK cell function in CHB patients. However, the presumed IT and GZ statuses of CHB patients based on the clinical parameters may not accurately reflect the inner immune status of these patients and should be reconsidered. Some patients excluded from treatment by the current treatment guidelines may be able to be selected as candidates for treatment.

GTSE1 promotes cell migration and invasion by regulating EMT in hepatocellular carcinoma and is associated with poor prognosis.

G2 and S phase-expressed-1 (GTSE1) regulates G1/S cell cycle transition. It was recently reported to be overexpressed in certain human cancers, but its significance and mechanism(s) in hepatocellular carcinoma (HCC) remain unknown. Here, we showed preferential GTSE1 upregulation in human HCC tissues and cell lines that positively correlated with Ki67. GTSE1 knockdown by short hairpin RNA resulted in deficient colony-forming ability and depleted capabilities of HCC cells to migrate and invade. Conversely, exogenous GTSE1 overexpression enhanced colony formation and stimulated HCC cell migration and invasion. Furthermore, GTSE1 silencing was associated with the downregulation of N-cadherin, ß-catenin, and Snail, whereas GTSE1 overexpression caused the opposite effects. GTSE1 upregulated Snail via both transcription and protein degradation pathways. Additionally, GTSE1 modulated the sensitivity of HCC to 5-fluorouracil therapy. High GTSE1 correlates with chemo-resistance, while low GTSE1 increases drug sensitivity. Kaplan-Meier survival analysis indicated that high GTSE1 levels were significantly associated with poor overall survival. In conclusion, high expression of GTSE1 is commonly noted in HCC and is closely correlated with migration and invasion by epithelial-to-mesenchymal transition (EMT) modulation. Activated GTSE1 significantly interferes with chemotherapy efficacy and influences the probability of survival of patients with HCC. GTSE1 may thus represent a promising molecular target.

HBV core promoter mutations and AKT upregulate S-phase kinase-associated protein 2 to promote postoperative hepatocellular carcinoma progression.

Mutations in the hepatitis B virus (HBV) core promoter (CP) have been shown to be associated with hepatocellular carcinoma (HCC). The CP region overlaps HBV X gene, which activates AKT to regulate hepatocyte survival. However, the cooperation between these two cascades in HCC progression remains poorly understood. Here, we assayed virological factors and AKT expression in liver tissues from 56 HCC patients with better prognoses (BHCC, ≥5-year survival) and 58 with poor prognoses (PHCC, <5-year survival) after partial liver resection. Results showed double mutation A1762T/G1764A (TA) combined with other mutation(s) (TACO) in HBV genome and phosphorylated AKT (pAKT) were more common in PHCC than BHCC. TACO and pAKT levels correlated with proliferation and microvascularization but inversely correlated with apoptosis in HCC samples. These were more pronounced when TACO and pAKT co-expressed. Levels of p21 and p27 were decreased in TACO or pAKT overexpressing HCC due to SKP2 upregulation. Levels of E2F1 and both mRNA and protein of SKP2 were increased in TACO expressing HCC. Levels of 4EBP1/2 decreased and SKP2 mRNA level remained constant in pAKT-overexpressing HCC. Therefore, TACO and AKT are two independent predictors of postoperative survival in HCC. Their co-target, SKP2 may be a diagnostic or therapeutic marker.

Relationship between MIF-173 G/C polymorphism and susceptibility to chronic hepatitis B and HBV-induced liver cirrhosis.

Macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine, played an important role in immune-mediated diseases. The promoter region of MIF, which had functional polymorphisms, controlled MIF expression. MIF polymorphism was associated with many inflammatory diseases. But the association of MIF polymorphism with chronic hepatitis B (CHB) or HBV-induced liver cirrhosis (HC) had not yet been reported. In present study, polymorphism of MIF-173 was genotyped in 95 CHB patients, 73 HC patients and 90 healthy controls in southern China. The frequency of MIF-173 C/C genotype in patients with CHB or HC was statistically significantly higher than that in healthy controls, respectively. Moreover, difference in the distribution of MIF-173 C allele between CHB patients and healthy controls was statistically significant. However, there was no statistical relationship between MIF-173 genotype and clinical features in patients with CHB or HC. Our results suggest that MIF-173 C/C polymorphism might be associated with increased risk of CHB or HC in Chinese southern population.

Dynamic changes of lipopolysaccharide levels in different phases of acute on chronic hepatitis B liver failure.

BACKGROUND: High serum levels of lipopolysaccharide (LPS) with LPS-MD-2/TLR4 complex activated NF-kb and cytokine cause hepatic necrosis in animal models. We investigated the dynamic changes of LPS levels in patients with acute on chronic hepatitis B liver failure (ACHBLF). METHODS: We enrolled ACHBLF patients for a 12-week study. Patients' LPS levels were measured along with 10 healthy controls. Patients on supportive care and recovered without intervention(s) were analyzed. Patients' LPS levels during the disease progression phase, peak phase, and remission phase were compared with healthy controls. RESULTS: Among 30 patients enrolled, 25 who received interventions or expired during the study period were excluded from the analysis, five patients on supportive care who completed the study were analyzed. Significant abnormal distributions of LPS levels were observed in patients in different phases (0.0168±0.0101 in progression phase; 0.0960±0.0680 in peak phase; 0.0249±0.0365 in remission phase; and 0.0201±0.0146 in controls; respectively, p<0.05). The highest level of LPS was in the peak phase and significantly elevated when compared to controls (0.0201±0.0146 vs. 0.0960±0.0680, p = 0.007). There were no statistically significant differences in LPS levels between healthy controls and subjects in the progression phase or remission phase. Dynamic changes of LPS were correlated with MELD-Na in the progression phase (p = 0.01, R = 0.876) and in the peak phase (p = 0.000, R = -1.00). CONCLUSIONS: Significant abnormal distributions of LPS levels were observed in ACHBLF with the highest level in the peak phase. The dynamic changes of LPS were correlated with disease severity and suggested LPS causing secondary hepatic injury.