Search

Background HIF-1α is relevant to inflammation and fibrosis in hepatitis B virus (HBV)-related liver diseases. Thus, we designed a predictive model for decompensated cirrhosis. Methods Peripheral plasma HIF-1α levels were measured in 52 subjects, including 20 patients with HBV-related-compensated-cirrhosis (HBV-CC), 20 patients with HBV-related-decompensated-cirrhosis (HBV-DC) that underwent transjugular intrahepatic portosystemic shunt (TIPS), and 12 healthy controls (HC). Portal plasma HIF-1α levels were detected in HBV-DC patients. The correlation between clinical data and HIF-1α levels was assessed, logistic regression and nomogram were used to develop prediction model. Results Plasma HIF-1α levels were significantly higher in HBV-DC patients than that in HBV-CC patients and healthy controls (DC: 656.34±417.96, CC: 294.23±138.03, HC: 194.63±54.14, pg/ml; P = 0.0004). Plasma HIF-1α levels were positively correlated with total bile acid, total bilirubin, APRI, FIB-4, and MELD scores, and negatively correlated with albumin and platelets. Multivariate logistic regression manifested that total bilirubin (OR = 19.439; 95% CI: 1.486–254.320, P = 0.024), spleen thickness (OR = 75.144; 95% CI: 4.157–1358.440, P = 0.003) and HIF-1α concentrations above 341.78 pg/ml (OR = 23.580; 95% CI: 1.842–301.781, P = 0.015) were markedly associated with HBV-DC and thus included in the nomogram. The terrific cut-off value for the probability of HBV-DC was > 45%, and area under the curve was 0.954 (P < 0.001), with 95% sensitivity and specificity. Conclusions HIF-1α is related to biochemical liver parameters, cirrhosis grade, and progression to HBV-DC. Our model has preferable predictive value for HBV-DC.

The relationship between the serum transforming growth factor (TGF)-β level and HBsAg loss has not been clearly elaborated in patients with chronic hepatitis B (CHB).Two cohorts of patients with CHB were studied. Cohort A: A total of 207 hepatitis B e antigen (HBeAg)-negative CHB patients who finished ≥1 year nucleos(t)ide analogue monotherapy and sequentially received PEGylated interferon treatment for less than 96 weeks were included. Cohort B: Forty HBeAg-positive patients who initially received entecavir therapy for at least 96 weeks were included. Their viral markers and serum TGF-β levels were measured at different time points during therapy.The levels of serum TGF-β and HBsAg (0-24 W) were significantly lower in the patients who had HBsAg0.05 IU/mL at 48 weeks than in patients who did not in cohort A. We got the same results when we further divided the patients into subgroups according to the initial HBsAg cut-off values (1000 IU/mL, 100 IU/mL, 50 IU/mL) in cohort A. However, HBeAg seroconversion did not lead to the downregulation of TGF-β levels. The levels of serum TGF-β were significantly correlated with HBsAg quantitation in cohort A (12-24 W) but not in cohort B (0-48 W). The levels of TGF-β at week 12 could be used as an early index to predict a functional cure (AUC=0.818) as well as the levels of HBsAg itself (AUC=0.882) in HBeAg-negative chronic hepatitis B patients treated with PEGylated interferon.The levels of serum TGF-β were significantly associated with HBsAg loss but not with HBeAg seroconversion and could be used as an early index to predict a functional cure in CHB patients treated with PEGylated interferon.

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.

Background: Patients with HBV-related acute-on-chronic liver failure (HBV-ACLF) are characterized by immune paralysis and susceptibility to infections. Macrophages are reported to polarize to proinflammatory or anti-inflammatory functional states in different morbid states. However, the molecular mechanisms of macrophage polarization in the disease progression of HBV-ACLF have not yet been elucidated. Aims: To investigate the dynamic macrophage polarization changes in different stages of HBV-related liver disease and explore the potential mechanism of macrophage polarization during HBV-ACLF. Methods: The functional status of peripheral blood mononuclear cells derived from macrophages from patients with mild chronic hepatitis B, HBV-related compensated liver cirrhosis, HBV-related decompensated liver cirrhosis, HBV-ACLF and healthy controls was determined. A transcriptome sequencing analysis was performed to investigate the pathways involved in macrophage polarization in HBV-ACLF. The chloride intracellular channel-3 (CLIC3) gene expression was suppressed in the human monocytic THP-1-derived macrophages to study its role in macrophage polarization. Results: Macrophages exhibited different functional statuses in different stages of HBV-related liver disease. Macrophages were mainly exhibiting an anti-inflammatory phenotype and functional characteristics in patients with HBV-ACLF, which was predictive of a poor clinical outcome. The expression of CLIC3, which is involved in immunological diseases, was reduced in HBV-ACLF patients, indicating a poor prognosis. In addition, CLIC3 could regulate proinflammatory macrophage polarization through the NF-κB and Akt pathways. Conclusion: Macrophage polarization changes dynamically in HBV-related liver diseases. CLIC3 suppression-mediated anti-inflammatory macrophage polarization plays an important role in the progression of HBV-ACLF, and CLIC3 expression is a potential indicator of the prognosis of HBV-ACLF patients. Funding Statement: Supported by the Guangzhou City Science and Technology Project (No. 201607010064), the Natural Fund of Guangdong Province (No. 2016A030313237), the National Science and Technology Major Project (2018ZX10302204) and The National Natural Science Foundation of China (81672701). Declaration of Interests: The authors declare no conflicts of interest. Ethics Approval Statement: This study was approved by the Third Affiliated Hospital of Sun Yat-Sen University Ethics Committee ([2018]02-432-01). If patients were unable to provide consent, informed consent was obtained from the next of kin.

Accumulating evidences indicate the elevated expression of αB-Crystallin (Cryab) is implicated in tumorigenesis. However, the expression and biologic role of Cryab in osteosarcoma (OS) are still unknown. In this study, we showed that Cryab expression was elevated in OS tissues and cell lines, and down-regulation of Cryab in MG-63 and U-2OS cells led to a decline in the cells' aggressiveness, and reduced secretion of matrix metalloproteinase-9 (MMP-9) in vitro, and lower metastasis potential in vivo. Further study indicated that the Cryab expression was positively associated with the activity of ERK1/2 which is responsible for the cells' aggressiveness and MMP-9 secretion. Clinically, our data confirmed that the high level of Cryab was associated with shorten survival and tumor recurrence for the postoperative OS patients. Together, our results indicate that high level of Cryab is a new adverse outcomes marker for OS patients and may be used as a new therapeutic target.

The aim of this study was to analyze the changes in serum protein levels in the progression of hepatitis B using isobaric tags for relative and absolute quantitation (iTRAQ) analysis, in addition to comparing the serum protein levels of patients with chronic hepatitis B (CHB), patients with hepatitis B virus-induced acute-on-chronic liver failure (HBV-induced ACLF) and normal individuals. Protein analysis was performed on 15 serum samples using iTRAQ. The study population included healthy controls (n=5), patients with CHB (n=5) and patients with HBV-induced ACLF (n=5). Western blotting was used to verify the results in an additional nine serum samples from healthy controls, patients with CHB and patients with HBV-induced ACLF (n=3, respectively). Using iTRAQ analysis, 16 different serum proteins with ≥1.5-fold differences in expression levels were identified in the patients with CHB and ACLF compared with the healthy controls. Five of those proteins, C-reactive protein precursor, hemoglobin β chain variant Hb S-Wake, apolipoprotein J precursor, platelet factor 4 precursor and vitronectin, which demonstrated the greatest differences in their expression levels and the most significant correlation with liver diseases, were subsequently verified using western blotting. The western blotting results were consistent with the results from the iTRAQ. Two of the five proteins are not classified by biological process, and the biological functions of all the proteins in HBV-induced ACLF remain unclear. This preliminary study demonstrated that a correlation between the expression of various serum proteins and the different pathogenetic conditions induced by HBV may exist. The analysis of a larger number of samples is required to identify potential protein biomarkers that may be involved in the pathogenesis and progression of hepatitis B.

Objective: The natural history of acute-on-chronic hepatitis B liver failure (ACHBLF) is complex and highly variable. However, the global clinical characteristics of this entity remain ill-defined. We aimed to investigate the dynamic patterns of the natural progression as well as their impact on the outcomes of ACHBLF. Methods: The clinical features and disease states were retrospectively investigated in 54 patients with ACHBLF at the China South Hepatology Center. The clinical and laboratory profiles including hepatic encephalopathy (HE), hepatorenal syndrome (HRS), and spontaneous bacterial peritonitis (SBP) were evaluated. The disease state estimated by the model for end-stage liver disease (MELD) score and the dynamic patterns during the clinical course of ACHBLF were extrapolated. Results: Twenty-two patients died during the 3-month follow-up period (40.74%). The patients were predominantly male (88.89%). Baseline characteristics showed that there were significant differences in only hepatitis B virus (HBV) DNA levels and platelet count between the deceased and surviving patients (P=0.014 and P=0.012, respectively). Other baseline characteristics were similar in both groups. The dynamic state of the MELD score gradually increased from an initial hepatic flare until week 4 of ACHBLF progression. There were notable changes of the dynamic state of the MELD score at two time points (week 2 and week 4) during ACHBLF progression. The MELD scores were significantly greater in the death group (24.80±2.99) than in the survival group (19.49±1.96, P

Depression in patients with chronic hepatitis B (CHB) can affect the quality of life, disease diagnosis and case fatality rate. The aim of this study was to explore depression in patients with CHB and cirrhosis, and the effect of the severity of liver cirrhosis on the depressive emotional state. The depressive emotional state was investigated using the Hamilton Depression Scale (HAMD) and Hamilton Anxiety Scale (HAMA) in 114 patients with CHB and cirrhosis, comprising 42 cases classified as Child-Pugh grade (CPG)-A, 38 cases classified as CPG-B and 34 cases classified as CPG-C at a single hepatology center. Patients with mood disorders accounted for 33.33% of the 114 cases with CHB and liver cirrhosis and comprised 10 cases of CPG-A, 12 cases of CPG-B and 16 cases of CPG-C classification. The results shows that HAMA and HAMD scores of patients in the CPG-C group were significantly higher than those in the CPG-A group (P0.05). The incidence rate of mood disorders in the CPG-C group was significantly higher than that in the CPG-B group (P=0.0336), and the incidence rate of mood disorders was higher in the CPG-B group compared with the CPG-A group, but the difference was not statistically significant (P=0.4370). The incidence rate of mood disorders in patients in the CPG-A group was significantly lower than that in the CPG-C group (P=0.0078). The study shows that a considerable proportion of patients with liver cirrhosis have mood disorders, and the depression rates of CHB-infected patients with liver cirrhosis are closely associated with the severity of the cirrhosis.

The ability of lymphocytes and macrophage-derived cytokines and chemokines to modulate the activation of stromal cells during immune responses is well-documented, but few studies have investigated whether liver myofibroblasts shape the phenotype and function of monocytes in liver disease. In the present study, Kupffer cells were demonstrated to be activated in the inflamed livers of patients with cirrhosis and be in close contact with liver myofibroblasts. The Kupffer cells from cirrhotic livers expressed significantly elevated levels of PD-L1 (also termed B7-H1), TLR4, CD80, CD32 and CD64 relative to those from normal livers. Consistent with this finding, the expression of these surface molecules was significantly upregulated in monocytes following exposure to liver myofibroblasts originating from inflamed livers. Accordingly, the liver myofibroblast-exposed monocytes exhibited a significant increase in dextran endocytosis. These data reveal that bidirectional interactions between liver myofibroblasts and Kupffer cells may function as an 'amplification loop' to enhance inflammation further in the liver. Liver myofibroblasts are central in the pathogenesis of liver diseases and should be considered as targets for the rational design of effective immune-based anti-inflammation therapies. Furthermore, it was also demonstrated that skin fibroblasts were as effective as liver myofibroblasts at inducing monocyte activation, suggesting that fibroblasts, which are numerous in the body, may represent an underrated cell population that is actively involved in immunomodulatory functions.

The objective of this study is to explore whether olfactory ensheathing cells (OECs) can promote the survival of newborn rat spiral ganglion cells (SGCs) and the underlying possible mechanisms. Co-culture of OECs from adult rats with SGCs from newborn rat cochlea was established and single culture of SGCs acted as control. OECs were obtained and purified based on their special rate of attachment which was different from the other harvested cell types during culture. OECs and SGCs were immunocytochemically characterized and confirmed by expression of low-affinity nerve growth factor receptor p75 or positive label of neuron-specific betaIII-tubulin. To investigate the mechanisms of the role of OECs in survival of SGCs, brain derived neurotrophic factor (BDNF) and anti-BDNF antibody (IgY) were added into the media of the co-cultures respectively, and the surviving SGCs were examined after treatment. Single layer of OECs (92% pure) was seen seven days after plating. Surviving SGCs, which extended their primary neurites, were found on the surface of the layer in the co-cultures. When OECs and SGCs were co-cultured, the number of surviving SGCs was significantly greater than that in the single culture (P0.01). Nine days after culture, there was even no change in the number of surviving SGCs in the co-culture while the number reduced to almost zero in the single culture. In comparison with co-culture without treatment, addition of BDNF (500 pg/mL) into the media had no obvious promoting effect on the survival of SGCs. The number of surviving SGCs reduced significantly when anti-BDNF antibody was applied into the media of co-cultures (P0.01). These results suggest that OECs can promote the survival of SGCs when they are co-cultured in vitro. BDNF released from OECs, as one of the survival factors, plays an important role in the survival of SGCs.

To study whether apoptosis plays a role in controlling the number of olfactory receptor neurons, so as to reveal the specialty and mystery of neurogenesis.Using terminal deoxynucleotidyl transferase-mediated dUTP-fluorescein nick end labeling (TUNEL) and transmission electron microscopy to detect apoptosis in olfactory mucosa of normal adult rats and damaged olfactory mucosa of 16, 32, 48 hours and 3, 7, 30 days after bulbectomy.In normal olfactory epithelium, a subpopulation of immature neurons, as well as mature neurons, showed internucleosomal DNA-fragmentation. The number of TUNEL-labeled neurons increased dramatically 32 hours after removal of olfactory bulb. Then it declined quickly and remained at low level. Ultrastructural data of olfactory mucosa showed that the feature of apoptotic neurons was chromatin condensation and cell shrinkage. Besides, some dying cells were characterized by the formation of numerous autophagic vacuoles, and few had some of the features of necrosis but without obvious mitochondrial swelling.Apoptosis might play a role in turnover of the olfactory epithelium and regeneration in adult rats. There might be other two types of neural death through different mechanism.

Purpose: The purpose of the current study was to establish an objective, simple, and sensitive prognostic scoring system for estimating the severity of acute-on-chronic liver failure in hepatitis B (ACLFB). Methods: A novel prognostic scoring system was calculated from six clinical indices including total bilirubin (TB), prothrombin activity (PTA), creatinine (Cr), hepatic encephalopathy (HE), infections, and the depth of ascites from 726 patients with ACLFB. Indices were scored from 1 to 4 according to their severity. Groups of the same patients were scored with three-indices (TB, PTA and Cr), four-indices (TB, PTA, Cr and HE), five-indices (TB, PTA, Cr, HE and the depth of ascites) or six-indices (TB, PTA, Cr, HE, the depth of ascites, and infections). The differences in the sensitivity and specificity of four scoring systems were analyzed. Results: The demarcation points of the three-, four-, five- and six-indices scoring systems were 4.62, 6.12, 7.88 and 9.57, respectively. The analysis of the areas under the receiver operating characteristic (ROC) curve indicated that the four-, five- and six-indices scoring systems were more exact, and objective than the three-indices prognostic scoring system. In the six-indices scoring system, the survival rates of patients with scores from 2 to 6 was 98.31% (233/237), and the mortality rate of patients with scores of 16 and above was 100.00% (140/140), while the mortality rates were 8.33% (3/36) and 96.43% (27/28) for those with scores from 7 to 15, respectively. Conclusion: A six-indices scoring system is an objective, pertinent, and sensitive system, and may be useful for the prognostic evaluation of ACLFB.