The expression of TLR-9, CD86, and CD95 phenotypes in circulating B cells of patients with chronic viral hepatitis B or C before and after antiviral therapy.

AIMS: This study aimed to assess the differential expression of specific B cell subtypes in patients with chronic viral hepatitis. METHODS: The frequencies of differential expression of specific B cell subtypes in patients with chronic viral hepatitis and healthy controls were assessed by flow cytometry using monoclonal antibodies specific for CD38, CD27, CD86, CD95, TLR-9, and IgD. The effect of adefovir treatment on B cell subsets in HBV patients was determined. The values of clinical parameters in the patients were also measured. RESULTS: The frequency of CD86+ B cells was not significantly different in chronic HBV patients but was higher in HCV patients compared with that in healthy controls. CD95 and IgD levels were lower in HBV and HCV patients than in healthy controls. A significant negative correlation occurred between the proportion of CD95+ B cells and HBV DNA viral load. The frequency of TLR-9 on the B cells in HBV and HCV patients was higher compared with that of healthy controls. After treatment with adefovir, the frequency of CD95 and IgD expressed on B cells was increased in HBV patients. CONCLUSIONS: Activated B cells and exhausted B cells homeostasis were commonly disturbed in HBV and HCV patients.

Tfh and plasma cells are correlated with hypergammaglobulinaemia in patients with autoimmune hepatitis.

BACKGROUND: This study aimed at examining the numbers of different subsets of circulating Tfh and B cells in patients with new onset autoimmune hepatitis (AIH). METHODS: A total of 17 patients with new onset AIH and 17 age-/gender-matched healthy controls (HC) were examined for the numbers of ICOS(+) , PD-1(+) and IL-21(+) Tfh cells, CD27(+) , CD38(+) , CD95(+) , CD86(+) and IL-10(+) B cells were quantified by flow cytometry. The concentrations of serum IL-21 and IL-10 were examined. RESULTS: In comparison with that in the HC, significantly increased numbers of circulating CD38(+) , CD86(+) or CD95(+) B cells, ICOS(+) and PD-1(+) Tfh cells and increased levels of serum IL-21, but reduced numbers of CD27(+) , IL-10(+) B cells were detected in the patients. The concentrations of serum IL-21 and IL-10 were positively correlated with the numbers of CD4(+) CXCR5(+) TFH and CD19(+) CD5(+) CD1d(+) B cells respectively. The numbers of ICOS(+) or PD-1(+) Tfh cells were correlated positively with CD86(+) or CD95(+) B cells in those patients respectively. The numbers of CD38(+) B cells, ICOS(+) or PD-1(+) Tfh cells were correlated positively with the concentrations of serum IgG or IgM in the patients respectively; the concentrations of serum IL-21 were correlated positively with serum IgG, IgA and IgM and the concentrations of serum IL-10 were correlated negatively with serum IgG and IgM in the patients. CONCLUSION: Circulating activated Tfh and plasma cells may be associated with hypergammaglobulinaemia during the pathogenic process of AIH in humans.

Downregulation and altered function of natural killer cells in hepatitis B virus patients treated with entecavir.

The aim of the present study was to investigate the natural killer (NK) cell phenotype and function in chronic hepatitis B virus (HBV) patients and to study the effects of entecavir therapy (10 mg/day, p.o.) on these responses. Peripheral blood NK cells were collected from 18 chronic HBV patients and 14 healthy controls. The effect of entecavir therapy on the phenotype and function of NK cells in chronic HBV patients was characterized by flow cytometry analysis. Concentrations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), HBV viral loads in both groups and potential associations between the frequency of peripheral NK cell subsets and clinical measures were determined. There was a significant reduction in the number of CD3(-)CD56(+) NK cells in chronic HBV patients compared with healthy controls. Furthermore, there were significant increases in the percentage of CD3(-)CD56(+)NKG2D(+) and CD3(-)CD56(+)NKP30(+) NK activating receptors in chronic HBV patients compared with healthy individuals, who exhibited downregulated expression following entecavir treatment. Spearman's correlation analysis revealed that there was a significant positive correlation between the percentage of NKG2D(+) and NKP30(+) NK cells and serum ALT levels. Characterization of NK cell degranulation indicated that the frequency of CD107a(+) NK cells in HBV patients (in response to K562 stimulation) was significantly greater than in healthy controls but decreased following entecavir treatment. Entecavir treatment of hepatitis B e antigen-positive chronic HBV-infected patients not only led to a reduction in HBV DNA loads and normalization of ALT and AST levels, but also resulted in the recovery of NK cell-mediated immunity.

High frequencies of CD158b+ NK cells are associated with persistent hepatitis C virus infections.

BACKGROUND: During the early phases of a hepatitis C virus (HCV) infection, NK cell activation appears to be critical to the induction of adaptive immune responses that have the potential of clearing the infection. This study aimed to investigate the phenotype and function of NK cells in chronic HCV (CHC) patients, particularly patients who cleared HCV infections spontaneously (SR-HCV). MATERIAL AND METHODS: Peripheral blood NK cells were compared between 36 CHC patients, 12 SR-HCV patients, and 14 healthy controls (HC). The phenotype and function of NK cells were characterized by flow cytometry. In addition, the potential associations between the frequency of NK cell subsets and ALT, AST and HCV viral loads were also analyzed. RESULTS: Our data revealed that the population of CD3-CD56+ NK cells was significantly decreased in CHC and SR-HCV patients compared to levels in HC (P = 0.031, P = 0.014). Interestingly, we found that the levels of the CD158b inhibitory receptor were higher in CHC patients compared to levels observed in HCand SR-HCV subjects (P = 0.018, P = 0.036). In addition, the percentages of the activation receptors NKp30 and NKp46 were significantly decreased in CHC and SR-HCV patients compared to their expression levels in HC (P < 0.05). Moreover, the frequencies of inducible CD107a (but not IFN-γ-secreting) NK cellsfrom both CHC and SR-HCV patients were significantly lower than frequencies observed in controls (P = 0.018, P = 0.027). CONCLUSION: Our data indicated that the higher frequency of inhibitory NK cells combined with fewer activated NK cells may be associated with HCV-related chronic inflammation involved in CHC pathogenesis.

Association between dietary intakes of B vitamins and nonalcoholic fatty liver disease in postmenopausal women: a cross-sectional study.

Background: Non-alcoholic fatty liver disease (NAFLD) is increasingly common globally, particularly among postmenopausal women. Diet plays a fundamental role in the treatment of NAFLD. However, clinical research on the dietary intakes of B vitamins, specifically in postmenopausal women, is scant. Hence, it is imperative to study the impact of B vitamin dietary intake in postmenopausal women. Methods: This study utilized National Health and Nutrition Examination Survey (NHANES) data for 668 postmenopausal women. Logistic regression analysis was conducted to investigate the association of the intakes of B vitamins with hepatic steatosis and liver fibrosis prevalence. The analysis accounted for various covariates and employed restricted cubic spline analysis to examine potential nonlinear relationships. Additionally, interactions among age, diabetes, and B-vitamin intakes, as well as the interaction between folate and vitamin B12 intake, were explored. Results: Higher intakes of folate [0.30 (0.10-0.88)], choline [0.26 (0.07-0.95)], vitamin B1, and vitamin B2 were associated with a reduced risk of hepatic steatosis in postmenopausal women. The associations of niacin (P-nonlinear = 0.0003), vitamin B1 (P-nonlinear = 0.036), and vitamin B2 (P-nonlinear<0.0001) intakes with hepatic steatosis showed a nonlinear pattern. However, no significant associations were observed between the intakes of niacin, vitamin B6 and vitamin B12 and hepatic steatosis. Furthermore, there were no significant associations between B-vitamin intakes and liver fibrosis. No interaction effects were observed. Conclusion: Dietary intakes of folate, choline, vitamin B1, and vitamin B2 may be associated with liver steatosis in postmenopausal women, these results suggest that optimizing the intake of these specific B vitamins may have a protective effect against liver steatosis in postmenopausal women, offering valuable insights into potential dietary strategies to promote their well-being.

Diagnostic performance of circulating tumor DNA as a minimally invasive biomarker for hepatocellular carcinoma: a systematic review and meta-analysis.

Purpose: This study aimed to assess the diagnostic performance of circulating tumor DNA (ctDNA) in hepatocellular carcinoma (HCC). Materials and Methods: We enrolled all relevant studies published up to 5 January 2022. Three primary subgroups were investigated: qualitative or quantitative ctDNA analyses, combined alpha-fetoprotein (AFP), and ctDNA assay. In addition to the three primary subgroups, we also evaluated the diagnostic value of methylated SEPTIN9 (mSEPT9), which has been studied extensively in the diagnosis of hepatocellular carcinoma. After a search based on four primary databases, we used a bivariate linear mixed model to analyze the pooled sensitivity (SEN), specificity (SPE), positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR). We also plotted hierarchical summary receiver operating characteristics (HSROC) and utilized lambda as well as the area under the curve (AUC) to create summary receiver operating characteristic (SROC) curves to estimate the diagnostic value of ctDNA. Results: A total of 59 qualified articles with 9,766 subjects were incorporated into our meta-analysis. The integrated SEN, SPE, and DOR in the qualitative studies were 0.50 (95% CI [0.43-0.56]), 0.90 (95% CI [0.86-0.93]), and 8.72 (95% CI [6.18-12.32]), respectively, yielding an AUC of 0.78 and lambda of 1.93 (95% CI [1.56-2.33]). For quantitative studies, the corresponding values were 0.69 (95% CI [0.63-0.74]), 0.84 (95% CI [0.77-0.89]), 11.88 (95% CI [7.78-18.12]), 0.81, and 2.32 (95% CI [1.96-2.69]), respectively. Six studies were included to evaluate the SETP9 methylation, which yielded an AUC of 0.86, a SEN of 0.80 (95% CI [0.71-0.87]), and a SPE of 0.77 (95% CI [0.68-0.85]). Likewise, ctDNA concentration yielded an AUC of 0.73, with a SEN of 0.63 (95% CI [0.56-0.70]) and a SPE of 0.86 (95% CI [0.74-0.93]). AFP combined with ctDNA assay resulted in an AUC of 0.89, with a SEN of 0.82 (95% CI [0.77-0.86]) and a SPE of 0.84 (95% CI [0.76-0.90]). Conclusion: This study shows that circulating tumor DNA, particularly mSEPT9, shows promising diagnostic potential in HCC; however, it is not enough to diagnose HCC independently, and ctDNA combined with conventional assays such as AFP can effectively improve diagnostic performance.

Lymphoepithelioma­Like Cholangiocarcinoma with Hepatitis C Virus Infection Treated by Microwave Ablation: A Literature Review and Case Report.

Background: Lymphoepithelioma-like cholangiocarcinoma (LELCC) is a rare type of intrahepatic tumor that is poorly understood. It is not associated with specific physical findings and is usually diagnosed incidentally, resulting in tumors that are often large-sized at diagnosis. At present, the main treatment approach is surgical resection. Case Presentation: Here, we report the case of a patient with LELCC treated with microwave ablation (MWA). Our patient was a Chinese man with chronic hepatitis C and a 51 mm-diameter intrahepatic tumor. Despite blood testing, gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging, and abdominal ultrasound, the tumor was not well diagnosed. However, the histopathological findings of ultrasound-guided percutaneous tumor biopsy led to a diagnosis of LELCC. The patient was treated with MWA, and no new lesions had occurred at 9 months after treatment. Conclusion: To our knowledge, this is the first patient with LELCC treated using MWA. Our experience suggests that MWA is an effective new therapeutic method for this disease.

T follicular helper cells improve the response of patients with chronic hepatitis B to interferon by promoting HBsAb production.

BACKGROUND AND AIMS: Hepatitis B surface antigen (HBsAg) seroconversion is considered the optimal outcome of the treatment of chronic hepatitis B virus (HBV) infection. In this study, we aimed to determine the cellular and molecular mechanisms by which pegylated interferon alpha (PEG-IFN-α) improves the seroconversion rate in patients with chronic hepatitis B (CHB). METHODS: Flow cytometry was performed using circulating T follicular helper (TFH) cells from 15 healthy individuals and 45 patients with CHB presenting different treatment responses [complete response group (CRG), incomplete response group (ICRG), and nonresponse group (NRG)] to the standard 48-week regimen of PEG-IFN-α monotherapy to examine the significance of circulating TFH cells in the therapeutic response of patients with CHB to PEG-IFN-α. In addition, the capacities of different TFH subsets to activate B cells and stimulate IgG production were assessed by performing coculture experiments. RESULTS: Longitudinal analysis revealed specific and significant increases in the numbers of CD40L+CD4+CXCR5+ TFH cells in the CRG compared with the NRG and ICRG. According to the results of in vitro coculture experiments, blocking CD40-CD40L signaling, but not ICOS-ICOSL signaling, specifically inhibits B-cell activation and IgG production. HBV may impair TFH cell function by enhancing inhibitory regulatory T-cell activity. Transcriptome analysis further revealed the upregulation of CD40L, but not of ICOS, in TFH cells isolated from the CRG. CONCLUSIONS: TFH cells, particularly those with CD40L expression, stimulate B-cell differentiation and improve the HBsAg seroconversion rate in patients with CHB treated with PEG-IFN-α monotherapy.

Allogeneic hematopoietic stem cell transplantation for Crohn disease complicated with myelodysplastic syndrome: A case report.

RATIONALE: Myelodysplastic syndrome (MDS) can be complicated with Crohn disease (CD). Irritable bowel disease (IBD) associated with MDS has already been reported in the past; however, hematopoietic stem cell transplantation (HSCT) is rarely performed. Herein, we report a case of CD with MDS for HSCT. PATIENT CONCERNS: A 41-year-old man was hospitalized due to abdominal pain and intermittent fever for 40 days. Two years later, he was readmitted due to abdominal pain and diarrhea with fever for 10 days. DIAGNOSIS: Symptoms, laboratory examinations, and imaging findings of the patient were indicative of CD complicated with MDS. INTERVENTIONS: An allogeneic HSCT was performed. OUTCOMES: He died of severe lung infection 125 days post-transplantation. LESSONS: The number of cases of CD combined with MDS remains insufficient, and no consensus opinions are available to date. Hence, HSCT is a very potential treatment method. Additional experiences are needed to determine its effectiveness.

Relationships between Metabolic Comorbidities and Occurrence, Severity, and Outcomes in Patients with Acute Pancreatitis: A Narrative Review.

Background. The population of patients with acute pancreatitis treated by the staff at our department of gastroenterology includes those with mild and self-limited disease ranging to those with severe and fatal disease. Early diagnosis and accurate prediction of the severity and outcome of this disease, which is commonly seen by our department, is important for a successful outcome. Metabolic comorbidities (e.g., diabetes mellitus, fatty liver, obesity, and metabolic syndrome) are relevant to the severity and progression of many diseases. The objective of this review was to examine clinical relationships between metabolic comorbidities and occurrence, severity, and outcome of acute pancreatitis.

Solitary nasopharynx metastasis from hepatocellular carcinoma after liver transplantation: A case report.

RATIONALE: Hepatocellular carcinoma (HCC) is the fifth most common cancer and third leading cause of cancer-related deaths worldwide. Nasopharyngeal metastasis of hepatocellular carcinoma is very rare. This is the first report of posttransplantation nasopharyngeal metastasis. PATIENT CONCERNS: A 45-year-old man with a history of hepatitis B related hepatocellular carcinoma (HCC) in the right segment of the liver received an orthotopic liver transplant. Two year after the transplantation, he suffered from severe headache, and head contrast enhanced CT scans did not show clues for brain or skull metastasis. Then he developed hoarseness and dysphagia. DIAGNOSIS: The nasopharyngeal cancer was confirmed to be metastatic tumor from liver histologically according to biopsy. INTERVENTIONS: This patient underwent radiotherapy (RT) of the metastatic nasopharyngeal tumor, and there was significant symptomatic relief. OUTCOMES: The patient died 3 months after nasopharyngeal metastasis was diagnosed. LESSONS: Recurrence of hepatocellular carcinoma with metastasis of nasopharyngeal carcinoma after liver transplantation is rare, but the prognosis is very poor. Close follow-up of patients should be paid attention to prevent the occurrence of such diseases.

Follicular helper T cell and memory B cell immunity in CHC patients.

Chronic hepatitis C (CHC) is associated with biological activity of T follicular helper (Tfh) cells and memory B cells (MBCs). However, the nature of Tfh cell subsets that are responsible for MBCs in CHC patients has not been evaluated. This study aimed to investigate Tfh and MBC immunity before and after direct-acting antiviral (DAA) therapy in patients with CHC. A total of 31 CHC patients and 15 healthy controls (HCs) were recruited. Individual patients were treated with sofosbuvir/ribavirin (SOF/RBV) or in combination with pegylated interferon alpha-2a (PEG-IFN-α-2a) for 12 weeks. Immunofluorescence revealed the frequency of ICOS+CD4+CXCR5+ active Tfh cells in liver tissue of CHC patients was higher than that of healthy control. Tfh and B cell co-culture experiments showed that Tfh2 cells from CHC patients have potential ability to induce B cell differentiation and IgG production. Flow cytometry showed that the frequencies of CD21-CD27+IgD- activated MBCs, ICOS+CD4+CXCR5+ activated Tfh cells, Tfh1 (IFN-γ+CD4+CXCR5+) cells, and Tfh2 (IL-4+CD4+CXCR5+) cells, but not of Tfh17 (IL-17+CD4+CXCR5+) cells, increased in CHC patients before and after DAA therapy. Collectively, ICOS+ Tfh, Tfh1, Tfh2 cells, and MBCs participated in the antiviral treatment process of SOF/RBV with or without PEG-IFN-α-2a in CHC patients, and their activity was further enhanced during the treatment. KEY MESSAGES: This study aimed to investigate Tfh cells and MBC immunity in CHC patients. CD21-CD27+IgD- activated MBCs increased in CHC patients before and after treatment. Tfh1 and Tfh2 cells increased in CHC patients before and after antiviral treatment. Intrahepatic activated Tfh cells increased in CHC patients before treatment. Tfh2 cells from CHC patients have a stronger ability to induce B cell differentiation.

Gallstones in Patients with Chronic Liver Diseases.

With prevalence of 10-20% in adults in developed countries, gallstone disease (GSD) is one of the most prevalent and costly gastrointestinal tract disorders in the world. In addition to gallstone disease, chronic liver disease (CLD) is also an important global public health problem. The reported frequency of gallstone in chronic liver disease tends to be higher. The prevalence of gallstone disease might be related to age, gender, etiology, and severity of liver disease in patients with chronic liver disease. In this review, the aim was to identify the epidemiology, mechanisms, and treatment strategies of gallstone disease in chronic liver disease patients.

Involvement of hypoxia-inducible factor-1α in the oxidative stress induced by advanced glycation end products in murine Leydig cells.

Hyperglycemia increases the formation of advanced glycation end products (AGEs), triggers oxidative impairments and influences inducible factor (HIF)-1α protein levels and transactivation function. Compromised HIF-1α in testis leads to male infertility. The aim of the study was to investigate the role of HIF-1α in oxidative stress induced by AGEs in murine Leydig TM3 cells. TM3 cells were treated with 50 µg/ml of AGEs, or HIF-1α siRNA or 500 µM of DMOG (dimethyloxalylglycine) respectively. The cells were also pretreated with HIF-1α siRNA or 500 µM of DMOG and then were treated with 50 µg/ml of AGEs. The formation of reactive oxygen species (ROS) and cell apoptosis was evaluated. The expression of caspase-3, Heme oxygenase (HO)-1, steroidogenic acute regulatory protein (StAR) and cytochrome P450 17α polypeptide 1 (CYP17A1) was examined by Western blotting. AGEs increased ROS production, induced apoptosis and activated HIF-1α and HO-1 in TM3 cells. HIF-1α attenuated the AGE-induced ROS formation and promoted apoptosis via the upregulation of caspase-3. Knockdown of HIF-1α inhibited the expression of CYP17A1 and StAR, and enhanced the inhibition of StAR and CYP17A1 by AGEs. These findings indicate that attenuated HIF-1α exacerbates the oxidative stress injury by AGEs in murine Leydig cells, and contributes to diabetic male infertility.

Seven major genomic deletions of vaccinia virus Tiantan strain are sufficient to decrease pathogenicity.

Attenuated strain TTVAC7, as a multi-gene-deleted vaccinia virus Tiantan strain (VTT), was constructed by knocking out parts of non-essential genes related to virulence, host range and immunomodulation of VTT, and by combining double marker screening with exogenous selectable marker knockout techniques. In this study, shuttle vector plasmids pTC-EGFP, pTA35-EGFP, pTA66-EGFP, pTE-EGFP, pTB-EGFP, pTI-EGFP and pTJ-EGFP were constructed, which contained seven pairs of recombinant arms linked to the early and late strong promoter pE/L, as well as to enhanced green fluorescent protein (EGFP) as an exogenous selectable marker. BHK cells were co-transfected/infected successively with the above plasmids and VTT or gene-deleted VTT, and homologous recombination and fluorescence plaque screening methods were used to knock out the gene fragments (TC: TC7L ∼ TK2L; TA35: TA35L; TA66: TA66R; TE: TE3L ∼ TE4L; TB: TB13R; TI: TI4L; TJ: TJ2R). The Cre/LoxP system was then applied to knock out the exogenous selectable marker, and ultimately the gene-deleted attenuated strain TTVAC7 was obtained. A series of in vivo and in vitro experiments demonstrated that not only the host range of TTVAC7 could be narrowed and its toxicity weakened significantly, but its high immunogenicity was maintained at the same time. These results support the potential of TTVAC7 to be developed as a safe viral vector or vaccine.

Use of lectin microarray to differentiate gastric cancer from gastric ulcer.

AIM: To investigate the feasibility of lectin microarray for differentiating gastric cancer from gastric ulcer. METHODS: Twenty cases of human gastric cancer tissue and 20 cases of human gastric ulcer tissue were collected and processed. Protein was extracted from the frozen tissues and stored. The lectins were dissolved in buffer, and the sugar-binding specificities of lectins and the layout of the lectin microarray were summarized. The median of the effective data points for each lectin was globally normalized to the sum of medians of all effective data points for each lectin in one block. Formalin-fixed paraffin-embedded gastric cancer tissues and their corresponding gastric ulcer tissues were subjected to Ag retrieval. Biotinylated lectin was used as the primary antibody and HRP-streptavidin as the secondary antibody. The glycopatterns of glycoprotein in gastric cancer and gastric ulcer specimens were determined by lectin microarray, and then validated by lectin histochemistry. Data are presented as mean ± SD for the indicated number of independent experiments. RESULTS: The glycosylation level of gastric cancer was significantly higher than that in ulcer. In gastric cancer, most of the lectin binders showed positive signals and the intensity of the signals was stronger, whereas the opposite was the case for ulcers. Significant differences in the pathological score of the two lectins were apparent between ulcer and gastric cancer tissues using the same lectin. For MPL and VVA, all types of gastric cancer detected showed stronger staining and a higher positive rate in comparison with ulcer, especially in the case of signet ring cell carcinoma and intra-mucosal carcinoma. GalNAc bound to MPL showed a significant increase. A statistically significant association between MPL and gastric cancer was observed. As with MPL, there were significant differences in VVA staining between gastric cancer and ulcer. CONCLUSION: Lectin microarray can differentiate the different glycopatterns in gastric cancer and gastric ulcer, and the lectins MPL and VVA can be used as biomarkers.

Serum interleukin-37 concentrations and HBeAg seroconversion in chronic HBV patients during telbivudine treatment.

IL-37 is a new anti-inflammatory cytokine that plays an important role in protecting against tissue injury during infections via limiting immune and inflammatory reactions. This study aimed at determining serum IL-37 concentrations and HBeAg seroconversion in chronic hepatitis B virus (HBV) patients during Telbivudine (LDT) treatment. The serum levels of IL-37 were determined using enzyme-linked immunosorbent assay (ELISA) in 40 chronic hepatitis B virus infection (CHB) patients (HBeAg positive), 30 chronic hepatitis C virus infection (CHC) patients [25 with spontaneously resolved hepatitis C virus (SR-CHC)], and 30 healthy controls (HCs). Anti-inflammatory cytokines such as IL-2 and IL-10 were measured using cytometric bead array, and the concentrations of clinical parameters such as serum hepatitis B surface antigen (HBsAg), hepatitis B nucleocapsid antigen (HBeAg), alanine transaminase (ALT), aspartate transaminase (AST), HBV DNA, and hepatitis C virus (HCV) RNA loads were measured. It was found that the serum levels of IL-37 were higher in chronic HBV patients with high virus loads, but the association was not statistically significant. The serum levels of IL-37 were decreased in HBeAg seroconverted CHB patients after 48 weeks of LDT treatment. The serum levels of IL-37 had no significant difference in CHC patients compared with SR-HCV and HCs. The levels of anti-inflammatory cytokine, IL-2 and IL-10, were lower in CHB and CHC patients than the HC, but IL-2 levels increased after LDT treatment in CHB patients. The concentrations of serum IL-37 in CHB and CHC patients with abnormal levels of serum ALT (>50 U/L) or AST (>40 U/L) were significantly higher than CHB, CHC patients with normal levels of ALT (<50 U/L) or AST (<40 U/L). These results suggest that IL-37 may play a significant role in the immune response of CHB patients with HBeAg seroconversion. The serum levels of IL-37 are associated with liver damage in CHB patients.

Potent growth-inhibitory effect of a dual cancer-specific oncolytic adenovirus expressing apoptin on prostate carcinoma.

Apoptin is a chicken anemia virus-derived, p53-independent, bcl-2-insensitive apoptotic protein with the ability to specifically induce apoptosis in various human tumor cells, but not in normal cells. To explore the use of apoptin in tumor gene therapy, we assessed a recombinant adenovirus expressing the apoptin protein (Ad-hTERTp-E1a-Apoptin) in order to determine its lethal and growth-inhibitory effects on PC-3 and RM-1 cells in vitro and its antitumor effect on solid tumors in vivo. 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT), acridine orange (AO)/ethidium bromide (EB), 4'-6-diamidino-2-phenylindole (DAPI), and Annexin V assays showed that Ad-hTERTp-E1a-Apoptin inhibited the proliferation of PC-3 and RM-1 cells in vitro by inducing apoptosis of prostate cancer cells, and that this inhibitory effect was dose and time-dependent. In the animal models, Ad-hTERTp-E1a-Apoptin significantly inhibited tumor growth and extended the lifespan of animals. Experimental results indicate that Ad-hTERTp-E1a-Apoptin has a potential application in tumor gene therapy.

Synergistic antitumor effects of endostar in combination with oxaliplatin via inhibition of HIF and CXCR4 in the colorectal cell line SW1116.

Combination treatment with endostar, a novel modified endostatin, and cytotoxic chemotherapies showed a survival benefit in Chinese clinical trials. However, the exact mechanism for this synergism remains unclear. In this study, we report for the first time that the chemokine receptor CXCR4 and the hypoxia-inducible transcription factors (HIF)-1α and HIF-2α are involved in these synergistic antitumor effects in human colorectal cancer SW1116 cells in vitro when endostar treatment is combined with the cytotoxic drug oxaliplatin. Under normoxia, we demonstrate that endostar and oxaliplatin treatments synergize to inhibit SW1116 cell proliferation, Matrigel adhesion and invasion by reduction of CXCR4 expression. Consistently, these antitumor abilities of endostar and oxaliplatin were markedly reduced by silencing of CXCR4 in SW1116 cells. Under low oxygen conditions (hypoxia, 1% oxygen), enhanced proliferation of SW1116 cells exposed to oxaliplatin was observed due to the emergence of drug resistance. Strikingly, endostar overcame oxaliplatin-resistance, most likely as a consequence of reduced HIF-2α and CXCR4 levels. CXCR4, is only dependent on HIF-2α, which promotes more aggressive phenotype and more significant for oxaliplatin resistance in SW1116 cells. Our data not only provide clues to aid understanding of the mechanism of the synergism of endostar and chemotherapy under either normoxia or hypoxia, but also suggests a new strategy of combination endostar and chemotherapy treatments which might potentiate therapeutic efficacies and/or counteract chemotherapy resistance.

Serum IL-33 levels are associated with liver damage in patients with chronic hepatitis B.

This aim of this study was to assess the potential role of IL-33 in the pathogenic process of chronic hepatitis B (CHB). The levels of serum IL-33 and soluble ST2 (sST2) in CHB patients and healthy controls (HC) were determined using enzyme-linked-immunosorbent serologic assay, and the Th1 (IFN-γ, TNF-α, IL-2) and Th2 (IL-4, IL-6, IL-10) cytokines by cytometric bead array. It was found that the levels of serum IL-33 in CHB patients were significantly higher than that of HC at the base line, but decreased after treatment with adefovir dipivoxil for 12 weeks. The levels of serum sST2, as a decoy receptor of IL-33, were significantly higher in CHB patients than the HC. There was no correlation between the levels of serum sST2 and IL-33. The concentrations of serum Th1 (IFN-γ, IL-2) and Th2 (IL-6, IL-10) cytokines in CHB patients significantly increased after treatment compared to the baseline. These results suggest that IL-33 is involved in the pathogenesis of CHB and that adefovir dipivoxil therapy can attenuate the production of IL-33 in patients with CHB.