Comprehensive investigating of MMR gene in hepatocellular carcinoma with chronic hepatitis B virus infection in Han Chinese population.

Hepatocellular carcinoma associated with chronic hepatitis B virus infection seriously affects human health. Present studies suggest that genetic susceptibility plays an important role in the mechanism of cancer development. Therefore, this study focused on single nucleotide polymorphisms (SNPs) of MMR genes associated with HBV-HCC. Five groups of participants were included in this study, which were healthy control group (HC), spontaneous clearance (SC), chronic hepatitis B group (CHB), HBV-related liver cirrhosis group (LC) and HBV-related hepatocellular carcinoma group (HBV-HCC). A total of 3128 participants met the inclusion and exclusion criteria for this study. 20 polymorphic loci on MSH2, MSH3 and MSH6 were selected for genotyping. There were four case-control studies, which were HC vs. HCC, SC vs. HCC, CHB vs. HCC and LC vs. HCC. We used Hardy-Weinberg equilibrium test, unconditional logistic regression, haplotype analysis, and gene-gene interaction for genetic analysis. Ultimately, after excluding confounding factors such as age, gender, smoking and drinking, 12 polymorphisms were found to be associated with genetic susceptibility to HCC. Haplotype analysis showed the risk haplotype GTTT (rs1805355_G, rs3776968_T, rs1428030_C, rs181747_C) was more frequent in the HCC group compared with the HC group. The GMDR analysis showed that the best interaction model was the three-factor model of MSH2-rs1981928, MSH3-rs26779 and MSH6-rs2348244 in SC vs. HCC group (P=0.001). In addition, we found multiplicative or additive interactions between genes in our selected SNPs. These findings provide new ideas to further explore the etiology and pathogenesis of HCC. We have attempted to explain the molecular mechanisms by which certain SNPs (MSH2-rs4952887, MSH3-rs26779, MSH3-rs181747 and MSH3-rs32950) affect genetic susceptibility to HCC from the perspectives of eQTL, TFBS, cell cycle and so on. We also explained the results of haplotypes and gene-gene interactions. These findings provide new ideas to further explore the etiology and pathogenesis of HCC.

Comprehensive investigating of mismatch repair genes (MMR) polymorphisms in participants with chronic hepatitis B virus infection.

Background and aim: In this study, we focused on the relationship between single nucleotide polymorphisms in MMR genes and the occurrence and development of HBV infection. Materials and methods: A total of 3,128 participants were divided into five groups: negative control group (NeC), spontaneous clearance group (SC), chronic hepatitis B group (CHB), liver cirrhosis group (LC) and hepatocellular carcinoma group (HCC), CHB, liver cirrhosis and hepatocellular carcinoma constitute HLD. We conducted three case-control studies: NeC (840 cases) vs. HLD (1792 cases), SC (486 cases) vs. HLD (1792 cases) and CHB + LC (1,371 cases) vs. HCC (421 cases). 11 polymorphic loci in MLH1, MLH3, MSH5, PMS1 and PMS2 were involved in genotyping by Sequenom MassArray. The SNPStats performed Hardy-Weinberg equilibrium test. Linkage disequilibrium patterns were visualized using Haploview4.2. The GMDR (v0.9) was conducted to generalized multifactor dimension reduction analysis. The correlation, multiplicative interaction and additive interaction analyses were calculated by Logistic Regression through SPSS21.0. Matrix and programmed excel were also involved in the calculation of additive interaction. Results: In NeC vs. HLD group, MSH5-rs1150793(G) was a risk base to HBV susceptibility (nominal p = 0.002, OR = 1.346). We found multiplicative interaction between MLH1-rs1540354 (AA + AT) and PMS1-rs1233255 (AA) (nominal p = 0.024, OR = 1.240). There was additive interaction between PMS1-rs1233255 (AA) and PMS1-rs256554(CA + CC). In SC vs. HLD group, MLH1-rs1540354 (TT) was a risk genotype (nominal p < 0.05, OR>1). Through haplotype analysis, we found the linkage disequilibrium of three loci in MLH1. The results of GMDR showed the optimal five-locus model about the spontaneous clearance of HBV. In CHB + LC vs. HCC group, PMS2-rs12112229(A) was related to the cancerization of liver. Conclusion: We found rs1150793(G), rs1540354(T) and rs12112229(A) were significantly related to HBV susceptibility, spontaneous clearance of HBV and cancerization after infection, respectively.

Genetic variants in IL33 and IL1RL1 genes confer susceptibility to HBV-related liver cirrhosis in Chinese Han population.

INTRODUCTION: Previous studies indicate that the IL-33/ST2 pathway is involved in hepatitis B virus (HBV) -related liver diseases. This study aimed to determine the relationship between genetic variants in IL-33/ST2 pathway with susceptibility to liver cirrhosis. MATERIALS AND METHODS: A total of 2632 Han Chinese samples met the inclusion and exclusion criteria, including 840 negative controls (NeC), 691 chronic hepatitis B (CHB), 680 HBV-related liver cirrhosis (LC) and 421 HBV-related hepatocellular carcinoma (HCC) (without LC) patients. Four polymorphisms (IL33-rs4742170, rs1048274, rs10975519 and IL1RL1-rs1041973) were selected and genotyping was performed. All statistical analyses were performed by SPSS21.0, mainly using the Hardy-Weinberg equilibrium test, Pearson chi-square, unconditional Logistic regression and haplotype analysis. RESULTS: After adjusting for age, sex, smoking and drinking, significant associations were observed between IL33-rs4742170, rs1048274 and rs10975519 polymorphisms with LC risk. NeC with IL33-rs4742170 CC genotype was 1.80 times more likely to develop LC compared with TT genotype, while NeC with rs10975519(TC + CC) genotype was 1.32 times more likely to develop LC when compared with the TT genotype. CHB cases with rs4742170(CC + TC) genotype had 1.30 times higher susceptibility to develop LC compared with the TT genotype. The IL33-rs1048274G allele occurred more frequently in the LC group compared with the HCC group in codominant model (AG/AA: P = 0.001, OR = 1.66, 95%CI = 1.22-2.25; GG/AA: P = 0.018, OR = 1.54, 95%CI = 1.08-2.20). The IL33 haplotype CG conformed by rs10975519C and rs1048274G was more frequent in the LC group than in the NeC group and CHB group. Moreover, the IL33 haplotype CCG conformed by rs4742170C, rs10975519C and rs1048274G was found to be more frequent in the LC group than the HCC group. However, there was no association between IL1RL1-rs1041973 and LC risk. CONCLUSION: Our findings demonstrate the association between genetic variants in IL33 with susceptibility to liver cirrhosis. IL33-rs4742170C, rs1048274G and rs10975519C could serve as biomarkers of LC.

Targeted inhibition of myeloid-derived suppressor cells in the tumor microenvironment by low-dose doxorubicin to improve immune efficacy in murine neuroblastoma.

BACKGROUND: High agglomeration of myeloid-derived suppressor cells (MDSCs) in neuroblastoma (NB) impeded therapeutic effects. This study aimed to investigate the role and mechanism of targeted inhibition of MDSCs by low-dose doxorubicin (DOX) to enhance immune efficacy in NB. METHODS: Bagg albino (BALB/c) mice were used as tumor-bearing mouse models by injecting Neuro-2a cells, and MDSCs were eliminated by DOX or dopamine (DA) administration. Tumor-bearing mice were randomly divided into 2.5 mg/kg DOX, 5.0 mg/kg DOX, 50.0 mg/kg DA, and control groups (n = 20). The optimal drug and its concentration for MDSC inhibition were selected according to tumor inhibition. NB antigen-specific cytotoxic T cells (CTLs) were prepared. Tumor-bearing mice were randomly divided into DOX, CTL, anti-ganglioside (GD2), DOX+CTL, DOX+anti-GD2, and control groups. Following low-dose DOX administration, immunotherapy was applied. The levels of human leukocyte antigen (HLA)-I, CD8, interleukin (IL)-2 and interferon (IFN)-γ in peripheral blood, CTLs, T-helper 1 (Thl)/Th2 cytokines, perforin, granzyme and tumor growth were compared among the groups. The Wilcoxon two-sample test and repeated-measures analysis of variance were used to analyze results. RESULTS: The slowest tumor growth (F = 6.095, P = 0.018) and strongest MDSC inhibition (F = 14.632, P = 0.001) were observed in 2.5 mg/kg DOX group. Proliferation of T cells was increased (F = 448.721, P < 0.001) and then decreased (F = 2.047, P = 0.186). After low-dose DOX administration, HLA-I (F = 222.489), CD8 (F = 271.686), Thl/Th2 cytokines, CD4+ and CD8+ lymphocytes, granzyme (F = 2376.475) and perforin (F = 488.531) in tumor, IL-2 (F = 62.951) and IFN-γ (F = 240.709) in peripheral blood of each immunotherapy group were all higher compared with the control group (all of P values < 0.05). The most significant increases in the aforementioned indexes and the most notable tumor growth inhibition were observed in DOX+anti-GD2 and DOX+CTL groups. CONCLUSIONS: Low-dose DOX can be used as a potent immunomodulatory agent that selectively impairs MDSC-induced immunosuppression, thereby fostering immune efficacy in NB.

Repeated exposure to the irrigative wastewater in Shijiazhuang induced precancerous lesion associated with cytochrome P450.

In the present study, the carcinogenic effects of the wastewater sample collected from the Dongming Canal in Shijiazhuang city were first detected by the rat medium-term liver bioassay. The experiment contained five groups: a negative control group, a DEN-alone group, 25% wastewater, 50% wastewater, and 100% wastewater. The body weight of rats decreased significantly as the dose increased. Morphologically, we also found that the damage of the hepatic lobule was more serious and the proliferation of liver cells was more obvious as the dose increased. In addition, we observed a significantly increased liver organ coefficient in rat. With the increase in dose, the damage of the hepatocytes was more serious, which was manifested in significantly elevated of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gammaglutamyl transfer peptide enzyme (γ-GT). And, the irrigative wastewater significantly increased GST-p in the liver of rats at both the transcriptional and translational levels dose-dependently, eventually causing precancerous lesions in the liver tissues. CYP1A1 and CYP1B1 expressions in the rat liver cells at the level of transcription and translation were also significantly increased dose-dependently. Our data clearly demonstrated that the irrigative wastewater had a carcinogenetic effect that was associated with CYP1A1 and CYP1B1. The risk of carcinogenic potential to human health might be due to joint action and accumulative effects over a long period of exposure. We can also concluded that the medium-term liver bioassay could be used as an effective method for evaluating the carcinogenicity of complex water mixtures such as irrigative wastewater.

Comparison of air pollutant-related hospitalization burden from AECOPD in Shijiazhuang, China, between heating and non-heating season.

Few researches have been investigated on the effects of ambient air pollutants from coal combustion on acute exacerbation of chronic obstructive pulmonary disease (AECOPD) hospitalizations. The whole time series was split into heating season and non-heating season. We used a quasi-Poisson generalized linear regression model combined with distributed lag non-linear models (DLNMs) to estimate the relative cumulative risk and calculate the air pollutant hospitalization burden of AECOPD for lag 0-7 days in heating season and non-heating season. There were higher PM2.5, PM10, NO2, SO2, and CO concentrations in heating seasons than non-heating season in Shijiazhuang; however, O3 was higher in non-heating season than heating season. The AECOPD-associated relative cumulative risks for PM2.5, PM10, NO2, and SO2 for lag 0-7 days were significantly positively associated with hospitalization in heating and non-heating season; we found that the cumulative relative risk of NO2 was the greatest in every 1 unit of air pollutants during the heating season and the cumulative relative risk of SO2 was the greatest during the non-heating season. The results showed that 17.8%, 12.9%, 1.7%, 16.7%, and 10.5% of AECOPD hospitalizations could be attributable to PM2.5, PM10, SO2, NO2, and CO exposure in heating season, respectively. However, the results showed that 19.5%, 22.4%, 15%, 8.3%, and 10.4% of AECOPD hospitalizations could be attributable to PM2.5, PM10, SO2, NO2, and O3 exposure in non-heating season, respectively. The attributable burden of AECOPD hospitalization in heating season and non-heating season are different. PM2.5, PM10, NO2, and CO are the main factors of heating season, while PM10, PM2.5, SO2, and O3 are the main factors of non-heating season. In conclusions, the centralized heating can change the influence of attributable risk. When government departments formulate interventions to reduce the risk of acute hospitalization of chronic obstructive pulmonary disease (COPD), the influence of heating on disease burden should be considered.

The hospitalization attributable burden of acute exacerbations of chronic obstructive pulmonary disease due to ambient air pollution in Shijiazhuang, China.

Few studies have investigated the acute exacerbations of chronic obstructive pulmonary disease (AECOPD)-associated attributable burden under exposure to high levels of air pollution among Asians. Data on hospitalization for AECOPD, air pollution and meteorological factors from 1 January 2013 to 31 December 2016 were collected in Shijiazhuang, China. We used a Poisson generalized linear regression model combined with a distributed lag nonlinear model (DLNM) to evaluate the relative cumulative risk for a lag of 0-7 days and examined the potential effect modifications by age and sex via stratification analyses, controlling for long-term trends, seasonal patterns, meteorological factors, and other possible confounders. Then, we computed hospitalization percentages attributable to air pollutants. The AECOPD-associated relative cumulative risks for PM2.5, PM10, NO2, SO2, and CO for a lag of 0-7 days were significantly positively correlated with hospitalization. The associations were stronger in females and retired patients. The NO2 Cum RR of AECOPD admission was the greatest. A 10µg/m3 increase in daily NO2 concentration was associated with 6.7% and 5.7% increases in COPD hospitalizations in the retired and female groups, respectively. The results showed that 13%, 9.4%, 1.7%, 9.7%, and 8.8% of AECOPD hospitalizations were attributable to exposure to PM2.5, PM10, SO2, NO2, and CO, respectively. If the air pollutant concentration was reduced to the 24-h average grade II levels of NAAQS of China, the AECOPD attributable percentage for PM2.5 and PM10 would decrease by 80%. The air pollutants PM2.5, PM10, SO2, NO2, and CO were significantly relevant to AECOPD-associated hospitalization. The associations differed by individual characteristics. The retired and female populations were highly vulnerable.

The effect and burden modification of heating on adult asthma hospitalizations in Shijiazhuang: a time-series analysis.

BACKGROUND: Previous studies have found associations between asthma morbidity and air pollution especially in young population, (PLoS One 12:e0180522, 2017; Can J Public Health 103:4-8, 2012; Environ Health Perspect 118:449-57, 2010; Am J Respir Crit Care Med 182:307-16, 2010; J Allergy Clin Immunol 104:717-22, 2008; J Allergy Clin Immunol 104:717-22, 1999; Environ Res 111:1137-47, 2011) but most of them were conducted in areas with relatively low air pollutant level. Moreover, very few studies have investigated the effect and burden modification of heating season during which the ambient air pollution level is significantly different from that during non-heating season in north China. OBJECTIVES: This study aimed to evaluate the effect and burden modification of heating on short-term associations between adult asthma hospitalizations and ambient air pollution in the north China city of Shijiazhuang. METHODS: Generalized additive models combined with penalized distributed lag nonlinear models were used to model associations between daily asthma hospitalizations and ambient air pollutants from 1 January 2013 to 16 December 2016 in Shijiazhuang city, adjusting for long-term and seasonality trend, day of week, statutory holiday, daily mean air pressure and temperature. Attributable risks were calculated to evaluate the burden of asthma hospitalizations due to air pollutants exposure. The effect of pollutants on hospitalization and the attributable measures were estimated in heating and non-heating season separately and the comparisons between the two seasons were conducted. RESULTS: All pollutants demonstrated positive and significant impacts on asthma hospitalizations both in heating season and non-heating season, except for O3 in heating season where a negative association was observed. However, the differences of the pollutant-specific effects between the two seasons were not significant. SO2 and NO2 exposure were associated with the heaviest burden among all pollutants in heating season; meanwhile, PM10 and PM2.5 were associated with the heaviest burden in heating season. CONCLUSIONS: In conclusion, we found evidence of the effect of ambient air pollutants on asthma hospitalizations in Shijiazhuang. The central heating period could modify the effects in terms of attributable risks. The disease burden modification of heating should be taken into consideration when planning intervention measures to reduce the risk of asthma hospitalization.

Role of GSPT1 and GSPT2 polymorphisms in different outcomes upon Hepatitis B virus infection and prognosis to lamivudine therapy.

Purpose.ERF3, having been found expressing differently in liver tissues in our previous work, including eRF3a and eRF3b, which are structural homologs named GSPT1 and GSPT2 Recent studies have indicated that eRF3b involved in the development and proliferation of HepG2 cell, and eRF3a may be associated with tumor susceptibility. Based on this, we tested the effects of GSPT1 and GSPT2 single-nucleotide polymorphisms for all major Hepatitis B virus (HBV) outcomes and lamivudine (LAM) treatment in Han Chinese. Method. A total of 1649 samples were enrolled, and peripheral blood samples were collected in the present study. The single-nucleotide polymorphisms in the GSPT1 and GSPT2 region were genotyped using MALDI-TOF MS. Results. Our study demonstrated there was no obvious relevance of either GSPT1-rs33635 or GSPT2-rs974285 polymorphisms with HBV susceptibility, spontaneous recovery, and development of HBV-related diseases. However, we showed for the first time to our knowledge that GSPT1-rs33635C was a predictor for LAM therapy (viral response: odds ratio (OR) = 2.436, P=0.022; biochemical response: OR = 3.328, P=1.73 × 10-4). Conclusions. These findings might provide potential implications for therapeutic guidance.

Oxidative Stress-Related Gene Polymorphisms Are Associated With Hepatitis B Virus-Induced Liver Disease in the Northern Chinese Han Population.

Oxidative stress is closely related to the occurrence and development of various diseases such as cancer, diabetes, and cardiovascular and infectious diseases. We identified six critical genetic variants related to oxidative stress, and evaluated their main effects and their interaction effects on hepatitis B virus (HBV)-induced liver diseases. We enrolled 3,128 Han Chinese subjects into five groups: healthy controls, chronic hepatitis B (CHB), liver cirrhosis (LC), hepatocellular carcinoma (HCC), and natural clearance. We then determined the genotypes in each group for CYBA-rs4673, NCF4-rs1883112, NOX4-rs1836882, rs3017887, SOD2-rs4880, and GCLM-rs41303970, and evaluated the association between these variants and HBV-induced liver diseases. Gene-gene interactions were evaluated using generalized multifactor dimensionality reduction, logistic regression, and four-by-two tables. Significant associations were observed between healthy controls and the CIB group (CHB+LC+HCC). The CYBA-rs4673AG genotype was associated with a 1.356 rate of susceptibility of HBV-induced liver disease compared to the wild type GG genotype. The NCF4-rs1883112G allele occurred more frequently in healthy controls than in the CIB group in all three models (dominant, codominant, and recessive). Nox4-rs1836882 TC showed a protective association, being more frequent in healthy controls compared to the wild type TT genotype. GCLM-rs41303970A was associated with HBV-induced liver disease. The overall best model by multifactor dimensionality reduction was a five factor interaction model that had the highest cross validation consistency (10/10) and test accuracy (0.5669), P = 0.001. Oxidative stress-related gene polymorphisms are likely to be associated with HBV-induced liver disease, suggesting that information on these variations is useful for risk assessment of HBV-induced liver disease.

Fine Particulate Matter-Induced Exacerbation of Allergic Asthma via Activation of T-cell Immunoglobulin and Mucin Domain 1.

BACKGROUND: Fine particulate matter (PM2.5) exacerbates airway inflammation and hyperreactivity in patients with asthma, but the mechanism remains unclear. The aim of this study was to observe the effects of prolonged exposure to high concentrations of PM2.5on the pathology and airway hyperresponsiveness (AHR) of BALB/c mice undergoing sensitization and challenge with ovalbumin (OVA) and to observe the effects of apoptosis and T-cell immunoglobulin and mucin domain 1 (TIM-1) in this process. METHODS: Forty female BALB/c mice were divided into four groups: control group, OVA group, OVA/PM group, and PM group (n = 10 in each group). Mice in the control group were exposed to filtered clean air. Mice in the OVA group were sensitized and challenged with OVA. Mice in the OVA/PM group were sensitized and challenged as in the OVA group and then exposed to PM2.5for 4 h per day and 5 days per week for a total of 8 weeks using a nose-only "PM2.5online enrichment system" in The Second Hospital of Hebei Medical University. Mice in the PM group were exposed to the PM2.5 online enrichment system only. AHR was detected. Bronchoalveolar lavage fluid (BALF) was collected for cell classification. The levels of interleukin-4 (IL-4), IL-5, and IL-33 in BALF were measured using enzyme-linked immunosorbent assay. Changes in histological structures were examined by light microscopy, and changes in ultramicrostructures were detected by electron microscopy. Apoptosis was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay in the lung tissues. Western blotting and immunohistochemistry were utilized to analyze the expression of Bcl-2, Bax, and TIM-1 in the lungs. RESULTS: The results showed that AHR in the OVA/PM group was significantly more severe than that in the OVA and PM groups (P < 0.05). AHR in the PM group was also considerably more severe than that in the control group (P < 0.05). The BALF of OVA/PM group (28.00 ± 6.08 vs. 12.33 ± 4.51, t = 4.631, P = 0.002) and PM group (29.00 ± 3.00 vs. 12.33 ± 4.51, t = 4.927, P = 0.001) had more lymphocytes than the BALF of the control group. The number of neutrophils in the BALF of the OVA/PM group (6.67 ± 1.53 vs. 3.33 ± 1.53, t = 2.886, P = 0.020) and PM group (6.67 ± 1.53 vs. 3.33 ± 1.53, t = 2.886, P = 0.020) was much higher than those in the BALF of OVA group (P < 0.05). TUNEL assays showed that the number of apoptotic cells in the OVA/PM group was significantly higher than that in the OVA group (Tunel immunohistochemical scores [IHS%], 1.20 ± 0.18 vs. 0.51 ± 0.03, t = 8.094, P < 0.001) and PM group (Tunel IHS%, 1.20 ± 0.18 vs. 0.51 ± 0.09, t = 8.094, P < 0.001), and that the number of apoptotic cells in the PM group was significantly higher than that in the control group (Tunel IHS%, 0.51 ± 0.09 vs. 0.26 ± 0.03, t = 2.894, P = 0.020). The concentrations of IL-4 (77.44 ± 11.19 vs. 48.02 ± 10.02 pg/ml, t = 4.595, P = 0.002) and IL-5 (15.65 ± 1.19 vs. 12.35 ± 0.95 pg/ml, t = 3.806, P = 0.005) and the Bax/Bcl-2 ratio (1.51 ± 0.18 vs. 0.48 ± 0.10, t = 9.654, P < 0.001) and TIM-1/ß-actin ratio (0.78 ± 0.11 vs. 0.40 ± 0.06, t = 6.818, P < 0.001) in the OVA/PM group were increased compared to those in the OVA group. The concentrations of IL-4 (77.44 ± 11.19 vs. 41.47 ± 3.40 pg/ml, t = 5.617, P = 0.001) and IL-5 (15.65 ± 1.19 vs. 10.99 ± 1.40 pg/ml, t = 5.374, P = 0.001) and the Bax/Bcl-2 ratio (1.51 ± 0.18 vs. 0.97 ± 0.16, t = 5.000, P = 0.001) and TIM-1/ß-actin ratio (0.78 ± 0.11 vs. 0.31 ± 0.06, t = 8.545, P < 0.001) in the OVA/PM group were increased compared to those in the PM group. The concentration of IL-4 (41.47 ± 3.40 vs. 25.46 ± 2.98 pg/ml, t = 2.501, P = 0.037) and the Bax/Bcl-2 ratio (0.97 ± 0.16 vs. 0.18 ± 0.03, t = 7.439, P < 0.001) and TIM-1/ß-actin ratio (0.31 ± 0.06 vs. 0.02 ± 0.01, t = 5.109, P = 0.001) in the PM group were also higher than those in the control group. CONCLUSIONS: Exacerbated AHR associated with allergic asthma caused by PM2.5is related to increased apoptosis and TIM-1 activation. These data might provide insights into therapeutic targets for the treatment of acute exacerbations of asthma induced by PM2.5.

Role of Thrombospondin-1 and Nuclear Factor-κB Signaling Pathways in Antiangiogenesis of Infantile Hemangioma.

BACKGROUND: Propranolol is the first-line drug for treatment of infantile hemangioma. However, its mechanism of action remains unclear. Nuclear factor-κB is highly expressed in tumors, directly or indirectly promoting angiogenesis. Thrombospondin-1 is the most important antiangiogenesis protein in vivo. These proteins mediate signaling pathways, probably playing an important role in hemangioma treatment. This study explored the synergistic regulation of thrombospondin-1 and nuclear factor-κB signaling pathways in the treatment of hemangioma with propranolol. METHODS: The hemangioma-derived endothelial cells were sorted out from the specimens of proliferative hemangioma by flow cytometry. Furthermore, a BALB/c nude mouse hemangioma model was established. Viability and proliferation of hemangioma-derived endothelial cells and the role of thrombospondin-1 and nuclear factor-κB signaling pathways were observed after propranolol administration in vitro and in vivo. RESULTS: The expression of thrombospondin-1 and its receptor CD36 in hemangioma-derived endothelial cells gradually increased with the increase in propranolol concentration, whereas the expression of nuclear factor-κBp65, phosphorylated inhibitor of κB alpha (p-IκBα), and phosphorylated inhibitor of nuclear factor-κB kinase beta (p-IκKß) weakened gradually (p < 0.05). In vivo, the tumors shrank gradually after propranolol treatment, with an increase in thrombospondin-1 and CD36 and a decrease in nuclear factor-κBp65, p-IκBα, and p-IκKß (p < 0.05). Glucocorticoid improved the antiangiogenesis mediated by thrombospondin-1/CD36 and inhibited the angiogenesis mediated by nuclear factor-κB/IκB (p < 0.05). Negative regulation occurred between the two signaling pathways. CONCLUSION: The treatment of infantile hemangioma with propranolol is promising to promote thrombospondin-1-mediated antiangiogenesis and to block nuclear factor-κB-mediated angiogenesis.

Comprehensive investigating of cytokine and receptor related genes variants in patients with chronic hepatitis B virus infection.

BACKGROUND & AIMS: Chronic hepatitis B virus (HBV) infection is a global health problem and the outcome are associated with both viral factors and host genetic factors. High Throughput Sequencing (HTS) technology were used to identify variants associated with liver disease. METHODS: Fifty-five Chronic hepatitis B (CHB) patients, fifty-three self-healing HBV (SH) patients and 53 healthy controls (HC) were recruited, 404 cytokine and cytokine receptor related genes were captured and sequenced at high depth (>900X), both variant (Fischer's exact test, P value < 0.05) and gene (SKAT-O gene level test, adjust P value < 0.05) level association were used to identify variants and genes associated with CHB. RESULTS: Total 5083 variants have been detected, fifty-four variants were found associated with CHB, most (29/32) variants were located in HLA region, including HLA-B, HLA-C, HLA-DQA1, HLA-DQB1, HLA-DQB2, HLA-DRB1 and HLA-DRB5. Several missense variants were found associated with CHB, including p.E226K in PVR (poliovirus receptor), p.E400A and p.C431R in IL4R (interleukin 4 receptor). Four variants located in 3'UTR (untranslated region) have also been found associated with CHB. CONCLUSION: Our study revealed that high through target region sequencing, combined with association analysis at variant and gene level, would be a good way to found variants and genes associated with CHB even at small sample size. Our data implied that chronic hepatitis B patients who carry these variants need intensive monitoring.

Routinely detected indicators in plasma have a predictive effect on the identification of HIV-infected patients with non-tuberculous mycobacterial and tuberculous infections.

BACKGROUND: It is difficult to quickly distinguish non-tuberculous mycobacterial (NTM) infection from tuberculosis (TB) infection in human immunodeficiency virus (HIV)-infected patients because of many similarities between these diseases. A simple and effective way to determine the differences using routine blood tests is necessary in developing countries. METHODS: A retrospective cohort study was conducted to recruit HIV-infected patients with either NTM infection or TB infection diagnosed for the first time according to mycobacterial culture and microscopic identification from May 2010 to March 2016. These data included the analysis of blood cells, liver function, renal function, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR), and were compared between the HIV/TB and HIV/NTM groups. RESULTS: A total of 240 patients were enrolled. The number of HIV/TB and HIV/NTM patients was 113 and 127, respectively. There were no significant differences in the CD4 T-cell count, age, sex, percentage of patients initiating antiretroviral therapy (ART) before the explicit diagnosis of TB or NTM infection. NTM infection was more likely to be restricted in the pulmonary while TB infection also involves extra-pulmonary sites. Both the leukocyte count(5.60 × 109/L) and the proportion of neutrophils in the leukocyte count (76.70%) in the HIV/TB group were significantly higher than those in the HIV/NTM group (4.40 × 109/L [P = 0.0014] and 69.30% [P < 0.001]. The analysis of liver function markers indicated that the concentration of albumin but not ALT and AST was significantly lower in the HIV/TB group than in the HIV/NTM group (P < 0.001). The creatinine and urea levels were not significantly different between the two groups. The ESR (84.00 mm/h) and the concentration of CRP (59.60 mg/L) were significantly higher in the HIV/TB group than in the HIV/NTM group (52.00 mm/h and 19.60 mg/L, respectively) (P < 0.001). To distinguish TB infection from NTM infection, the best cut-off value was 69.5 mm/h for ESR, with a positive predictive value (PPV) of 0.740 and negative predictive value (NPV) of 0.721, and 48.8 mg/L for CRP, with a PPV of 0.676 and NPV of 0.697. CONCLUSION: The dissemination character as well as stronger immune response characterized by higher inflammation markers (e.g. WBC, ESR, CRP) can help distinguish TB from NTM infection in HIV-infected patients who need empirical therapy or diagnostic therapy immediately in low-income areas.

Comprehensive investigation of cytokine- and immune-related gene variants in HBV-associated hepatocellular carcinoma patients.

Host genotype may be closely related to the different outcomes of Hepatitis B virus (HBV) infection. To identify the association of variants and HBV infection, we comprehensively investigated the cytokine- and immune-related gene mutations in patients with HBV associated hepatocellular carcinoma (HBV-HCC). Fifty-three HBV-HCC patients, 53 self-healing cases (SH) with HBV infection history and 53 healthy controls (HCs) were recruited, the whole exon region of 404 genes were sequenced at >900× depth. Comprehensive variants and gene levels were compared between HCC and HC, and HCC and SH. Thirty-nine variants (adjusted P<0.0001, Fisher's exact test) and 11 genes (adjusted P<0.0001, optimal unified approach for rare variant association test (SKAT-O) gene level test) were strongly associated with HBV-HCC. Thirty-four variants were from eight human leukocyte antigen (HLA) genes that were previously reported to be associated with HBV-HCC. The novelties of our study are: five variants (rs579876, rs579877, rs368692979, NM_145007:c.*131_*130delTG, NM_139165:exon5:c.623-2->TT) from three genes (REAT1E, NOD-like receptor (NLR) protein 11 (NLRP11), hydroxy-carboxylic acid receptor 2 (HCAR2)) were found strongly associated with HBV-HCC. We found 39 different variants in 11 genes that were significantly related to HBV-HCC. Five of them were new findings. Our data implied that chronic hepatitis B patients who carry these variants are at a high risk of developing HCC.

Correction to: Routinely detected indicators in plasma have a predictive effect on the identification of HIV-infected patients with non-tuberculous mycobacterial and tuberculous infections.

CORRECTION: After publication of this article [1] it came to our attention that the affiliation of Jun Chen and Hong-zhou Lu were incorrectly shown.Jun Chen's affiliation should have been given as Department of Infectious Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.Hong-zhou Lu should have been given as Department of Infectious Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China. Huashan Hospital affiliated to Fudan University, Shanghai, China. Medical College of Fudan University, Shanghai, China.The original article has been updated to reflect this change.

Genotoxicity Evaluation of Irrigative Wastewater from Shijiazhuang City in China.

In the present study, the wastewater sample collected from the Dongming discharging river in Shijiazhuang city was analysed using both chemical analysis and biological assays including the Salmonella mutagenicity test, micronucleus test and single-cell gel electrophoresis. Chemical analysis of the sample was performed using gas chromatography mass spectrometry and inductively coupled plasma mass spectrometry. The Salmonella mutagenicity test was performed on Salmonella typhimurium TA97, TA98, TA100 and TA102 strains with and without S9 mixture. The mice received the wastewater in natura through drinking water at concentrations of 25%, 50%, and 100%. One group of mice was exposed for 2 consecutive days, and the other group of mice was exposed for 15 consecutive days. To establish the levels of primary DNA damage, single-cell gel electrophoresis was performed on treated mouse liver cell. The concentrations of chromium and lead in the sample exceeded the national standard (GB20922-2007) by 0.78 and 0.43-fold, respectively. More than 30 organic compounds were detected, and some of the detected compounds were mutagens, carcinogens and environmental endocrine disrupters. A positive response for Salmonella typhimurium TA98 strain was observed. Mouse exposure via drinking water containing 50% and 100% of wastewater for 15 consecutive days caused a significant increase of MN frequencies in a dose-response manner. Mouse exposure via drinking water containing 50% and 100% of wastewater for 15 consecutive days caused a significant increase of the Olive tail moments in a dose-response manner. All the results indicated that the sample from the Dongming discharging river in Shijiazhuang city exhibited genotoxicity and might pose harmful effects on the local residents.

Correlation between polymorphisms in DNA mismatch repair genes and the risk of primary hepatocellular carcinoma for the Han population in northern China.

PURPOSE: This study investigated correlations between polymorphisms in DNA mismatch repair (MMR) genes and the risk of primary hepatocellular carcinoma (PHC). METHODS: Single nucleotide polymorphisms (SNPs) in the DNA MMR genes MLH3 (rs175080), PMS1 (rs5742933), PMS2 (rs1059060), MSH3 (rs26279), MSH5 (rs1150793, rs2075789) and MSH6 (rs1042821) were detected using the SNaPshot method in 250 PHC cases and in 308 patients without PHC in the Han population in northern China. RESULTS: The AA genotype in MLH3 (rs175080) increased the risk of PHC (odds ratio [OR] = 3.424; 95% confidence interval [CI]: 1.097-10.689). The AG and GG genotypes in MSH3 (rs26279) increased the risk of PHC (OR: 1.644 and 3.300; 95% CI: 1.112-2.428 and 1.765-6.168, respectively). The AA genotype in MSH5 (rs2075789) increased the risk of PHC (OR: 9.229; 95% CI: 1.174-72.535). The CT genotype in MSH6 (rs1042821) reduced the risk of PHC (OR: 0.629; 95% CI: 0.428-0.924). CONCLUSIONS: Our study suggests that polymorphisms in MLH3 (rs175080), MSH3 (rs26279), MSH5 (rs2075789) and MSH6 (rs1042821) may be independent risk factors for PHC.

Gene polymorphisms of interleukin-28, p21-activated protein kinases 4, and response to interferon-α based therapy in Chinese patients with chronic hepatitis B.

BACKGROUND: Peg-Interferon-α treatment is expensive and associated with considerable adverse effects, selection of patients with the highest probability of response is essential for clinical practice. The objective of this study was to assess the relationship between the gene polymorphisms of interleukin-28 (IL-28), p21-activated protein kinase 4 (PAK4) and the response to interferon treatment in chronic hepatitis B patients. METHODS: Two hundred and forty interferon-naive treatment HBeAg seropositive chronic hepatitis B patients were enrolled in the present prospective nested case-control study. Peripheral blood samples were collected, including 92 with favorable response and 148 without response to the interferon treatment. Rs8099917, rs12980602, and rs9676717 SNP was genotyped using matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS). RESULTS: IL-28 genotype was not associated with response to interferon treatment (OR for GT/GG vs. TT, 0.881 (95%CI 0.388 - 2.002); P = 0.762; OR for CT/CC vs. TT, 0.902 (95%CI 0.458 - 1.778); P = 0.766). Rs9676717 in PAK4 genotype was independently associated with the response (OR for CT/CC vs. TT, 0.524 (95%CI 0.310 - 0.888); P = 0.016). When adjusting for age, gender, smoking, drinking, levels of hepatitis B virus DNA, and alanine aminotransferase (ALT), rs9676717 genotype TT appeared to be associated with a higher probability of response for interferon treatment (OR, 0.155 (95%CI 0.034 - 0.700); P = 0.015). CONCLUSION: Genotype TT for rs9676717 in PAK4 gene and no drinking may be predictive of the interferon-a treatment success.

Association between gene polymorphisms of IL-28 and response to lamivudine in Chinese rural patients with chronic hepatitis B.

OBJECTIVE: To assess the association between gene polymorphisms (single nucleotide polymorphisms [SNPs]) of rs8099917 and rs12980602 in the IL-28 gene and the response to lamivudine treatment in naïve of Chinese rural patients. MATERIAL AND METHODS: Three hundred and fifty-four naïve chronic hepatitis B (CHB) patients treated with lamivudine were enrolled in this study. Rs8099917 and rs12980602 SNPs were genotyped using matrix-assisted laser desorption/ionization time of flight mass spectrometry. Baseline characteristics and genotypes were compared between 181 patients with treatment response and 173 without response. RESULTS: The IL-28 genotypes were independently associated with responses at 1 year post-treatment with lamivudine in CHB patients (OR for rs8099917 GT/GG vs. TT, 4.097 [95% CI, 1.342-12.512; p = 0.015]; OR for rs12980602CT/CC vs. TT, 2.27 [95% CI, 1.202-4.284; p =0.014]). When adjusting for age, gender, smoking, drinking, and levels of hepatitis B virus (HBV) DNA, alanine aminotransferase, and HBV genotype, the rs8099917 genotype GT (OR, 4.025 [95% CI, 1.316-12.354; p = 0.013] and fibrosis stage (OR, 0.716 [95% CI, 0.432-0.986; p = 0.036] appeared to be associated with a higher probability of response to lamivudine treatment. CONCLUSION: The genotype G/T for rs8099917 of IL-28 gene and early fibrosis stage may be predictive of treatment success.