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Cancer vaccines can amplify existing antitumor responses or prime naïve T cells to elicit effector T-cell functions in patients through immunization. Antigen-specific CD8+ T cells are crucial for the rejection of established tumors. We constructed XCL1-GPC3 fusion molecules as a liver cancer vaccine by linking the XCL1 chemokine to glypican-3 (GPC3), which is overexpressed in hepatocellular carcinoma (HCC). Cells expressing XCL1-GPC3 chemoattracted murine XCR1+CD8α+ dendritic cells (DC) and human XCR1+CD141+ DCs in vitro and promoted their IL12 production. After subcutaneous mXcl1-GPC3 plasmid injection, mXCL1-GPC3 was mainly detected in CD8α+ DCs of mouse draining lymph nodes. XCL1-GPC3–targeted DCs enhanced antigen-specific CD8+ T-cell proliferation and induced the de novo generation of GPC3-specific CD8+ T cells, which abolished GPC3-expressing tumor cells in mouse and human systems. We immunized a murine autochthonous liver cancer model, with a hepatitis B background, with the mXcl1-GPC3 plasmid starting at 6 weeks, when malignant hepatocyte clusters formed, or at 14 weeks, when liver tumor nodules developed, after diethylnitrosamine administration. mXcl1-GPC3–immunized mice displayed significantly inhibited tumor formation and growth compared with GPC3-immunized mice. After mXcl1-GPC3 immunization, mouse livers showed elevated production of IFNγ, granzyme B, IL18, CCL5, CXCL19, and Xcl1 and increased infiltration of GPC3-specific CD8+ T cells, activated natural killer (NK) cells, and NKT cells. The antitumor effects of these immune cells were further enhanced by the administration of anti–PD-1. Anti-HCC effects induced by hXCL1-GPC3 were confirmed in an HCC-PDX model from 3 patients. Thus, XCL1-GPC3 might be a promising cancer vaccine to compensate for the deficiency of the checkpoint blockades in HCC immunotherapy.

Supplementary Tables 1-2 and Supplementary Figures 1-8

Cell-free DNA (cfDNA)–based liquid biopsy is a promising approach for the early detection of cancer. A major hurdle is the limited yield of cfDNA from one blood draw, limiting the use of most samples to one test of either mutation or methylation. Here, we develop a technology, Mutation Capsule Plus (MCP), which enables multiplex profiling of one cfDNA sample, including simultaneous detection of genetic and epigenetic alterations and genome-wide discovery of methylation markers. With this technology, we performed de novo screening of methylation markers on cfDNA samples from 30 hepatocellular carcinoma (HCC) cases and 30 non-HCC controls. The methylation markers enriched in HCC cfDNA were further profiled in parallel with a panel of mutations on a training cohort of 60 HCC and 60 non-HCC cases, resulting in an HCC detection model. We validated the model in an independent retrospective cohort with 58 HCC and 198 non-HCC cases and got 90% sensitivity with 94% specificity. Furthermore, we applied the model to a prospective cohort of 311 asymptomatic hepatitis B virus carriers with normal liver ultrasonography and serum AFP concentration. The model detected four of the five HCC cases in the cohort, showing 80% sensitivity and 94% specificity. These findings demonstrate that the MCP technology has potential for the discovery and validation of multiomics biomarkers for the noninvasive detection of cancer. This study also provides a comprehensive database of genetic and epigenetic alterations in the cfDNA of a large cohort of HCC cases and high-risk non-HCC individuals.

Breakthrough infections of hepatitis B virus (HBV) after neonatal vaccination occurred in some adolescents and young adults who were born to mothers with hepatitis B surface antigen (HBsAg). We aimed to determine the impacts of prenatal HBsAg exposure on the generation of T follicular helper (Tfh) cells and antibodies (anti-HBs) specific to HBsAg. To mimic human prenatal HBsAg exposure, we mated female Alb1-HBV (HBV-M) mice with male C57BL/6J mice. Of their first filial generation (F1), HBV-M/F1+ expressed HBsAg in liver tissues and blood, and HBV-M/F1− mice exposed HBsAg in amniotic fluid. At their four weeks old, each HBV-M/F1 mouse was immunized with hepatitis B vaccine containing 5 μg HBsAg subcutaneously. Both HBV-M/F1− and HBV-M/F1+ mice had reduced generation of HBsAg-specific CD4+CXCR5+PD1+ Tfh cells and CD138+IgD− plasma cells in comparison with C57BL/6J mice. Results of coculturing the Tfh cells with B cells that were isolated from different strains of mice indicated that CD4+ T cell activation in response to HBsAg was critical for anti-HBs generation after prenatal HBsAg exposure. When interleukin (IL) 21 was supplemented, the generation of HBsAg-specific Tfh and plasma cells in HBV-M/F1− mice was improved, while supplementation showed little effect in HBV-M/F1+ mice. In HBV-M/F1− mice, HBV vaccine booster improved the generation of Tfh cells and plasma cells, and enhanced anti-HBs production. Conclusion Impaired generation of HBsAg-specific Tfh cells and plasma cells after prenatal HBsAg exposure can be improved by HBV vaccine booster, most likely increasing IL-21 production.

Aflatoxin exposure is a crucial factor in promoting the development of primary hepatocellular carcinoma (HCC) in individuals infected with the hepatitis virus. However, the molecular pathways leading to its bioactivation and subsequent toxicity in hepatocytes have not been well-defined. Here, we carried out a genome-wide CRISPR-Cas9 genetic screen to identify aflatoxin B1 (AFB1) targets. Among the most significant hits was the aryl hydrocarbon receptor (AHR), a ligand-binding transcription factor regulating cell metabolism, differentiation, and immunity. AHR-deficient cells tolerated high concentrations of AFB1, in which AFB1 adduct formation was significantly decreased. AFB1 triggered AHR nuclear translocation by directly binding to its N-terminus. Furthermore, AHR mediated the expression of P450 induced by AFB1. AHR expression was also elevated in primary tumor sections obtained from AFB1-HCC patients, which paralleled the upregulation of PD-L1, a clinically relevant immune regulator. Finally, anti-PD-L1 therapy exhibited greater efficacy in HCC xenografts derived from cells with ectopic expression of AHR. These results demonstrated that AHR was required for the AFB1 toxicity associated with HCC, and implicate the immunosuppressive regimen of anti-PD-L1 as a therapeutic option for the treatment of AFB1-associated HCCs.

Objective Hepatocellular carcinoma (HCC) development among hepatitis B surface antigen (HBsAg) carriers shows gender disparity, influenced by underlying liver diseases that display variations in laboratory tests. We aimed to construct a risk-stratified HCC prediction model for HBsAg-positive male adults. Methods HBsAg-positive males of 35-69 years old (N=6,153) were included from a multi-center population-based liver cancer screening study. Randomly, three centers were set as training, the other three centers as validation. Within 2 years since initiation, we administrated at least two rounds of HCC screening using B-ultrasonography and α-fetoprotein (AFP). We used logistic regression models to determine potential risk factors, built and examined the operating characteristics of a point-based algorithm for HCC risk prediction. Results With 2 years of follow-up, 302 HCC cases were diagnosed. A male-ABCD algorithm was constructed including participant's age, blood levels of GGT (γ-glutamyl-transpeptidase), counts of platelets, white cells, concentration of DCP (des-γ-carboxy-prothrombin) and AFP, with scores ranging from 0 to 18.3. The area under receiver operating characteristic was 0.91 (0.90-0.93), larger than existing models. At 1.5 points of risk score, 26.10% of the participants in training cohort and 14.94% in validation cohort were recognized at low risk, with sensitivity of identifying HCC remained 100%. At 2.5 points, 46.51% of the participants in training cohort and 33.68% in validation cohort were recognized at low risk with 99.06% and 97.78% of sensitivity, respectively. At 4.5 points, only 20.86% of participants in training cohort and 23.73% in validation cohort were recognized at high risk, with positive prediction value of 22.85% and 12.35%, respectively. Conclusions Male-ABCD algorithm identified individual's risk for HCC occurrence within short term for their HCC precision surveillance.

We aimed to evaluate the long-term efficacy of the hepatitis B vaccine in China. In an initial efficacy study, participants were collected from a cluster-randomized clinical trial conducted in 1983-90 in Qidong. All the participants in the vaccination group were vaccinated at birth, 1 and 6 months of age, and no intervention was implemented to the control group. In this 37-year extended follow-up study, the Poisson regression method was employed to derive rates per 10

As an emerging pollutant, the increasing use of antibiotics in wastewater posed a serious threat to non-target organisms in the environment. Duckweed (Spirodela polyrrhiza) is a common higher aquatic plant broadly used in phytotoxicity tests for xenobiotic substances. The aim of this study was to evaluate the chronic toxicity of norfloxacin (NOR) on Spirodela polyrrhiza during 18 days of exposure. Our study investigated the addition of NOR into the medium with environment-related concentrations (0, 0.1, 10, and 1000 μg L

Objective The number of liver cancer patients in China accounts for more than half of the world. However, China currently lacks national, multicenter economic burden data, and meanwhile, measuring the differences among different subgroups will be informative to formulate corresponding policies in liver cancer control. Thus, the aim of the study was to measure the economic burden of liver cancer by various subgroups. Methods A hospital-based, multicenter and cross-sectional survey was conducted during 2012-2014, covering 39 hospitals and 21 project sites in 13 provinces across China. The questionnaire covers clinical information, sociology, expenditure, and related variables. All expenditure data were reported in Chinese Yuan (CNY) using 2014 values. Results A total of 2,223 liver cancer patients were enrolled, of whom 59.61% were late-stage cases (III-IV), and 53.8% were hepatocellular carcinoma. The average total expenditure per liver cancer patient was estimated as 53,220 CNY, including 48,612 CNY of medical expenditures (91.3%) and 4,608 CNY of non-medical expenditures (8.7%). The average total expenditures in stage I, II, III and stage IV were 52,817 CNY, 50,877 CNY, 50,678 CNY and 54,089 CNY (P>0.05), respectively. Non-medical expenditures including additional meals, additional nutrition care, transportation, accommodation and hired informal nursing were 1,453 CNY, 839 CNY, 946 CNY, 679 CNY and 200 CNY, respectively. The one-year out-of-pocket expenditure of a newly diagnosed patient was 24,953 CNY, and 77.2% of the patients suffered an unmanageable financial burden. Multivariate analysis showed that overall expenditure differed in almost all subgroups (P

Cancer vaccines can amplify existing antitumor responses or prime naïve T cells to elicit effector T-cell functions in patients through immunization. Antigen-specific CD8+ T cells are crucial for the rejection of established tumors. We constructed XCL1-GPC3 fusion molecules as a liver cancer vaccine by linking the XCL1 chemokine to glypican-3 (GPC3), which is overexpressed in hepatocellular carcinoma (HCC). Cells expressing XCL1-GPC3 chemoattracted murine XCR1+CD8α+ dendritic cells (DC) and human XCR1+CD141+ DCs in vitro and promoted their IL12 production. After subcutaneous mXcl1-GPC3 plasmid injection, mXCL1-GPC3 was mainly detected in CD8α+ DCs of mouse draining lymph nodes. XCL1-GPC3–targeted DCs enhanced antigen-specific CD8+ T-cell proliferation and induced the de novo generation of GPC3-specific CD8+ T cells, which abolished GPC3-expressing tumor cells in mouse and human systems. We immunized a murine autochthonous liver cancer model, with a hepatitis B background, with the mXcl1-GPC3 plasmid starting at 6 weeks, when malignant hepatocyte clusters formed, or at 14 weeks, when liver tumor nodules developed, after diethylnitrosamine administration. mXcl1-GPC3–immunized mice displayed significantly inhibited tumor formation and growth compared with GPC3-immunized mice. After mXcl1-GPC3 immunization, mouse livers showed elevated production of IFNγ, granzyme B, IL18, CCL5, CXCL19, and Xcl1 and increased infiltration of GPC3-specific CD8+ T cells, activated natural killer (NK) cells, and NKT cells. The antitumor effects of these immune cells were further enhanced by the administration of anti–PD-1. Anti-HCC effects induced by hXCL1-GPC3 were confirmed in an HCC-PDX model from 3 patients. Thus, XCL1-GPC3 might be a promising cancer vaccine to compensate for the deficiency of the checkpoint blockades in HCC immunotherapy.

Objective: In rural areas of China with highly endemic for hepatitis B virus (HBV) infection, protective efficacy was observed in adulthood when a one-dose HBV vaccine booster was administered to high-risk children born to mothers who were positive for hepatitis B surface antigen (HBsAg). The aim of this study was to estimate the cost-effectiveness of an HBV vaccine booster in this specific group of children when given at 10 years of age. Methods: Two potential strategies were considered: strategy 1 was a one-dose booster given if the child was negative on HBsAg screening; strategy 2 was a one-dose booster given if the child was negative on both HBsAg plus anti-HBs screening. A decision tree combined with a Markov model was developed to simulate the booster intervention process and to simulate the natural history of HBV infection in a cohort of 10-year-old children who were born to HBsAg-positive mothers. The model was calibrated based on multiple selected outcomes. Costs and quality-adjusted life years (QALYs) were measured from a societal perspective. Cost-effectiveness ratios (CERs) of the different strategies were compared in both base-case and one-way sensitivity analyses. Results: Compared to the current practice of ‘no screening and no booster’, both strategy 1 and strategy 2 were cost-saving, with CERs estimated at US$ −6961 and US$ −6872 per QALY gained, respectively. In the one-way sensitivity analysis for strategy 1, all the CERs were found to be less than US$ −5000 per QALY gained after considering the uncertainty of all the variables, including vaccination protective efficacy, natural history, behavior, and various costs and utility weights. In a ‘worst case’ scenario (all parameter values simultaneously being at the worst), the CER of strategy 1 increased to US$ 3263 per QALY gained, which was still less than the GDP per capita of China in 2016 (US$ 8126). Conclusions: A hepatitis B vaccine booster given to children born to HBsAg-positive mothers in rural China would be cost-effective and could be considered in HBV endemic areas. Keywords: Hepatitis B vaccine, Adolescent booster, Cost-effectiveness analysis

Background Combining radiotherapy (RT) with programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors has been shown to enhance anti-tumor effects in the treatment of non-small cell lung carcinoma (NSCLC). Pulmonary toxicity is a major adverse effect of thoracic RT in NSCLC patients, whether it is administered alone or in combination with PD-1/PD-L1 inhibitors. This study aimed to evaluate the potential pulmonary toxicity of RT combined with concurrent PD-1 inhibitor and to clarify the underlying mechanisms. Methods Radiation-induced lung injury (RILI) was induced in C57BL/6 mice by given 24 Gy in three fractions on consecutive days, with or without concurrent injection of anti-PD-1 antibody. On days 3, 7, 14, and 28 after the first exposure to irradiation, lung tissue and peripheral blood samples were collected from the mice. Histological injury was analyzed, and inflammatory cell infiltration and interleukin (IL)-17A production in the lung tissues were quantified. Results Mice that received irradiation with concurrent administration of anti-PD-1 antibody had the highest histological score for RILI. In the murine lung tissues, the levels of PD-1 and IL-17A expression were increased in γδ T cells but not in the other CD3+ T cells after irradiation. Concurrent blockade of PD-1 enhanced IL-17A production from γδ T cells in the lung tissues after irradiation. In the mice with acute RILI, concurrent administration of anti-PD-1 antibody exaggerated pulmonary inflammation, with significantly increased levels of neutrophilic infiltration and IL-17A detected in both the lung and blood. Conclusions PD-1 could restrain IL-17A production from γδ T cells to modulate acute RILI. The concurrent administration of anti-PD-1 antibody aggravates the severity of acute RILI. More attention should be paid to pulmonary toxicity in patients undergoing thoracic RT with concurrent anti-PD-1 immunotherapy.

BACKGROUND: Hepatocellular carcinoma (HCC) development among hepatitis B surface antigen (HBsAg) carriers shows gender disparity, influenced by underlying liver diseases that display variations in laboratory tests. We aimed to construct a risk-stratified HCC prediction model for HBsAg-positive male adults.METHODS: HBsAg-positive, 35-69 years males (N=6 153) were recruited from a multi-center population-based liver cancer screening study. Randomly, three centers were set as training, the other three centers as validation. Within 2 years since initiation, we administrated at least two rounds of HCC screening using B-ultrasonography and α-fetoprotein (AFP). We used logistic regression models to determine potential risk factors, built and examined the operating characteristics of a point-based algorithm for HCC risk prediction.RESULTS: With 2 years of follow-up, 302 HCC cases were diagnosed. A male-ABCD algorithm was constructed including participant’s Age, Blood levels of GGT (γ-glutamyl-transpeptidase), Counts of platelets, white cells, Concentration of DCP (des-γ-carboxy-prothrombin) and AFP, with scores ranging from 0 to 18.3. The area under receiver operating characteristic was 0.91(0.89-0.93), larger than existing models. At 1.5 points of risk-score, 26.10% of the participants in training, 14.94% in validation were recognized at-low-risk, with sensitivity of identifying HCC remained 100%. At 2.5 points, 46.51% of the participants in training, 33.68% in validation were recognized at-low-risk with 99.06% and 97.78% of sensitivity. At 4.5 points, only 20.86% of training, 23.73% of validation were recognized at-high-risk, with positive prediction value of 22.85% and 12.35% respectively.DISCUSSION: Male-ABCD algorithm identified individual’s risk for HCC occurrence within short-term for their HCC precision surveillance.

Among elder children/young adults who received hepatitis B virus (HBV) vaccination during infancy, the serological status of HBsAg-negative and anti-HBc-positive [HBsAg(–)/anti-HBc(+)] was frequently reported, indicating potential occult HBV infection (OBI). It is required to define the long-term protection of neonatal vaccination against OBI in their mature adulthood. Building upon the 1983–1990 established Qidong Hepatitis B Intervention Study, we sampled 10% of the 28–35-year-old participants, who remained in the cohort by 2012. Each participant was tested for serological markers of HBsAg, anti-HBs, HBeAg, anti-HBe and anti-HBc. HBV-DNA and relaxed circular DNA (rcDNA) were determined in some HBsAg(–)/anti-HBc(+) individuals. Totally, 3615 individuals from the neonatal vaccination group and 3100 individuals from the control group donated blood samples, respectively. In the vaccination group, the prevalence of HBsAg was 1.58% (57/3615), HBsAg(–)/anti-HBc(+) was 4.70% (170/3615), significantly lower than in the control group, which was 7.45% (231/3100) and 19.48% (640/3100) respectively (all p

Premelanosome protein (PMEL) is crucial for the formation of melanosomal fibrils through the transition from stage I to stage II melanosomes. It was used as a target antigen in some adoptive T-cell therapy of melanoma. The correlation of PMEL to prognosis and immune cell infiltration level are unknown in melanoma. The PMEL expression was evaluated via Tumor Immune Estimation Resource, Oncomine and Gene Expression Profiling Interactive Analysis (GEPIA). We also evaluate the influence of PMEL on overall survival via GEPIA, PrognoScan, and immunohistochemistry in human tissue microarray. The correlation between PMEL expression level and immune cell or gene markers of immune infiltration level was explored on Tumor Immune Estimation Resource and GEPIA. PMEL expression was significantly higher in skin cutaneous melanoma (SKCM) and SKCM-metastasis in comparison with the other cancers. In SKCM, PMEL expression in high levels was associated with poor overall survival. In both SKCM and SKCM-metastasis patients, PMEL expression is negatively correlated with the infiltration cells of CD8+ T cells, macrophages, and neutrophils. Programmed cell-death protein 1 just showed response rates ranging from 20% to 40% in patients with melanoma, so it is critical to discover a new therapeutic target. PMEL is negatively associated with immune cell infiltration and can be as a negative prognosis marker or new immunotherapy target in SKCM and SKCM-metastasis.

A substantial proportion of liver cancers is attributable to chronic infection with hepatitis B and C (HBV/HCV). Liver cancer could become the second cancer, after cervical, to be effectively controlled globally, if proven interventions such as vaccination can be implemented on a large scale. In 2018, the global mortality rate for liver cancer was estimated to be 8.5 per 100 000 individuals. Given patterns of HBV infection and immigration across countries, liver cancer control requires combined, global action. Liver cancer trends vary between countries, in some Western countries, the incidence rates were relatively low but have increased in recent decades; conversely, in several Asian countries, the incidence rates have decreased over time. China has in the past contributed more than half of the global burden of liver cancer but more recently a national decline in liver cancer incidence has been observed. Here, we review the liver cancer burden and exposure to risk factors in China, compared to other countries. We also review the implementation status for primary and secondary prevention interventions and major outcomes achieved over the past three decades. Using Bayesian age-period-cohort analysis, we examine recent trends and based on these, predict that by 2050, the incidence of liver cancer in China could fall by half. We additionally survey the literature to identify current research needs, and review relevant national policies on liver cancer control in China. A comprehensive set of interventions is proposed to progress toward the long-term goal of liver cancer elimination based on the natural history and evidence-based interventions.

Objective: This study aims to understand the medical expenditure for liver cancer during 2002-2011 in urban areas of China. Materials and Methods: This is a retrospective study. Based on a stratified cluster sampling method, a medical expenditure survey collected basic personal information from related medical records. Two-tailed independent sample t-test, variance analysis, and Student–Newman–Keuls Tests were used in cost analysis for the corresponding data types. Results: A total of 12,342 liver cancer patients were included in the analysis. Overall average medical expenditure per case for liver cancer diagnosis and treatment in China has increased from ¥21, 950 to ¥40, 386 over the study period. For each liver cancer patient diagnosed between 2009 and 2011, the average expenditures were 29,332 CNY for stage I, 35,754 CNY for stage II, 34,288 CNY for stage III, and 30,275 CNY for stage IV diseases (P < 0.001). Pharmaceuticals accounted for the biggest part of the medical expenditure and it rose from 48.01% to 52.96% during these ten years, and the share of nursing fee expenses was the lowest (around 1%). Over the entire 10-year data period, the per capita expenditure of the east region (32,983 CNY) was higher than that of the west region (26,219 CNY) and slightly higher than the central region (31,018 CNY, P < 0.001). Discussion: As a major cancer in China, liver cancer accounts for a large portion of health economic burden and its medical expenditure is heavy for families. Early diagnosis and treatment for liver cancer will save medical expenditure. Conclusion: The economic burden of liver cancer is high in China and related medical expenditure has increased.

To control the infection of hepatitis B virus (HBV) plasma-derived hepatitis B vaccine, the first generation vaccine, was administrated to millions of infants. In addition, due to various reasons, the HBIG was not administrated to the high-risk infants who were born to HBsAg-positive mother in many low- and middle-income countries and areas. Nowadays, plasma-derived hepatitis B vaccine was totally replaced by recombinant HBV vaccines and most of the high-risk infants were immunized together with HBIG administration. As the population who were vaccinated with plasma-derived hepatitis B vaccine stepped into their third decades, we could get some experiences from them by monitoring the HBV serological markers.

Introduction: The aim of this study was to determine the impact of hepatitis B virus (HBV) and/or hepatitis C virus (HCV) on primary liver cancer (PLC) in China north areas. Methods: A total of 2172 histologically confirmed PLC patients attending the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences during the period January 1, 2003 to December 31, 2014 were enrolled. Details of hepatitis B surface antigen (HBsAg), antibodies against HBV core antigen (anti-HBc), and antibodies against HCV (anti-HCV) status were recorded. Sequencing of the HBV PreS-S gene and the C/E1 and NS5B fragments of HCV was performed and the genotypes were analyzed for some of the patients with hepatocellular carcinoma (HCC). Results: Among the 2172 histologically confirmed PLC cases, 1823 (83.9%) had HCC and 238 (11.0%) had intrahepatic cholangiocarcinoma (iCCA). Among HCC cases, HBV infection alone, indicated by HBsAg-neg/pos + anti-HBc-pos, was found in 1567 (86.0%) cases; of these, 18.2% (331/1823) were HBsAg-neg + anti-HBc-pos. Serum HBV-DNA was detectable in 70% of HBsAg-neg + anti-HBc-pos HCC cases. The dominant HBV genotype was HBV-C2 (94.4%). HCV infection alone, indicated by anti-HCV-pos, was found in 2.5% (46/1823) of cases; HCV-1b (72.1%) was the dominant genotype. HBV + HCV co-infection markers were found in 6.7% (122/1823) of cases. Only 88 (4.8%) cases had no HBV and no HCV markers. Among the 238 iCCA cases, 54 (22.7%) were HBsAg-pos + anti-HBc-pos; none was anti-HCV-pos alone. Conclusions: HBV remains the major contributor to PLC in China north areas Individuals with occult HBV infection should not be ignored in liver cancer screening. Keywords: Hepatocellular carcinoma, Intrahepatic cholangiocarcinoma, Hepatitis B virus, Hepatitis C virus, Etiology, Serum alpha-fetoprotein

The multiple-contamination of heavy metals and nutrients worsens increasingly and Ulva sp. green tide occurs almost simultaneously. To reveal the biological mechanism for outbreak of the green tide, Ulva pertusa was exposed to seven-day-multiple-contamination. The relation between pH variation (VpH), Chl a content, ratio of (Chl a content)/(Chl b content) (Rchla/chlb), SOD activity of U. pertusa (ASOD) and contamination concentration is [Formula: see text] (p

The tumor necrosis factor receptor-associated factor 7 (TRAF7) is a component of the tumor necrosis factor alpha (TNF-α)/nuclear factor kappa B (NF-κB) pathway and is a putative E3-ubiquitin ligase. Based on importance of chronic inflammation in hepatocellular carcinoma (HCC), we investigated the biological effects and the molecular mechanisms of deregulated TRAF7 signaling in HCC. Our results showed that high TRAF7 expression in HCC samples was inversely associated with Kruppel-like factor 4 (KLF4) expression and the prognosis of HCC patients. TRAF7 could degrade KLF4 protein through ubiquitin by interacting with its N-terminus. The up-regulation of TRAF7 promoted HCC cell migration and invasion in vivo and in vitro, and TRAF7 knockdown had the opposite effects. Restoration of KLF4 abrogated the motility promotion induced by TRAF7. TRAF7 promotes HCC cell motility through inducing KLF4 protein turnover.

The combination of chronic dietary exposure to the fungal toxin, aflatoxin B(1) (AFB(1)), and hepatitis B viral (HBV) infection is associated with an increased risk for early onset hepatocellular carcinomas (HCCs). An in-depth knowledge of the mechanisms driving carcinogenesis is critical for the identification of genetic risk factors affecting the susceptibility of individuals who are HBV infected and AFB(1) exposed. AFB(1)-induced mutagenesis is characterized by G to T transversions. Hence, the DNA repair pathways that function on AFB(1)-induced DNA adducts or base damage from HBV-induced inflammation are anticipated to have a strong role in limiting carcinogenesis. These pathways define the mutagenic burden in the target tissues and ultimately limit cellular progression to cancer. Murine data have demonstrated that NEIL1 in the DNA base excision repair pathway was significantly more important than nucleotide excision repair relative to elevated risk for induction of HCCs. These data suggest that deficiencies in NEIL1 could contribute to the initiation of HCCs in humans. To investigate this hypothesis, publicly-available data on variant alleles of NEIL1 were analyzed and compared with genome sequencing data from HCC tissues derived from individuals residing in Qidong County (China). Three variant alleles were identified and the corresponding A51V, P68H, and G245R enzymes were characterized for glycosylase activity on genomic DNA containing a spectrum of oxidatively-induced base damage and an oligodeoxynucleotide containing a site-specific AFB(1)-formamidopyrimidine guanine adduct. Although the efficiency of the P68H variant was modestly decreased, the A51V and G245R variants showed nearly wild-type activities. Consistent with biochemical findings, molecular modeling of these variants demonstrated only slight local structural alterations. However, A51V was highly temperature sensitive suggesting that its biological activity would be greatly reduced. Overall, these studies have direct human health relevance pertaining to genetic risk factors and biochemical pathways previously not recognized as germane to induction of HCCs.

Liquid biopsies, based on cell free DNA (cfDNA) and proteins, have shown the potential to detect early stage cancers of diverse tissue types. However, most of these studies were retrospective, using individuals previously diagnosed with cancer as cases and healthy individuals as controls. Here, we developed a liquid biopsy assay, named the hepatocellular carcinoma screen (HCCscreen), to identify HCC from the surface antigen of hepatitis B virus (HBsAg) positive asymptomatic individuals in the community population. The training cohort consisted of individuals who had liver nodules and/or elevated serum α-fetoprotein (AFP) levels, and the assay robustly separated those with HCC from those who were non-HCC with a sensitivity of 85% and a specificity of 93%. We further applied this assay to 331 individuals with normal liver ultrasonography and serum AFP levels. A total of 24 positive cases were identified, and a clinical follow-up for 6-8 mo confirmed four had developed HCC. No HCC cases were diagnosed from the 307 test-negative individuals in the follow-up during the same timescale. Thus, the assay showed 100% sensitivity, 94% specificity, and 17% positive predictive value in the validation cohort. Notably, each of the four HCC cases was at the early stage (

Objective Liver cancer is one of the most common cancers and major cause of cancer deaths in China, which accounts for over 50% of new cases and deaths worldwide. The systematic liver cancer statistics including of projection through 2030 could provide valuable information for prevention and control strategies in China, and experience for other countries. Methods The burden of liver cancer in China in 2014 was estimated using 339 cancer registries' data selected from Chinese National Cancer Center (NCC). Incident cases of 22 cancer registries were applied for temporal trends from 2000 to 2014. The burden of liver cancer through 2030 was projected using age-period-cohort model. Results About 364,800 new cases of liver cancer (268,900 males and 95,900 females) occurred in China, and about 318,800 liver cancer deaths (233,500 males and 85,300 females) in 2014. Western regions of China had the highest incidence and mortality rates. Incidence and mortality rates decreased by about 2.3% and 2.6% per year during the period of 2000-2014, respectively, and would decrease by more than 44% between 2014 and 2030 in China. The young generation, particularly for those aged under 40 years, showed a faster down trend. Conclusions Based on the analysis, incidence and mortality rates of liver cancer are expected to decrease through 2030, but the burden of liver cancer is still serious in China, especially in rural and western areas. Most cases of liver cancer in China can be prevented through vaccination and more prevention efforts should be focused on high risk groups.

Hongda Chen,1,* Yue Zhang,1,2,* Siwen Li,3,* Ni Li,1 Yuhan Chen,4 Bei Zhang,3 Chunfeng Qu,1 Huiguo Ding,4 Jian Huang,3,5 Min Dai1 1National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; 2Office of Scientific Research, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China; 3Liver Research Center, Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, Beijing, China; 4Department of Gastrointestinal and Hepatology, Beijing You’ An Hospital Affiliated to Capital Medical University, Beijing, China; 5National Clinical Research Center of Digestive Diseases, Beijing, China *These authors contributed equally to this work Background: Although a number of serum biomarkers for detection of hepatocellular carcinoma (HCC) have been explored, their exact diagnostic value remains unclear. We aimed to conduct a direct comparison of five representative serum biomarkers for detecting HCC and to derive multi-marker prediction algorithms. Patients and methods: In total, 846 patients were recruited from three hospitals in China, including 202 HCC patients, 226 liver cirrhosis patients, 215 chronic hepatitis B virus-infected patients, and 203 healthy volunteers. Serum levels of alpha-fetoprotein (AFP), lens culinaris agglutinin-reactive AFP (AFP-L3), des-gamma-carboxyprothrombin (DCP), squamous cell carcinoma antigen, and centromere protein F autoantibody were measured by ELISA. The diagnostic performances of individual biomarkers and multi-marker combinations were evaluated by receiver operating characteristics analysis. The bootstrapping method was adopted to adjust for potential overfitting of all diagnostic indicators. Results: DCP exhibited the best diagnostic performance, with areas under the curve (AUC) for detecting HCC of 0.82 (95% CI 0.64–0.80) and sensitivity of 65.2% (95% CI 63.3–82.1%) at 90% specificity. Of note, DCP showed similar diagnostic efficacy for detecting AFP-positive and AFP-negative HCC. After a comprehensive search for multi-marker combinations, a two-marker prediction algorithm including AFP and DCP was constructed and yielded an AUC of 0.87 (95% CI 0.68–0.84) for detecting HCC. In addition, the combination showed good ability in discriminating early-stage HCC and decompensated liver cirrhosis, with an AUC of 0.81 (95% CI 0.75–0.86). Conclusion: DCP could be a complementary biomarker in the early diagnosis of HCC. The constructed multi-marker prediction algorithms could contribute toward distinguishing HCC from non-malignant chronic liver diseases. Keywords: early detection, liver cirrhosis, prediction model

Background: Glypican-3 (GPC3) is one of the key tissue markers that could discriminate malignant precancerous lesions from benign hepatic lesions in cirrhotic patients. We aimed to develop a GPC3 cancer vaccine to induce specific T cells to intervene in hepatocellular carcinoma (HCC) development. Methods: Synthesizing mannosylated liposomes (LPMan) as vaccine delivery system, incorporating one Toll-like receptor (TLR)-7/8 agonist CL097 as adjuvant, we prepared a GPC3 nanovaccine, LPMan-GPC3/CL097. We injected 25 mg/kg diethylnitrosamine intraperitoneally to induce autochthonous HCC in HBV-transgenic mice, which persistently express hepatitis B surface antigen in hepatocytes. Starting from week 8 after diethylnitrosamine injection when malignant hepatocytes generated, we immunized the mice subcutaneously every 2 weeks 4 times with LPMan-GPC3/CL097 containing 5 µg of GPC3 plus 5 µg of CL097. Results: The vaccine efficiently targeted draining lymph nodes where naïve T cells reside and enhanced the expression of molecules involved in antigen presentation in migratory dendritic cells (DCs). Antigen was professionally processed in endoplasmic reticulum-Golgi system of DCs, subsequently priming both CD4+ and CD8+ T cells. The LPMan-GPC3/CL097 immunization generated significantly more GPC3-specific CD4+ IFNγ- and CD8+ IFNγ-producing T cells in mice spleens and livers, which specifically eliminated GPC3-expressing tumor cells. One week after last immunization (week 15 after diethylnitrosamine), 5/5 un-immunized, 5/5 sham (LPMan-CL097) and 1/5 LPMan-GPC3/CL097-immunized mice developed HCC. By week 20 after diethylnitrosamine, significantly less HCC developed in LPMan-GPC3/CL097-immunized mice than in sham-immunized mice (P

// Di Jin 1* , Jun Tao 2* , Dan Li 3 , Yanan Wang 2 , Li Li 2 , Zhongdong Hu 4 , Zhenzhen Zhou 5 , Xiuli Chang 6 , Chunfeng Qu 6 and Hongbing Zhang 1,2 1 Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China 2 State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China 3 Cell Engineering Research Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China 4 Modern Research Center for Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China 5 Department of Physiology, Dalian Medical University, Dalian, China 6 State Key Laboratory of Molecular Oncology, Cancer Institute/Hospital, Chinese Academy of Medical Sciences, Beijing, China * These authors have contributed equally to this work Correspondence to: Hongbing Zhang, email: // Keywords : GP73, matrix metalloproteinase-13, hepatocellular carcinoma, invasion Received : March 09, 2015 Accepted : August 23, 2015 Published : September 10, 2015 Abstract Golgi Protein 73 (GP73) is a serum biomarker for hepatocellular carcinoma (HCC), however its role in HCC is not clear. We report that GP73 promotes cell invasion, the hallmark of malignancy, through the upregulation of matrix metalloproteinase-13 (MMP-13). GP73 enhances MMP-13 expression through cAMP responsive element binding protein (CREB)-mediated transcription activation. Levels of GP73 and MMP-13 are increased and positively correlated in human HCC tissues. Augmented MMP-13 potentiates HCC cell metastasis. Thus, the GP73-CREB-MMP-13 axis potentiates cancer cell invasion and may be a target for HCC treatment.