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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.

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.

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

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

Biannual screening of hepatocellular carcinoma (HCC) by ultrasonography and serum α-fetoprotein has been proposed to the HBsAg-seropositive individuals. The widespread application to all of them was restricted due to limited acceptability of resource and anxiety-producing procedures. We recently developed a novel liquid biopsy assay to identify HCC cases in asymptomatic HBsAg-positive individuals.

Qidong City, China, has had high liver cancer incidence from endemic hepatitis B virus (HBV) infection and dietary exposure to aflatoxin. Based on etiologic studies, we began interventions in 1980 to reduce dietary aflatoxin and initiate neonatal HBV vaccination. We studied trends in liver cancer incidence rates in the 1.1 million inhabitants of Qidong and examined trends in aflatoxin exposure, staple food consumption, HBV infection markers and annual income. Aflatoxin exposure declined greatly in association with economic reform, increased earnings and educational programs to shift staple food consumption in the total population from moldy corn to fresh rice. A controlled neonatal HBV vaccination trial began in 1983 and ended in November, 1990, when vaccination was expanded to all newborns. Liver cancer incidence fell dramatically in young adults. Compared with 1980–83, the age-specific liver cancer incidence rates in 2005–08 significantly decreased 14-fold at ages 20–24, 9-fold at ages 25–29, 4-fold at ages 30–34, 1.5-fold at ages 35–39, 1.2-fold at ages 40–44 and 1.4-fold at ages 45–49, but increased at older ages. The 14-fold reduction at ages 20–24 might reflect the combined effects of reduced aflatoxin exposure and partial neonatal HBV vaccination. Decrease incidence in age groups >25 years could mainly be attributable to rapid aflatoxin reduction. Compared with 1980–83, liver cancer incidence in 1990–93 significantly decreased 3.4-fold at ages 20–24, and 1.9-fold at ages 25–29 when the first vaccinees were

Neutralizing antibodies (anti-HBs) after immunization with hepatitis B virus (HBV) vaccines against HBV surface antigen (HBsAg) wane after 10-15years. We analyzed the effect of an adolescent booster given to vaccination-protected children born to mothers with different HBsAg-carrying status against HBV infection in their mature adulthood.A total of 9793 individuals, who were HBsAg-negative at childhood (baseline) and donated blood samples, both during childhood and adulthood, from the vaccination group in "Qidong Hepatitis B Intervention Study", were enrolled. Among them 7414 received a one-dose, 10μg-recombinant HBV vaccine booster at 10-14years of age. At endpoint (23-28years of age), we determined the HBV serological markers and quantified their serum HBV-DNA in each of the chronic HBV-infected adults.Fifty-seven adults were identified as chronic HBV infection, indicated by HBsAg(+)anti-HBc(+) for more than 6months. The individuals who were born to HBsAg-positive mothers (high-risk adults) had significantly increased risk of developing chronic HBV infections in adulthood compared with those who were born to HBsAg-negative mothers; the adjusted odds ratio (OR) was 12.56, 95%CI:7.14-22.08. The seronegative status of anti-HBs at 10-11years of age significantly increased the risk of HBV infections among the high-risk adults. When HBsAg(-)anti-HBc(+) children who were born to HBsAg-positive mothers 70% of them remained as the status and 10% of them developed HBsAg(+)anti-HBc(+). While when they were born to HBsAg-negative mothers 1.05% HBsAg(-)anti-HBc(+) children developed HBsAg(+)anti-HBc(+) and 24.74% of them remained as the status in 12-18years. One dose of adolescent booster showed significant protection on high-risk adults from chronic HBV infection; P for trend was 0.015.Maternal HBsAg-positive status was an independent risk factor for vaccination-protected children to develop HBV breakthrough infection in adulthood. Adolescent boosters might be appropriate for high-risk individuals who were born to HBsAg-positive mothers when their serum anti-HBs10mIU/ml.

Transmission of hepatitis B virus (HBV) during the perinatal period and in young children has been effectively prevented in recent years, with increased rates of coverage and timely immunization of hepatitis B vaccine to neonates in mainland China. Prevalence of HBV surface antigen (HBsAg) and chronic HBV infection in children have decreased both in rural and urban areas. The incidence of hepatitis B and primary hepatocellular carcinoma has also been reduced in children and young people. The effects of immunoprotection against HBV infection were found to last for at least 20 years. The presence of immune memory was associated with titers of antibody to HBV surface antigen (anti-HBs) in young children vaccinated at an early age. Results from our recent clinical investigation suggest that a universal booster immunization is not necessary for children and teenagers after neonatal vaccination. In this review, issues arising from representative vaccination-coverage areas, including Qidong, Jiangsu Province, are also discussed. These include immunoprophylaxis failure against vertical transmission, low or no response to the vaccines, isolated anti-HBc positivity, occult HBV infection after vaccination, and the effects of vaccination on HBV genotype and mutation.

Background Primary liver cancer (PLC) is a common cancer worldwide, especially in developing countries. Several previous studies using different datasets have summarized PLC incidence rates and trends in different populations. However, with changes in exposure to risk factors and the implementation of preventive measures, the epidemiology of PLC worldwide may have changed. Methods We extended the analyses using the latest data from Cancer Incidence in Five Continents over the 35-year period 1973–2007 from 24 populations in Americas, Asia, Europe and Oceania using Joinpoint regression analysis. We examined age-standardized rates (ASRs) of PLC by histologic subtypes for both males and females in 24 populations during the period 2003–2007. Results We found that during the period 2003–2007, the highest ASRs for PLC were observed in some Asian populations, ranging from 19.0 to 26.7 per 100,000 in males and 4.8 to 8.7 per 100,000 in females. The international trends between 1973 and 2007 showed that ASRs for PLC were declining in several Asian populations. In contrast, ASRs for PLC were increasing in some European, American and Oceanian populations. Conclusions Although the reasons were not fully clear for these trends, public health measures in Asian populations and HCV transmission in European, American and Oceanian populations were likely to have contributed to these patterns. Meanwhile, other possible risk factors such as the consumption of alcohol, obesity, and nonalcoholic fatty liver disease should also be concerned for the burden of PLC.

In a 30-year follow-up of the Qidong Hepatitis B Intervention Study, Yawei Zhang and colleagues examine the effects of neonatal vaccination on liver diseases. Please see later in the article for the Editors' Summary, Background Neonatal hepatitis B vaccination has been implemented worldwide to prevent hepatitis B virus (HBV) infections. Its long-term protective efficacy on primary liver cancer (PLC) and other liver diseases has not been fully examined. Methods and Findings The Qidong Hepatitis B Intervention Study, a population-based, cluster randomized, controlled trial between 1985 and 1990 in Qidong, China, included 39,292 newborns who were randomly assigned to the vaccination group in which 38,366 participants completed the HBV vaccination series and 34,441 newborns who were randomly assigned to the control group in which the participants received neither a vaccine nor a placebo. However, 23,368 (67.8%) participants in the control group received catch-up vaccination at age 10–14 years. By December 2013, a total of 3,895 (10.2%) in the vaccination group and 3,898 (11.3%) in the control group were lost to follow-up. Information on PLC incidence and liver disease mortality were collected through linkage of all remaining cohort members to a well-established population-based tumor registry until December 31, 2013. Two cross-sectional surveys on HBV surface antigen (HBsAg) seroprevalence were conducted in 1996–2000 and 2008–2012. The participation rates of the two surveys were 57.5% (21,770) and 50.7% (17,204) in the vaccination group and 36.3% (12,184) and 58.6% (17,395) in the control group, respectively. Using intention-to-treat analysis, we found that the incidence rate of PLC and the mortality rates of severe end-stage liver diseases and infant fulminant hepatitis were significantly lower in the vaccination group than the control group with efficacies of 84% (95% CI 23%–97%), 70% (95% CI 15%–89%), and 69% (95% CI 34%–85%), respectively. The estimated efficacy of catch-up vaccination on HBsAg seroprevalence in early adulthood was 21% (95% CI 10%–30%), substantially weaker than that of the neonatal vaccination (72%, 95% CI 68%–75%). Receiving a booster at age 10–14 years decreased HBsAg seroprevalence if participants were born to HBsAg-positive mothers (hazard ratio [HR] = 0.68, 95% CI 0.47–0.97). Limitations to consider in interpreting the study results include the small number of individuals with PLC, participants lost to follow-up, and the large proportion of participants who did not provide serum samples at follow-up. Conclusions Neonatal HBV vaccination was found to significantly decrease HBsAg seroprevalence in childhood through young adulthood and subsequently reduce the risk of PLC and other liver diseases in young adults in rural China. The findings underscore the importance of neonatal HBV vaccination. Our results also suggest that an adolescence booster should be considered in individuals born to HBsAg-positive mothers and who have completed the HBV neonatal vaccination series. Please see later in the article for the Editors' Summary, Editors' Summary Background Hepatitis B is a life-threatening liver infection caused by the hepatitis B virus (HBV). HBV, which is transmitted through contact with the blood or other bodily fluids of an infected person, can cause both acute (short-term) and chronic (long-term) liver infections. Acute infections rarely cause any symptoms and more than 90% of adults who become infected with HBV (usually through sexual intercourse with an infected partner or through the use of contaminated needles) are virus-free within 6 months. However, in sub-Saharan Africa, East Asia, and other regions where HBV infection is common, HBV is usually transmitted from mother to child at birth or between individuals during early childhood and, unfortunately, most infants who are infected with HBV during the first year of life and many children who are infected before the age of 6 years develop a chronic HBV infection. Such infections can cause liver cancer, liver cirrhosis (scarring of the liver), and other fatal liver diseases. In addition, HBV infection around the time of birth can cause infant fulminant hepatitis, a rare but frequently fatal condition. Why Was This Study Done? HBV infections kill about 780,000 people worldwide annually but can be prevented by neonatal vaccination—immunization against HBV at birth. A vaccine against HBV became available in 1982 and many countries now include HBV vaccination at birth followed by additional vaccine doses during early childhood in their national vaccination programs. But, although HBV vaccination has greatly reduced the rate of chronic HBV infection, the protective efficacy of neonatal HBV vaccination against liver diseases has not been fully examined. Here, the researchers investigate how well neonatal HBV vaccination protects against primary liver cancer and other liver diseases by undertaking a 30-year follow-up of the Qidong Hepatitis B intervention Study (QHBIS). This cluster randomized controlled trial of neonatal HBV vaccination was conducted between 1983 and 1990 in Qidong County, a rural area in China with a high incidence of HBV-related primary liver cancer and other liver diseases. A cluster randomized controlled trial compares outcomes in groups of people (towns in this study) chosen at random to receive an intervention or a control treatment (here, vaccination or no vaccination; this study design was ethically acceptable during the 1980s when HBV vaccination was unavailable in rural China but would be unethical nowadays). What Did the Researchers Do and Find? The QHBIS assigned nearly 80,000 newborns to receive either a full course of HBV vaccinations (the vaccination group) or no vaccination (the control group); two-thirds of the control group participants received a catch-up vaccination at age 10–14 years. The researchers obtained data on how many trial participants developed primary liver cancer or died from a liver disease during the follow-up period from a population-based tumor registry. They also obtained information on HBsAg seroprevalence—the presence of HBsAg (an HBV surface protein) in the blood of the participants, an indicator of current HBV infection—from surveys undertaken in1996–2000 and 2008–2012. The researchers estimate that the protective efficacy of vaccination was 84% for primary liver cancer (vaccination reduced the incidence of liver cancer by 84%), 70% for death from liver diseases, and 69% for the incidence of infant fulminant hepatitis. Overall, the efficacy of catch-up vaccination on HBsAg seroprevalence in early adulthood was weak compared with neonatal vaccination (21% versus 72%). Notably, receiving a booster vaccination at age 10–14 years decreased HBsAg seroprevalence among participants who were born to HBsAg-positive mothers. What Do These Findings Mean? The small number of cases of primary liver cancer and other liver diseases observed during the 30-year follow-up, the length of follow-up, and the availability of incomplete data on seroprevalence all limit the accuracy of these findings. Nevertheless, these findings indicate that neonatal HBV vaccination greatly reduced HBsAg seroprevalence (an indicator of current HBV infection) in childhood and young adulthood and subsequently reduced the risk of liver cancer and other liver diseases in young adults. These findings therefore support the importance of neonatal HBV vaccination. In addition, they suggest that booster vaccination during adolescence might consolidate the efficacy of neonatal vaccination among individuals who were born to HBsAg-positive mothers, a suggestion that needs to be confirmed in randomized controlled trials before booster vaccines are introduced into vaccination programs. Additional Information Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001774. The World Health Organization provides a fact sheet about hepatitis B (available in several languages) and information about hepatitis B vaccination The World Hepatitis Alliance (an international not-for-profit, non-governmental organization) provides information about viral hepatitis, including some personal stories about hepatitis B from Bangladesh, Pakistan, the Philippines, and Malawi The UK National Health Service Choices website provides information about hepatitis B The not-for-profit British Liver Trust provides information about hepatitis B, including Hepatitis B: PATH B, an interactive educational resource designed to improve the lives of people living with chronic hepatitis B MedlinePlus provides links to other resources about hepatitis B (in English and Spanish) Information about the Qidong Hepatitis B intervention Study is available Chinese Center for Disease Control and Prevention provides links about hepatitis B prevention in Chinese

BACKGROUND: The generation of antibodies (anti-HBe) against hepatitis B virus (HBV) e antigen (HBeAg) often coincides with clinical remission in chronic HBV patients. We aimed to examine the effect of maternal anti-HBe in protection against HBV mother-to-child transmission (MTCT).METHODS: A total of 140 chronic HBV-infected pregnant women participated in this study. Before delivery, maternal HBV serological markers and HBV viral load were determined and anti-HBe titers were semi-quantified. Neonatal hepatitis B surface antigen (HBsAg) and HBV-DNA status were determined from cord blood. The children were followed to age 1-3 years.RESULTS: The HBV-DNA positive rate in cord blood was 75.61% (31/41) in those who were born to mothers with serum HBV-DNA >10(6) IU/ml, which was significantly higher than in those who were born to mothers with HBV-DNA 10(6) IU/ml had no detectable HBV-DNA in cord blood; anti-HBe was positive with a median titer of 10 (interquartile range 10-55). A total of 84 children who received hepatitis B immune globulin (HBIG) within 12h after birth and who completed three doses of recombinant HBV vaccination were followed to age 1-3 years (up to May 2014). All 56 children who were born to mothers with serum HBV-DNA levels 10(6) IU/ml acquired an HBsAg-positive status. However, none of the six children who were born to anti-HBe-positive/weak-positive mothers with serum HBV-DNA >10(6) IU/ml acquired an HBsAg-positive status.CONCLUSIONS: The presence of maternal anti-HBe is protective against HBV MTCT, independent of the maternal serum HBV viral load.

Neonatal vaccination against hepatitis B virus (HBV) infection was launched in the 1980s in Qidong, China, where HBV and hepatocellular carcinoma were highly prevalent. Presence of immune memory and immunity against HBV in adults needs to be clarified. From a cohort of 806 who received plasma-derived Hep-B-Vax as neonates and were consecutively followed at ages 5, 10, and 20 years, 402 twenty-four-year-old adults were recruited for booster test. Among them 4 (1%) were found to be HBsAg(+), 27 (6.7%) were HBsAg(-)anti-HBc(+), 121 (30.2%) were HBsAg(-)anti-HBc(-)anti-HBs(+), and 252 (62.4%) were HBsAg(-)anti-HBc(-)anti-HBs(-). Of them, 141 subjects with HBsAg(-)anti-HBc(-) were boosted with 10-μg recombinant HBV vaccine on day-0 and 1-month. The conversion rates of anti-HBs ≥ 10 mIU/ml on D10-12 and 1-month post-booster were 71.4% and 87.3% respectively in the vaccinees who were anti-HBs(+) at age 5, higher than in those who were anti-HBs(-) at age 5, 57.5% and 80.0% respectively, but no statistically significant. After the second dose of booster, all subjects with anti-HBs(+) at age 5 had anti-HBs500 mIU/ml. However, 6/40 subjects, with anti-HBs(-) at age 5, had anti-HBs10 mIU/ml, geometric mean concentration was 3.6 (95% CI 2.0-7.7). Of the subjects received booster, 44 subjects were determined the presence of T cell immunity on D10-12, 41 had HBsAg-specific T cells detectable, including 7/10 subjects whose anti-HBs were10 mIU/ml 10-12 days post-booster. Among 27 HBsAg(-)anti-HBc(+) subjects, 19 had detectable serum HBV-DNA, and an "a" epitope mutation was found in 1/5 HBV isolates. One subject who was anti-HBc(+) at age 20 converted into HBsAg(+) 4 years later. The adults received neonatal HBV vaccination had immune memory and immunity against HBV infection. However, 31.9% of neonatal HBV vaccinees who responded weakly at an early age might be susceptible to HBV infection after childhood.

Previous follow-up on our neonatal HB vaccination cohorts with 80,000 individuals in Qidong, China, showed significant protective efficacy of immunization against HBV infection in childhood. However, some vaccinees were found to be HBsAg negative, but anti-HBs positive and anti-HBc positive at age 10-11 years. To study this phenomenon, 2919 vaccinees at age 19-21 years were sampled from the cohort. HBsAg(-), anti-HBs(+) and anti-HBc(+) were found in 124/2919 (4.2%) of the vaccinees. HBV DNA was detectable in 81/106 sample sera by using nested PCR. The PreS-S regions of HBV were sequenced in 41 randomly sampled sera. All the HBV isolates were HBV genotype C. Twenty one isolates (21/41, 51.2%) were identical to an HBV isolated in this area (GU434374). Only 4/41 (9.8%) showed mutations at the "a" epitope and three of them were G145A. The other mutations were found outside of the "a" epitope. Most of the sera contained

Monocytes are circulating mononuclear phagocytes with a fundamental capacity to differentiate into macrophages. This differentiation can, in the presence of the right environmental cues, be re-directed instead to dendritic cells (DCs). Recent advances have been made in understanding the role of monocytes and their derivatives in presenting antigen to drive immune responses, and we review this topic herein. We briefly discuss the heterogeneity of monocytes in the blood and subsequently raise the possibility that one of the major monocyte phenotypes in the blood corresponds with a population of “blood DCs” previously proposed to drive T-independent antibody reactions in the spleen. Then we evaluate the role of monocytes in T-dependent immunity, considering their role in acquiring antigens for presentation prior to exiting the bloodstream and their ability to differentiate into macrophages versus antigen-presenting DCs. Finally, we review recent literature on the role of monocyte-derived cells in cross-presentation and discuss the possibility that monocyte-derived cells participate critically in processing antigen for cross-priming, even if they do not present that antigen to T cells themselves.

treatment-naive HIV/HCV coinfected patients in China across a broad spectrum of HCV genotypes. Methods: Population-basedNS3/4A sequencingwas completed for 826 HIV/HCV coinfected patients enrolled between 2004 and 2013, from 12 provinces across China. All patients were naive to antiretroviral treatment for HIV and any prior or investigational treatment for HCV. In-house primers for genotypes 1–6were used. NS3 sequences were aligned against reference sequences and mutations were manually identified in the following positions reported to confer resistance to HCV protease inhibitors: 36, 41, 43, 54, 55, 80, 109, 122, 132, 155, 156, 168, and 170. Findings: Overall, 81% (632/778) of all HCV sequences had at least one mutation associated with resistance to HCV protease inhibitors. Mutations were found in 4% (1/28) of genotype 1a, 44% (73/165) of genotype 1b, 100% (23/23) of genotype 2a, 100% (125/125) of genotype 3a, 100% (112/112) of genotype 3b, 99% (299/303) of genotype 6a, and none (0/22) of genotype 6n/u/v sequences. The Q80K mutation was present in 98% of genotype 6a sequences. Mutations with the potential to cause high-level decreased drug susceptibility are rare, occurring in only 0.8% of patients. Interpretation: The low frequency of high-level mutations associated with primary protease inhibitor drug resistance among most genotypes is encouraging, but the presence of theQ80Kmutation among patients with HCV genotype 6a is concerning given the association with decreased simeprevir efficacy in genotype 1a. Further phenotypic studies and clinical research are needed.

Background and Aims Primary hepatocellular carcinoma (HCC) is usually presented in inflamed fibrotic/cirrhotic liver with extensive lymphocyte infiltration. We examined the associations between the HCC early recurrence and alterations in serum levels of inflammatory cytokines. Methods A cohort of 105 HCC patients with chronic hepatitis B virus infection were included. Pre-therapy, we quantified their serum concentrations of Th1-, Th2-, Th17-, Treg-related, and other cytokines that have been reported to be associated with poor prognosis in human cancers. IL17-producing T-cells were generated in vitro from HCC patients and co-cultured with HCC cell lines separated by a 0.4 µM transwell. Results All the 105 cases of HCC patients had liver cirrhosis. The patients who suffered from HCC early recurrence had higher pre-therapy serum levels of IL17 and lower levels of IL10 than those who did not suffer from recurrence after curative hepatectomy. After adjustment for general tumor clinicopathological factors, elevated serum levels of IL17 (≥0.9 pg/ml) was found to be an independent risk factor for HCC early recurrence with a hazard ratio of 2.46 (95%CI 1.34–4.51). Patients with bigger tumors (>5 cm in diameter) and elevated serum levels of IL17 had the highest risk of early recurrence as compared to those with only one of these factors (P = 0.009) or without any (P

AIM: To evaluate the diagnostic value of glypican-3 (GPC3) in serum and liver for primary hepatocellular carcinoma (HCC). METHODS: Serum levels of GPC3 and α-fetoprotein (AFP) were measured in 75 patients with primary HCC and 32 patients with liver cirrhosis. Expression of GPC3 and AFP in 58 HCC and 12 cirrhotic specimens was detected with immunohistochemical staining. RESULTS: When the cut-off value of serum GPC3 was set at 300 ng/L, its sensitivity and specificity for HCC were 47.0% and 93.5%, respectively. Among the 14 patients with HCC at stage according to the Barcelona Clinic Liver Cancer staging system, the serum GPC3 level was higher than 300 ng/L in 50% (7/14) patients, the serum AFP level was not ≥ 400 μg/L in any patient. Combined serum AFP and GPC3 significantly increased the sensitivity to the diagnosis of HCC. The GPC3 expression was detected in cytoplasm of HCC cells but not in hepatocytes and bile ducts of benign tumors. Among the 58 HCC patients, the GPC3 was expressed in 100% (28/28) patients with their serum AFP level ≥ 400 μg/L, and in 90% (27/30) patients with their AFP level < 400 μg/L, respectively. The GPC3 was weakly or negatively expressed in all paracarcinomatous and cirrhotic tissue samples. AFP positive HCC cells were only found in 1 out of the 58 HCC patients. CONCLUSION: GPC3 protein is a sensitive and specific serum marker for diagnosis of early HCC. Its expression in liver tissues can be used to discriminate tumor cells from benign hepatic cells.