Yibo Ding

Associations of pri-miR-34b/c and pre-miR-196a2 Polymorphisms and Their Multiplicative Interactions with Hepatitis B Virus Mutations with Hepatocellular Carcinoma Risk

Background Genetic polymorphisms of pri-miR-34b/c and pre-miR-196a2 have been reported to be associated with the susceptibility to cancers. However, the effect of these polymorphisms and their interactions with hepatitis B virus (HBV) mutations on the development of hepatocellular carcinoma (HCC) remains largely unknown. We hypothesized that these polymorphisms might interact with the HBV mutations and play a role in hepatocarcinogenesis. Methods Pri-miR-34b/c rs4938723 (T>C) and pre-miR-196a2 rs11614913 (T>C) were genotyped in 3,325 subjects including 1,021 HBV-HCC patients using quantitative PCR. HBV mutations were determined by direct sequencing. Contributions of the polymorphisms and their multiplicative interactions with gender or HCC-related HBV mutations to HCC risk were assessed using multivariate regression analyses. Results rs4938723 CC genotype was significantly associated with HCC risk compared to HBV natural clearance subjects, adjusted for age and gender (adjusted odds ratio [AOR] = 2.01, 95% confidence interval [CI] = 1.16–3.49). rs4938723 variant genotypes in dominant model significantly increased HCC risk in women, compared to female healthy controls (AOR = 1.85, 95% CI = 1.20–2.84) or female HCC-free subjects (AOR = 1.62, 95% CI = 1.14–2.31). rs4938723 CC genotype and rs11614913 TC genotype were significantly associated with increased frequencies of the HCC-related HBV mutations T1674C/G and G1896A, respectively. rs11614913 was not significantly associated with HCC risk, but its CC genotype significantly enhanced the effect of rs4938723 in women. In multivariate regression analyses, rs4938723 in dominant model increased HCC risk (AOR = 1.62, 95% CI = 1.05–2.49), whereas its multiplicative interaction with C1730G, a HBV mutation inversely associated with HCC risk, reduced HCC risk (AOR = 0.34, 95% CI = 0.15–0.81); rs11614913 strengthened the G1896A effect but attenuated the A3120G/T effect on HCC risk. Conclusions rs4938723 might be a genetic risk factor of HCC but its effect on HCC is significantly affected by the HBV mutations. rs11614913 might not be a HCC susceptible factor but it might affect the effects of the HBV mutations or rs4938723 on HCC risk.

Periostin expression in intra-tumoral stromal cells is prognostic and predictive for colorectal carcinoma via creating a cancer-supportive niche

Periostin (POSTN) expression in cancer cells and circulation has been related to poor prognosis of colorectal carcinoma (CRC). However, the role of POSTN expressed in intra-tumoral stroma on CRC progression remains largely unknown. This study enrolled 1098 CRC patients who received surgical treatment in Shanghai and Guangzhou, Mainland China. In Shanghai cohort, immunohistochemistry score of stromal POSTN expression increased consecutively from adjacent mucosa, primary CRC tissues, to metastatic CRC tissues (P < 0.001), while medium- and high-stromal POSTN expression, rather than epithelial POSTN expression, independently predicted unfavorable prognoses of CRC, adjusted for covariates including TNM stage and postoperative chemotherapy in multivariate Cox models. The results in Shanghai cohort were faithfully replicated in Guangzhou cohort. Stromal POSTN expression dose-dependently predicted an unfavorable prognosis of stage III CRC patients with postoperative chemotherapy in both cohorts. POSTN derived from colonic fibroblasts or recombinant POSTN significantly promoted proliferation, anchorage independent growth, invasion, and chemo-resistance of CRC cells; whereas these effects were counteracted via targeting to PI3K/Akt or Wnt/β-catenin signaling pathway. CRC cell RKO-derived factor(s) significantly induced POSTN production in colonic fibroblasts and autocrine POSTN promoted proliferation, migration, and anchorage independent growth of fibroblasts. Conclusively, stromal POSTN is prognostic and predictive for CRC via creating a niche to facilitate cancer progression. Targeting POSTN-induced signaling pathways may be therapeutic options for metastatic or chemoresistant CRC.

Serum miRNAs as predictive and preventive biomarker for pre-clinical hepatocellular carcinoma.

The extremely poor prognosis of patients with symptomatic hepatocellular carcinoma (HCC) diagnosed clinically at advanced stages suggests an urgent need for biomarkers that can be used for prospective surveillance and pre-clinical screening for early presence of pre-malignant lesions and tumors. In a retrospective longitudinal phase 3 biomarker study in seven medical centers of China, time-series and 6 months interval-serum samples were collected from chronic hepatitis B virus infected (CHB) patient cohorts at the pre-malignant or pre-clinical stages (average 6 months prior to clinical diagnosis) and CHB patients that did not develop cancer, and circulating miRNAs measured. A set of serum miRNAs including miR-193a-3p, miR-369-5p, miR-672, miR-429 and let-7i* were identified in pre-clinical HCC patients and have the potential to screen for CHB patients at high risk to develop HCC 6-12 months after miRNAs measurement. These circulating miRNAs combined with the conventional screening tools using α-fetoprotein and ultrasound, may have great promise for the prediction and prevention of HCC in high-risk populations.

Apodemus agrarius is a potential natural host of severe fever with thrombocytopenia syndrome (SFTS)—causing novel bunyavirus

BACKGROUND Severe fever with thrombocytopenia syndrome (SFTS) is a tick-borne, novel bunyavirus-caused emerging infectious disease. It becomes a threat to public health due to its high fatality rate. OBJECTIVE To clarify the epidemiological characteristics of SFTS and natural host(s) of SFTS-causing virus (SFTSV) in East China. STUDY DESIGN Serum antibody against SFTSV in 496 healthy villagers was examined by ELISA. SFTSV in acute sera of SFTS cases and lung tissues of house and field mouse/rats were identified using quantitative RT-PCR, cell culture, and sequencing. RESULTS A total of 22 laboratory-confirmed SFTS cases were diagnosed between 2012 and 2014, of which 5 (22.7%) reported a history of tick-bites. The seroprevalance of SFTSV antibody was 10.5% in healthy villagers. SFTSV genomic RNAs were identified in 2 of 8 Apodemus agrarius but not in Rattus norvegicus (n=40) and Rattus losea (n=4). The 3 segments of SFTSV from 11 SFTS cases and 2 A. agrarius were successfully sequenced. Phylogenetic analyses indicated that at least 3 different SFTSV strains (inland-type, Ningbo-native-type, and their reassortant-type) were present in Ningbo. The 3 segments of the 2 SFTSV isolates from A. agrarius shared great sequence homologies to those isolated from the patients living in nearby villages. CONCLUSION The present study indicated that A. agrarius might be a natural host of SFTSV in East China.

The role of hazard vulnerability assessments in disaster preparedness and prevention in China.

China is prone to disasters and escalating disaster losses. Effective disaster mitigation is the foundation for efficient disaster response and rescue and for reducing the degree of hazardous impacts on the population. Vulnerability refers to the population’s capacity to anticipate, cope with, and recover from the impact of a hazardous event. A hazard vulnerability assessment (HVA) systematically evaluates the damage that could be caused by a potential disaster, the severity of the impact, and the available medical resources during a disaster to reduce population vulnerability and increase the capacity to cope with disasters. In this article, we summarized HVA team membership, content (disaster identification, probability and consequences), and methods and procedures for an HVA that can be tailored to China’s needs. We further discussed the role of epidemiology in an HVA. Disaster epidemiology studies the underlying causes of disasters to achieve effective disaster prevention and reduction. In addition, we made several recommendations that are already in practice in developed countries, such as the U.S., for future implementation in China and other developing countries. An effective HVA plan is crucial for successful disaster preparedness, response, and recovery.

A genetic polymorphism affects the risk and prognosis of renal cell carcinoma: Association with follistatin-like protein 1 expression

Few single nucleotide polymorphisms (SNPs) associated with the risk of renal cell carcinoma (RCC) have been identified, yet genetic predisposition contributes significantly to this malignancy. We previously showed that follistatin-like 1 (FSTL1) was significantly down-regulated in clear cell RCC (ccRCC), in particular metastatic ccRCC. In the present study, we systemically investigated the associations of the 6 SNPs within FSTL1-coding genomic region with RCC risk and postoperative prognosis. Age- and gender-matched case-control study (417 vs 855) indicated that rs1259293 variant genotype CC was significantly associated with an increased risk of RCC, with an odds ratio of 2.004 (95% confidence internal [CI] = 1.190–3.375). Multivariate Cox regression analysis in 309 of 417 cases showed that rs1259293 genotype (CC vs TT + CT) independently predicted an unfavorable prognosis, with a hazard ratio of 2.531 (95% CI = 1.052–6.086). Expression of FSTL1 was significantly higher in adjacent renal tissues than in tumors, and significantly higher in the tissues with rs1259293 TT genotype than in those with rs1259293 TC+CC genotypes. rs1259293 C allele might generate a CTCF binding site that blocks trans-activation of FSTL1 expression. Our results indicate that rs1259293 is associated with an increased risk and unfavorable postoperative prognosis of RCC, possibly by down-regulating FSTL1 expression in renal tissues.

Hepatitis B Virus Combo Mutations Improve the Prediction and Active Prophylaxis of Hepatocellular Carcinoma: A Clinic-Based Cohort Study

We aimed to evaluate whether hepatitis B virus (HBV) mutations at the core promoter region could improve the prediction and specific prophylaxis of hepatocellular carcinoma (HCC) in chronic HBV-infected patients. A total of 2,114 HBV-infected patients enrolled between August 1998 and December 2007 were followed-up for 18,406 person-years. Of those, 612 received ≥48 week treatments with nucleos(t)ide analogue (NA) and/or IFNα. Baseline HBV mutations were identified by sequencing. Propensity score matching was applied to reduce baseline differences between antiviral and control cohorts. Multivariate Cox regression analyses, including baseline characteristics of 2,114 patients, showed that age, male, cirrhosis, and HBV mutations (C1653T, T1753V, and A1762T/G1764A) independently increased HCC risk. In control patients carrying A1762T/G1764A, addition of C1653T and/or T1753V significantly increased HCC risk (HR, 1.57; P = 0.038); combo mutations with C1653T, T1753V, and A1762T/G1764A improved the validity of HCC prediction by age, male, and cirrhosis (P = 0.002). In the matched cohorts, antiviral treatment reduced HCC incidence (13.90/1,000 vs. 7.70/1,000 person-years, P = 0.005); NA treatment for ≥60 months was required for the prophylaxis of HCC in cirrhotic patients (P = 0.03); antiviral treatment reduced HCC risk in patients carrying A1762T/G1764A (HR, 0.40; P = 0.002) or C1653T (HR, 0.45; P = 0.04) and in those without T1753V (HR, 0.42; P = 0.005), but could not reduce HCC risk in patients without A1762T/G1764A or C1653T and in those with T1753V. In summary, HBV mutation A1762T/G1764A, C1653T, and T1753V in combination improve HCC prediction in HBV-infected patients. To prevent HCC, patients infected with HBV carrying A1762T/G1764A or C1653T, but not T1753V, should be given priority of receiving antiviral treatments. Cancer Prev Res; 8(10); 978–88. ©2015 AACR.

Cancer mortality trends in an industrial district of Shanghai, China, from 1974 to 2014, and projections to 2029

We aimed to characterize the trends and projections of cancer mortalities in Yangpu, an industry restructuring district of Shanghai, China. With high-quality data from the death registration system, the authors analyzed the trends in cancer mortalities during 1974-2014 and their relationship with pollution control and socioeconomic improvements. Cancer burden was projected into 2029. During 1974-2014, cancer death accounted for 28.80% of all-cause death. The 5 leading causes of cancer death were cancers of the lung & bronchus, stomach, liver, colon & rectum, and esophagus. Age-standardized mortality of all cancers was higher in men than in women (153.1/105 vs. 88.8/105, p<0.001) and increased from 1974 to 1991 and decreased thereafter. The mortalities of cancers of the larynx, bladder, liver, nasopharynx, lung & bronchus, esophagus, lip oral & pharynx, stomach, kidney, and lymphoma were significantly higher in men than in women. Age-standardized mortalities of cancers of the esophagus, stomach, leukemia, female nasopharynx, female bladder, liver, and bone decreased especially after the 1990s, those of the colon & rectum, kidney, prostate, pancreas, breast, gallbladder, and ovary increased significantly. Lung cancer, breast cancer, colorectal cancer, and pancreas cancer in women and lung cancer, colorectal cancer, prostate cancer, and stomach cancer in men will be the leading causes of cancer death in 2025-2029. Cancer-caused life loss kept increasing since 2000. Conclusively, cancers associated with pollutions and infection decreased, especially after the 1990s, while those related to metabolic syndrome increased. These trends are related to closedown of polluted industries in the 1980s and lifestyle changes.

Strategy and technology to prevent hospital-acquired infections: Lessons from SARS, Ebola, and MERS in Asia and West Africa

Hospital-acquired infections (HAIs) are serious problems for healthcare systems, especially in developing countries where public health infrastructure and technology for infection preventions remain undeveloped. Here, we characterized how strategy and technology could be mobilized to improve the effectiveness of infection prevention and control in hospitals during the outbreaks of Ebola, Middle East respiratory syndrome (MERS), and severe acute respiratory syndrome (SARS) in Asia and West Africa. Published literature on the hospital-borne outbreaks of SARS, Ebola, and MERS in Asia and West Africa was comprehensively reviewed. The results showed that healthcare systems and hospital management in affected healthcare facilities had poor strategies and inadequate technologies and human resources for the prevention and control of HAIs, which led to increased morbidity, mortality, and unnecessary costs. We recommend that governments worldwide enforce disaster risk management, even when no outbreaks are imminent. Quarantine and ventilation functions should be taken into consideration in architectural design of hospitals and healthcare facilities. We also recommend that health authorities invest in training healthcare workers for disease outbreak response, as their preparedness is essential to reducing disaster risk.

Hepatitis B virus mutations during mother-to-children transmission: a preliminary study

Objective To explore the mutations of hepatocellular carcinoma(HCC)-related hepatitis B virus(HBV)during mother-to-child transmission,so as to provide theoretic evidence for prophylaxis of HCC from the very beginning.Methods A total of 413 HBsAg-positive mothers and their newborns were enrolled in this study.Serum HBV DNA levels in maternal peripheral blood and cord blood of the newborns were measured using real-time quantitative PCR.Nested PCR together with cloning and sequencing methods were applied to examine the HCC-related HBV mutations in the preS and basal core promoter regions of HBV genome.All the newborns received standard HBV vaccination.Of the 413 newborns,104were successfully followed-up 7 months after birth,and the HBV mutations were examined if their circulating HBV DNA was detectable.Results Of the 413 newborns,41(9.9%)had HBV DNA level103 copies/mL in their cord blood.Four(3.8%)of the 104 newborns who were successfully followed up had circulating HBV DNA level103 copies/mL 7months after birth.Compared to mothers without HBV trans-placental transmission,those with HBV trans-placental transmission had no increase in HBV mutations in the basal core promoter region.However,the viral mutations containing T2898G/C,C3000 T,C3116T,T31 C,and T52 Cin the preS region of HBV subgenotype C2 significantly increased the risk of HBV trans-placental transmission(P0.05).The frequencies of the HCC-related mutations in the preS and basal core promoter regions of HBV genome were not significantly different between maternal peripheral blood and the cord blood of the newborns.Importantly,the HCC-related mutations were rarely found in the HBV-positive infants at 7months after birth.Conclusion The HBV mutations in the preS region of HBV subgenotype C2 may affect the trans-placental transmission of HBV.However,the quasispecies of HCC-related HBV mutants have no advantage in causing chronic HBV infection in infants.The HBV mutants which can promote HCC are selected during the long term chronic infection.