Publications by authors named "Guangwen Cao"

116 Publications

Nucleotide variants in hepatitis B virus preS region predict the recurrence of hepatocellular carcinoma.

Aging (Albany NY) 2021 Sep 17;13(18):22256-22275. Epub 2021 Sep 17.

Department of Epidemiology, Faculty of Navy Medicine, Second Military Medical University, Shanghai, China.

Background: Hepatitis B virus (HBV) variants in the preS region have been associated with hepatocellular carcinoma (HCC). However, the effect of the preS variants on HCC prognosis remains largely unknown. We aimed to identify the preS variants that reliably predict postoperative prognosis in HCC.

Methods: RNA-seq data of 203 HCC patients retrieved from public database were screened for the preS variants related to HCC prognosis. The variants in the sera and tumors were then validated in our prospective cohort enrolling 103 HBV-associated HCC patients.

Results: By analyzing prognosis-related gene sets in the RNA-seq data, 12 HBV preS variants were associated with HCC recurrence. Of those, G40C and C147T in the sera predicted an unfavorable recurrence-free survival in our cohort (hazard ratio [HR]=2.18, 95% confidence interval [CI]=1.37-3.47, =0.001 for G40C; HR=1.84, 95% CI=1.15-2.92, =0.012 for C147T). G40C and C147T were significantly associated with microscopic vascular invasion, larger tumor size, and abnormal liver function. Multivariate Cox regression analysis showed that G40C significantly increased the risk of HCC recurrence in patients with postoperative antiviral treatment. The HCC prognosis-prediction model consisting of α-fetoprotein and G40C in the sera achieved the best performance (sensitivity=0.80, specificity=0.70, and area under the curve=0.79). Functional analysis indicated that these two variants were associated with cell proliferation, chromosome instability, carcinogenesis, metastasis, and anticancer drug resistance.

Conclusions: G40C and C147T are serological biomarkers for HCC prognosis and the prognostic model consisting of serological α-fetoprotein and G40C achieved the best performance in predicting postoperative prognosis.
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http://dx.doi.org/10.18632/aging.203531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8507287PMC
September 2021

Glucose Intolerance and Cancer Risk: A Community-Based Prospective Cohort Study in Shanghai, China.

Front Oncol 2021 30;11:726672. Epub 2021 Aug 30.

Department of Epidemiology, Second Military Medical University, Shanghai, China.

Background: Cancer becomes the leading cause of premature death in China. Primary objective of this study was to determine the major risk factors especially glucose intolerance for cancer prophylaxis.

Methods: A cluster sampling method was applied to enroll 10,657 community-based adults aged 15-92 years in Shanghai, China in 2013. A structured questionnaire and physical examination were applied in baseline survey. Prediabetes was diagnosed using 75-g oral glucose tolerance test. After excluding 1433 subjects including 224 diagnosed with cancer before and 1 year after baseline survey, the remaining 9,224 subjects were followed-up to December 31, 2020.

Results: A total of 502 new cancer cases were diagnosed. The cancer incidence was 10.29, 9.20, and 5.95/1,000 person-years in diabetes patients, those with prediabetes, and healthy participants, respectively (<0.001). The multivariate Cox regression analysis indicated that age, prediabetes and diabetes, were associated with an increased risk of cancer in those <65 years, the hazard ratios (95% confidence interval) for prediabetes and diabetes were, 1.49(1.09-2.02) and 1.51(1.12-2.02), respectively. Glucose intolerance (prediabetes and diabetes) were associated with increased risks of stomach cancer, colorectal cancer, and kidney cancer in those <65 years. Anti-diabetic medications reduced the risk of cancer caused by diabetes. The multivariate Cox analysis showed that age, male, <9 years of education, and current smoking were associated with increased risks of cancer in those ≥65 years independently.

Conclusions: Glucose intolerance is the prominent cancer risk factor in adults <65 years. Lifestyle intervention and medications to treat glucose intolerance help prevent cancer in this population.
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http://dx.doi.org/10.3389/fonc.2021.726672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8435720PMC
August 2021

Verification of a multi-function closed maze for the detection of affective disorder and spatial cognitive impairment in post-weaning socially isolated rats.

Neurosci Lett 2021 10 19;763:136192. Epub 2021 Aug 19.

Shenyang Medical College, PR China; Key Laboratory of Behavioral and Cognitive Neuroscience of Liaoning Province, Shenyang Medical Colleges, PR China. Electronic address:

Objective: To verify a behavioral device for the detection of learning, memory, and affective disorders in post-weaning socially isolated rats.

Methods: We tested the behavioral changes in post-weaning socially isolated rats using a multi-function closed maze, a self-developed behavioral device, against the classical mood disorder detection method, the IntelliCage system and Morris water maze.

Results: In the multifunctional closed maze experiment, the spatial learning and memory ability of post-weaning socially isolated rats decreased, which was consistent with the results of the water maze and IntelliCage system. Furthermore, the behavioral changes in the post-weaning socially isolated rats in the multi-function closed maze test were the same as those of the forced swimming and open field tests, indicating that the rats had depression- and anxiety-like behaviors.

Conclusion: A multi-function closed maze can detect emotional changes, spatial learning ability, and memory ability.
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http://dx.doi.org/10.1016/j.neulet.2021.136192DOI Listing
October 2021

Characterization of SARS-CoV-2 worldwide transmission based on evolutionary dynamics and specific viral mutations in the spike protein.

Infect Dis Poverty 2021 Aug 21;10(1):112. Epub 2021 Aug 21.

Department of Epidemiology, Second Military Medical University, 800 Xiangyin Road, Shanghai, 200433, China.

Background: The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) is pandemic. However, the origins and global transmission pattern of SARS-CoV-2 remain largely unknown. We aimed to characterize the origination and transmission of SARS-CoV-2 based on evolutionary dynamics.

Methods: Using the full-length sequences of SARS-CoV-2 with intact geographic, demographic, and temporal information worldwide from the GISAID database during 26 December 2019 and 30 November 2020, we constructed the transmission tree to depict the evolutionary process by the R package "outbreaker". The affinity of the mutated receptor-binding region of the spike protein to angiotensin-converting enzyme 2 (ACE2) was predicted using mCSM-PPI2 software. Viral infectivity and antigenicity were tested in ACE2-transfected HEK293T cells by pseudovirus transfection and neutralizing antibody test.

Results: From 26 December 2019 to 8 March 2020, early stage of the COVID-19 pandemic, SARS-CoV-2 strains identified worldwide were mainly composed of three clusters: the Europe-based cluster including two USA-based sub-clusters; the Asia-based cluster including isolates in China, Japan, the USA, Singapore, Australia, Malaysia, and Italy; and the USA-based cluster. The SARS-CoV-2 strains identified in the USA formed four independent clades while those identified in China formed one clade. After 8 March 2020, the clusters of SARS-CoV-2 strains tended to be independent and became "pure" in each of the major countries. Twenty-two of 60 mutations in the receptor-binding domain of the spike protein were predicted to increase the binding affinity of SARS-CoV-2 to ACE2. Of all predicted mutants, the number of E484K was the largest one with 86 585 sequences, followed by S477N with 55 442 sequences worldwide. In more than ten countries, the frequencies of the isolates with E484K and S477N increased significantly. V367F and N354D mutations increased the infectivity of SARS-CoV-2 pseudoviruses (P < 0.001). SARS-CoV-2 with V367F was more sensitive to the S1-targeting neutralizing antibody than the wild-type counterpart (P < 0.001).

Conclusions: SARS-CoV-2 strains might have originated in several countries simultaneously under certain evolutionary pressure. Travel restrictions might cause location-specific SARS-CoV-2 clustering. The SARS-CoV-2 evolution appears to facilitate its transmission via altering the affinity to ACE2 or immune evasion.
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http://dx.doi.org/10.1186/s40249-021-00895-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8379592PMC
August 2021

Trends in cancer mortality in China from 2004 to 2018: A nationwide longitudinal study.

Cancer Commun (Lond) 2021 Oct 12;41(10):1024-1036. Epub 2021 Jul 12.

Shanghai East Hospital, Key Laboratory of Arrhythmias, Ministry of Education, Tongji University School of Medicine, Tongji University, Shanghai, 200120, P. R. China.

Background: The long-term trend in cancer death in a rapidly developing country provides information for cancer prophylaxis. Here, we aimed to identify the trends in cancer mortality in China during the 2004-2018 period.

Methods: Using raw data from the national mortality surveillance system of China, we assessed the mortalities of all cancer and site-specific cancers during the 2004-2018 period. The participants were divided into three age groups: ≥65 years, 40-64 years, and ≤39 years. Changing trends in cancer death by gender, residency, and tumor location were estimated using fitting joinpoint models to log-transformed crude mortality rates (CMRs) and age-standardized mortality rates (ASMRs).

Results: Cancer death accounted for 24% of all-cause of death in China during 2014-2018. The CMR of all cancer was 150.0 per 100,000 persons. Cancer was the leading cause of death in the population <65 years. The six major cancer types (lung/bronchus cancer, liver cancer, stomach cancer, esophagus cancer, colorectal cancer, and pancreas cancer) accounted for 75.85% of all cancer deaths. The CMR of all cancer increased while the ASMR decreased during 2014-2018 (P < 0.001). Lung/bronchus cancer and liver cancer were the leading causes of cancer death in the population <65 years, accounting for 45.31% (CMR) and 44.35% (ASMR) of all cancer death, respectively. The ASMR of liver cancer was higher in the 40-64 years population than in the ≥65 years population, in contrast to the other five major cancers. The ASMRs of liver cancer, stomach cancer, and esophagus cancer decreased although they were higher in rural residents than in urban residents; the ASMRs of lung/bronchus cancer, colorectal cancer, and pancreas cancer increased in rural residents although they were higher in urban residents than in rural residents during 2014-2018.

Conclusion: Although the ASMR of all cancer decreased in China during 2004-2018, lung/bronchus cancer and liver cancer remained the leading causes of cancer-related premature death. Lung/bronchus cancer, colorectal cancer, and pancreas cancer increased in rural residents.
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http://dx.doi.org/10.1002/cac2.12195DOI Listing
October 2021

Epidemiological feature, viral shedding, and antibody seroconversion among asymptomatic SARS-CoV-2 carriers and symptomatic/presymptomatic COVID-19 patients.

J Infect Public Health 2021 Jul 27;14(7):845-851. Epub 2021 May 27.

Department of Epidemiology, Second Military Medical University, Shanghai 200433, China. Electronic address:

Background: Novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is pandemic. However, data concerning the epidemiological features, viral shedding, and antibody dynamics between asymptomatic SARS-CoV-2 carriers and COVID-19 patients remain controversial.

Methods: We enrolled 193 SARS-CoV-2 infected subjects in Ningbo and Zhoushan, Zhejiang, China, from January 21 to March 6, 2020. All subjects were followed up to monitor the dynamics of serum antibody immunoglobulin M (IgM) and IgG against SARS-CoV-2 using colloidal gold-labeled and enzyme-linked immunosorbent assays.

Results: Of those, 31 were asymptomatic SARS-CoV-2 carriers, 148 symptomatic COVID-19 patients, and 14 presymptomatic COVID-19 patients. Compared to symptomatic COVID-19 patients, asymptomatic carriers were younger and had higher levels of white blood cell and lymphocyte, lower level of C-reactive protein, and shorter viral shedding duration. Conversion of IgM from positive to negative was shorter in asymptomatic carriers than in COVID-19 patients (7.5 vs. 25.5 days, P = 0.030). The proportion of those persistently seropositive for IgG against SARS-CoV-2 was higher in COVID-19 patients than in asymptomatic carriers (66.1% vs. 33.3%, P = 0.037). Viral load was higher in symptomatic patients than presymptomatic patients (P = 0.003) and asymptomatic carriers (P = 0.004). Viral shedding duration was longer in presymptomatic COVID-19 patients than in asymptomatic carriers (48.0 vs. 24.0 days, P = 0.002). Asymptomatic carriers acquired infection more from intra-familial transmission than did COVID-19 patients (89.0% vs. 61.0%, P = 0.028). In 4 familial clusters of SARS-CoV-2 infection, asymptomatic carriers were mainly children and young adults while severe COVID-19 was mainly found in family members older than 60 years with comorbidities.

Conclusion: Asymptomatic carriers might have a higher antiviral immunity to clear SARS-CoV-2 than symptomatic COVID-19 patients and this antiviral immunity should be contributable to innate and adaptive cellular immunity rather than humoral immunity. The severity of COVID-19 is associated with older age and comorbidities in familial clustering cases.
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http://dx.doi.org/10.1016/j.jiph.2021.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154191PMC
July 2021

Large-scale analysis of 2,152 Ig-seq datasets reveals key features of B cell biology and the antibody repertoire.

Cell Rep 2021 May;35(6):109110

Department of Epidemiology, Second Military Medical University, 800 Xiangyin Rd., Shanghai 200433, China. Electronic address:

Antibody repertoire sequencing enables researchers to acquire millions of B cell receptors and investigate these molecules at the single-nucleotide level. This power and resolution in studying humoral responses have led to its wide applications. However, most of these studies were conducted with a limited number of samples. Given the extraordinary diversity, assessment of these key features with a large sample set is demanded. Thus, we collect and systematically analyze 2,152 high-quality heavy-chain antibody repertoires. Our study reveals that 52 core variable genes universally contribute to more than 99% of each individual's repertoire; a distal interspersed preferences characterize V gene recombination; the number of public clones between two repertoires follows a linear model, and the positive selection dominates at RGYW motif in somatic hypermutations. Thus, this population-level analysis resolves some critical features of the antibody repertoire and may have significant value to the large cadre of scientists.
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http://dx.doi.org/10.1016/j.celrep.2021.109110DOI Listing
May 2021

Genome-wide analysis identifies critical DNA methylations within NTRKs genes in colorectal cancer.

J Transl Med 2021 02 16;19(1):73. Epub 2021 Feb 16.

Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.

Background: Neurotrophic tropomyosin receptor kinases (NTRKs) are a gene family function as oncogene or tumor suppressor gene in distinct cancers. We aimed to investigate the methylation and expression profiles and prognostic value of NTRKs gene in colorectal cancer (CRC).

Methods: An analysis of DNA methylation and expression profiles in CRC patients was performed to explore the critical methylations within NTRKs genes. The methylation marker was validated in a retrospectively collected cohort of 229 CRC patients and tested in other tumor types from TCGA. DNA methylation status was determined by quantitative methylation-specific PCR (QMSP).

Results: The profiles in six CRC cohorts showed that NTRKs gene promoter was more frequently methylated in CRC compared to normal mucosa, which was associated with suppressed gene expression. We identified a specific methylated region within NTRK3 promoter targeted by cg27034819 and cg11525479 that best predicted survival outcome in CRC. NTRK3 promoter methylation showed independently predictive value for survival outcome in the validation cohort (P = 0.004, HR 2.688, 95% CI [1.355, 5.333]). Based on this, a nomogram predicting survival outcome was developed with a C-index of 0.705. Furthermore, the addition of NTRK3 promoter methylation improved the performance of currently-used prognostic model (AIC: 516.49 vs 513.91; LR: 39.06 vs 43.64, P = 0.032). Finally, NTRK3 promoter methylation also predicted survival in other tumors, including pancreatic cancer, glioblastoma and stomach adenocarcinoma.

Conclusions: This study highlights the essential value of NTRK3 methylation in prognostic evaluation and the potential to improve current prognostic models in CRC and other tumors.
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http://dx.doi.org/10.1186/s12967-021-02740-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885252PMC
February 2021

Compartmentalized evolution of hepatitis B virus contributes differently to the prognosis of hepatocellular carcinoma.

Carcinogenesis 2021 04;42(3):461-470

Department of Epidemiology, Faculty of Navy Medicine, Second Military Medical University, 8 Panshan Rd, Yangpu District, Shanghai 200433, China.

Serum hepatitis B virus (HBV) mutations can predict hepatocellular carcinoma (HCC) occurrence. We aimed to clarify if HBV evolves synchronously in the sera, adjacent liver and tumors and predict HCC prognosis equally. A total of 203 HBV-positive HCC patients with radical hepatectomy in Shanghai, China, during 2011-15 were enrolled in this prospective study. Quasispecies complexity (QC) in HBV core promoter region was assessed using clone-based sequencing. We performed RNA sequencing on tumors and paired adjacent tissues of another 15 HCC patients and analyzed it with three public data sets containing 127 samples. HBV QC was positively correlated to APOBEC3s' expression level (r = 0.28, P < 0.001), higher in the adjacent tissues than in the tumors (P = 6.50e-3), and higher in early tumors than in advanced tumors (P = 0.039). The evolutionary distance between the sera-derived HBV strains and the tumor-derived ones was significantly longer than that between the sera-derived ones and the adjacent tissue-derived ones (P < 0.001). Multivariate Cox regression analyses indicated that high HBV QC in the sera predicted an unfavorable overall survival (P = 0.002) and recurrence-free survival (RFS; P = 0.004) in HCC, whereas, in the tumors, it predicted a favorable RFS (P < 0.001). APOBECs-related HBV mutations, including G1764A, were more frequent in the sera than in the adjacent tissues. High-frequent A1762T/G1764A in the sera predicted an unfavorable RFS (P < 0.001), whereas, in the tumors, it predicted a favorable RFS (P = 0.035). In conclusion, HBV evolves more advanced in the sera than in the tumors. HBV QC and A1762T/G1764A in the sera and tumors have contrary prognostic effects in HCC.
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http://dx.doi.org/10.1093/carcin/bgaa127DOI Listing
April 2021

Epigenetic Inactivation of α-Internexin Accelerates Microtubule Polymerization in Colorectal Cancer.

Cancer Res 2020 12 13;80(23):5203-5215. Epub 2020 Oct 13.

Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.

DNA methylation contributes to malignant transformation, but little is known about how the methylation drives colorectal cancer evolution at the early stages. Here we identify aberrant INA (α-internexin) gene methylation in colon adenoma and adenocarcinoma by filtering data obtained from a genome-wide screen of methylated genes. The gene encoding INA, a type IV intermediate filament, was frequently hypermethylated in CpG islands located in the promoter region. This hypermethylation preferentially occurred in large tumors and was a prognostic marker for poor overall survival in patients with colorectal cancer. This type of epigenetic alteration silenced INA expression in both adenoma and adenocarcinoma tissues. Gene silencing of INA in colorectal cancer cells increased cell proliferation, migration, and invasion. Restored INA expression blocked migration and invasion and reduced lung metastasis . Mechanistically, INA directly inhibited microtubule polymerization and decreased intracellular microtubule plus-end assembly rates. A peptide array screen surveying the tubulin-binding sites in INA identified a tubulin-binding motif located in the N-terminal head domain that plays a tumor-suppressive role by binding to unpolymerized tubulins and impeding microtubule polymerization. Thus, epigenetic inactivation of INA is an intermediate filament reorganization event that is essential to accelerate microtubule polymerization in the early stages of colorectal cancer. SIGNIFICANCE: This work provides insight into the epigenetic inactivation of INA, a novel identified tumor suppressor, which increases microtubule polymerization during colorectal cancer progression.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1590DOI Listing
December 2020

Associations of socioeconomic factors with cause-specific Mortality and burden of cardiovascular diseases: findings from the vital registration in urban Shanghai, China, during 1974-2015.

BMC Public Health 2020 Aug 26;20(1):1291. Epub 2020 Aug 26.

Shanghai East Hospital, Key Laboratory of Arrhythmias, Ministry of Education, Tongji University School of Medicine, Tongji University, Shanghai, 200120, China.

Background: Cardiovascular disease (CVD) is the leading cause of mortality worldwide. The effect of socioeconomic factors on cause-specific mortality and burden of CVD is rarely evaluated in low- and middle-income countries, especially in a rapidly changing society.

Methods: Original data were derived from the vital registration system in Yangpu, a representative, population-stable district of urban Shanghai, China, during 1974-2015. Temporal trends for the mortality rates and burden of CVD during 1974-2015 were evaluated using Joinpoint Regression Software. The burden was evaluated using age-standardized person years of life loss per 100,000 persons (SPYLLs). Age-sex-specific CVD mortality rates were predicted by using age-period-cohort Poisson regression model.

Results: A total of 101,822 CVD death occurred during 1974-2015, accounting for 36.95% of total death. Hemorrhagic stroke, ischemic heart disease, and ischemic stroke were the 3 leading causes of CVD death. The age-standardized CVD mortality decreased from 144.5/100,000 to 100.7/100,000 in the residents (average annual percentage change [AAPC] -1.0, 95% confidence interval [CI] -1.7 to - 0.2), which was mainly contributed by women (AAPC -1.3, 95% CI - 2.0 to - 0.7), not by men. Hemorrhagic stroke, the major CVD death in the mid-aged population, decreased dramatically after 1991. The crude mortality of ischemic heart disease kept increasing but its age-adjusted mortality decreased continually after 1997. SPYLLs of CVD death increased from 1974 to 1986 (AAPC 2.1, 95% CI 0.4 to 3.8) and decreased after 1986 (AAPC 1.8, 95% CI - 2.3 to - 1.3). These changes were in concert with the implementation of policies including extended medical insurance coverage, pollution control, active prophylaxis of CVD including lifestyle promotion, and national health programs. The mortality of CVD increased in those born during 1937-1945, a period of the Japanese military occupation, and during 1958-1965, a period including the Chinese Famine. Sequelae of CVD and ischemic heart disease are predicted to be the leading causes of CVD death in 2029.

Conclusions: Exposure to serious malnutrition in early life might increase CVD mortality in later life. Improvements in medical services, pollution control, and lifestyle could decrease CVD death. New strategy is needed to prevent the aging-related CVD death and burden in the future.
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http://dx.doi.org/10.1186/s12889-020-09390-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448450PMC
August 2020

The genetic polymorphism down-regulating HLA-DRB1 enhancer activity facilitates HBV persistence, evolution and hepatocarcinogenesis in the Chinese Han population.

J Viral Hepat 2020 11 7;27(11):1150-1161. Epub 2020 Jul 7.

Department of Epidemiology, Naval Medical University, Shanghai, China.

Genetic predisposition of human leucocyte antigen (HLA)-DR has been linked to nonresponse to hepatitis B virus (HBV) vaccination. We sought to reveal their effects on chronic infection and evolution of HBV and development of hepatocellular carcinoma (HCC). Genetic polymorphisms at HLA-DR enhancer regions were genotyped in 4588 participants using quantitative PCR. HBV mutations were determined by sequencing. A dual-luciferase assay was applied to detect the enhancer activity. Associations between HLA-DR polymorphisms and postoperative prognosis were investigated in another cohort of 397 HBV-infected HCC patients. Variant alleles (rs3135395-T, rs3135338-C and rs477515-T) were significantly associated with a decreased risk of HBV persistence in Chinese patients. rs3135395-T, rs3135338-C, rs477515-T and rs2395178-G also significantly decreased HCC risk. rs3135395-T, rs477515-T and rs2395178-G were inversely associated with the generation of A1762T/G1764A, T1753V and C1653T, the HCC-risk HBV mutations. Multiplicative interactions of the variant genotypes with the HCC-risk HBV mutations were significantly associated with a decreased risk of HCC. In multivariate Cox analysis, rs477515-T independently predicted a favourable prognosis, with a hazard ratio of 0.48 (P = .002). The activity of the HLA-DRB1 enhancer with rs477515-T was significantly higher than that with rs477515-C. The activity of the HLA-DRB1 enhancer with rs477515-T and that with rs477515-C was significantly up-regulated by interferon-γ and interleukin-4, respectively. Interleukin-6 significantly inhibited the HLA-DRB1 enhancer activity, and this effect was more evident in those carrying rs477515-T. Polymorphisms predisposing to down-regulation of HLA-DR facilitate the Th1-to-Th2 transition and promote HCC development, possibly via selecting the HCC-risk HBV mutations. This can be transformed into specific prophylaxis of HCC.
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http://dx.doi.org/10.1111/jvh.13353DOI Listing
November 2020

Knowledge-based analyses reveal new candidate genes associated with risk of hepatitis B virus related hepatocellular carcinoma.

BMC Cancer 2020 May 11;20(1):403. Epub 2020 May 11.

Department of Psychiatry, the University of Hong Kong, Pokfulam, Hong Kong.

Background: Recent genome-wide association studies (GWASs) have suggested several susceptibility loci of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) by statistical analysis at individual single-nucleotide polymorphisms (SNPs). However, these loci only explain a small fraction of HBV-related HCC heritability. In the present study, we aimed to identify additional susceptibility loci of HBV-related HCC using advanced knowledge-based analysis.

Methods: We performed knowledge-based analysis (including gene- and gene-set-based association tests) on variant-level association p-values from two existing GWASs of HBV-related HCC. Five different types of gene-sets were collected for the association analysis. A number of SNPs within the gene prioritized by the knowledge-based association tests were selected to replicate genetic associations in an independent sample of 965 cases and 923 controls.

Results: The gene-based association analysis detected four genes significantly or suggestively associated with HBV-related HCC risk: SLC39A8, GOLGA8M, SMIM31, and WHAMMP2. The gene-set-based association analysis prioritized two promising gene sets for HCC, cell cycle G1/S transition and NOTCH1 intracellular domain regulates transcription. Within the gene sets, three promising candidate genes (CDC45, NCOR1 and KAT2A) were further prioritized for HCC. Among genes of liver-specific expression, multiple genes previously implicated in HCC were also highlighted. However, probably due to small sample size, none of the genes prioritized by the knowledge-based association analyses were successfully replicated by variant-level association test in the independent sample.

Conclusions: This comprehensive knowledge-based association mining study suggested several promising genes and gene-sets associated with HBV-related HCC risks, which would facilitate follow-up functional studies on the pathogenic mechanism of HCC.
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http://dx.doi.org/10.1186/s12885-020-06842-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216662PMC
May 2020

Direct-acting antivirals and interferon-based therapy on hepatocellular carcinoma risk in chronic hepatitis-C patients.

Future Oncol 2020 Apr 30;16(11):675-686. Epub 2020 Mar 30.

Department of Epidemiology, Navy Medical University, Shanghai, PR China.

It was controversial whether direct-acting antiviral (DAA) is better than interferon-based therapy (IBT) in preventing HCV-related hepatocellular carcinoma (HCC). Therefore, we accomplished this large, stepwise meta-analysis. The PubMed, Cochrane and ScienceDirect were searched for studies published during January 2009-March 2019. Antiviral type, number of chronic hepatitis C (CHC) patients, number of HCC cases from CHC patients, sustained virological response (SVR) status and important covariate data were extracted from each study. It is demonstrated that antiviral treatment reduces the occurrence of HCC in patients with CHC; achieving SVR to antiviral treatment reduces HCC; DAA treatment is not better than IBT in the prophylaxis of HCC; DAA treatment and cirrhosis are independently associated with a higher incidence of HCC than IBT in middle-aged CHC patients who achieve SVR.
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http://dx.doi.org/10.2217/fon-2019-0845DOI Listing
April 2020

Contribution of Hepatitis B Virus Infection to the Aggressiveness of Primary Liver Cancer: A Clinical Epidemiological Study in Eastern China.

Front Oncol 2019 21;9:370. Epub 2019 May 21.

Department of Epidemiology, Second Military Medical University, Shanghai, China.

The contribution of hepatitis B virus (HBV) infection to the aggressiveness of primary liver cancer (PLC) remains controversial. We aimed to characterize this in eastern China. We enrolled 8,515 PLC patients whose specimens were reserved at the BioBank of the hepatobiliary hospital (Shanghai, China) during 2007-2016. Of those, 3,124 who received primary radical resection were involved in survival analysis. A nomogram was constructed to predict the survivals using preoperative parameters. Hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), and combined hepatocellular cholangiocarcinoma (CHC) accounted for 94.6, 3.7, and 1.7%, respectively. The rates of HBV infection were 87.5, 49.2, and 80.6%, respectively. HBV infection was significantly associated with 10-year earlier onset, more cirrhosis, higher α-fetoprotein, higher carbohydrate antigen 19-9 (CA19-9), more microvascular invasion (MVI), lower neutrophil-to-lymphocyte ratio (NLR), and lower platelet-to-lymphocyte ratio (PLR) in HCC. HBV infection was also associated with 7-year earlier onset, more cirrhosis, higher α-fetoprotein, more MVI, and lower PLR in ICC. In the multivariate Cox analysis, high circulating HBV DNA, α-fetoprotein, CA19-9, NLR, tumor size, number, encapsulation, Barcelona Clinic Liver Cancer (BCLC) stage, and MVI predicted an unfavorable prognosis in HCC; only CA19-9 and BCLC stage, rather than HBV-related parameters, had prognostic values in ICC. A nomogram constructed with preoperative HBV-related parameters including HBV load, ultrasonic cirrhosis, and α-fetoprotein perform better than the current staging systems in predicting postoperative survival in HCC. HBV promotes the aggressiveness of HCC in Chinese population. The contributions of HBV to ICC and other etiological factors to HCC might be indirect arousing non-resolving inflammation.
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http://dx.doi.org/10.3389/fonc.2019.00370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6537574PMC
May 2019

APOBEC3B interaction with PRC2 modulates microenvironment to promote HCC progression.

Gut 2019 10 1;68(10):1846-1857. Epub 2019 Jun 1.

Center for New Drug Safety Evaluation and Research, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.

Objective: APOBEC3B (A3B), a cytidine deaminase acting as a contributor to the APOBEC mutation pattern in many kinds of tumours, is upregulated in patients with hepatocellular carcinoma (HCC). However, APOBEC mutation patterns are absent in HCC. The mechanism of how A3B affects HCC progression remains elusive.

Design: A3B -promoter luciferase reporter and other techniques were applied to elucidate mechanisms of A3B upregulation in HCC. A3B overexpression and knockdown cell models, immunocompetent and immune-deficient mouse HCC model were conducted to investigate the influence of A3B on HCC progression. RNA-seq, flow cytometry and other techniques were conducted to analyse how A3B modulated the cytokine to enhance the recruitment of myeloid--derived suppressor cells (MDSCs) and tumour--associated macrophages (TAMs).

Results: A3B upregulation through non-classical nuclear factor-κB (NF-κB)signalling promotes HCC growth in immunocompetent mice, associated with an increase of MDSCs, TAMs and programmed cell death1 (PD1) exprssed CD8 T cells. A CCR2 antagonist suppressed TAMs and MDSCs infiltration and delayed tumour growth in A3B and A3B- expressing mouse tumours. Mechanistically, A3B upregulation in HCC depresses global H3K27me3 abundance via interaction with polycomb repressor complex 2 (PRC2) and reduces an occupancy of H3K27me3 on promoters of the chemokine CCL2 to recruit massive TAMs and MDSCs.

Conclusion: Our observations uncover a deaminase-independent role of the A3B in modulating the HCC microenvironment and demonstrate a proof for the concept of targeting A3B in HCC immunotherapy.
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http://dx.doi.org/10.1136/gutjnl-2018-317601DOI Listing
October 2019

Genetic Polymorphisms Predisposing the Interleukin 6-Induced APOBEC3B-UNG Imbalance Increase HCC Risk via Promoting the Generation of APOBEC-Signature HBV Mutations.

Clin Cancer Res 2019 09 31;25(18):5525-5536. Epub 2019 May 31.

Department of Epidemiology, Second Military Medical University, Shanghai, China.

Purpose: APOBEC3-UNG imbalance contributes to hepatitis B virus (HBV) inhibition and somatic mutations. We aimed to explore the associations between hepatocellular carcinoma (HCC) risk and genetic polymorphisms predisposing the imbalance. Genetic polymorphisms at promoter and enhancer regions were genotyped in 5,621 participants using quantitative PCR. HBV mutations (nt.1600-nt.1945, nt.2848-nt.155) were determined by Sanger sequencing. Dual-luciferase reporter assay was applied to detect the transcriptional activity. Effects of / SNPs and expression levels on HCC prognosis were evaluated with a cohort of 400 patients with HCC and public databases, respectively.

Results: rs2267401-G allele and rs3890995-C allele significantly increased HCC risk. rs2267401-G allele was significantly associated with the generation of APOBEC-signature HBV mutation whose frequency consecutively increased from asymptomatic HBV carriers to patients with HCC. Multiplicative interaction of rs2267401-G allele with rs3890995-C allele increased HCC risk, with an adjusted OR (95% confidence interval) of 1.90 (1.34-2.81). rs2267401 T-to-G and rs3890995 T-to-C conferred increased activities of promoter and enhancer, respectively. IL6 significantly increased promoter activity and inhibited enhancer activity, and these effects were more evident in those carrying rs2267401-G and rs3890995-C, respectively. rs2267401-GG genotype, higher APOBEC3B expression, and higher APOBEC3B/UNG expression ratio in HCCs indicated poor prognosis. APOBEC-signature somatic mutation predicts poor prognosis in HBV-free HCCs rather than in HBV-positive ones.

Conclusions: Polymorphic genotypes predisposing the APOBEC3B-UNG imbalance in IL6-presenting microenvironment promote HCC development, possibly via promoting the generation of high-risk HBV mutations. This can be transformed into specific prophylaxis of HBV-caused HCC.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3083DOI Listing
September 2019

Novel Assay for Quantitative Analysis of DNA Methylation at Single-Base Resolution.

Clin Chem 2019 05 8;65(5):664-673. Epub 2019 Feb 8.

Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China;

Background: The DNA methylation profile provides valuable biological information with potential clinical utility. Several methods, such as quantitative methylation-specific PCR (qMSP), have been developed to examine methylation of specific CpG sites. Existing qMSP-based techniques fail to examine the genomic methylation at a single-base resolution, particularly for loci in gene bodies or extensive CpG open seas lacking flanking CpGs. Therefore, we established a novel assay for quantitative analysis of single-base methylation.

Methods: To achieve a robust single-base specificity, we developed a PCR-based method using paired probes following bisulfite treatment. The 6-carboxyfluorescein- and 2'-chloro-7'phenyl-1,4-dichloro-6-carboxy-fluorescein-labeled probes conjugated with minor groove binder were designed to specifically bind to the methylated and unmethylated allele of targeted single CpGs at their 3' half regions, respectively. The methylation percentage was calculated by values of methylation / (methylation + unmethylation).

Results: In the detection of single CpGs within promoters or bodies of 4 human genes, the quantitative analysis of the single-base methylation assay showed a detection capability in the 1 to 1:10000 dilution experiments with linearity over 4 orders of magnitude ( = 0.989-0.994; all < 0.001). In a cohort of 10 colorectal cancer samples, the assay showed a comparable detection performance with bisulfite pyrosequencing ( = 0.875-0.990; all < 0.001), which was better than conventional qMSP methods normalized by input control reaction ( = 0.841 vs 0.769; = 0.002 vs 0.009).

Conclusions: This assay is highly specific and sensitive for determining single-base methylation and, thus, is potentially useful for methylation-based panels in diagnostic and prognostic applications.
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http://dx.doi.org/10.1373/clinchem.2018.298570DOI Listing
May 2019

Urban-Rural Disparity in Cancer Incidence, Mortality, and Survivals in Shanghai, China, During 2002 and 2015.

Front Oncol 2018 3;8:579. Epub 2018 Dec 3.

Department of Epidemiology, Second Military Medical University, Shanghai, China.

Disparities in the incidence, mortality, and survival of cancer types between urban and rural areas in China reflect the effects of different risk factor exposure, education, and different medical availability. We aimed to characterize the disparities in the incidence, mortality, and survivals of cancer types between urban and rural areas in Shanghai, China, 2002-2015. The incidence and mortality were standardized by Segi's world standard population. Trends in the incidence and mortality of cancers were compared using annual percent change. The 5-year observed and relative survivals were calculated with life table and Ederer II methods. Age-standardized incidences and mortalities were 212.55/10 and 109.45/10 in urban areas and 210.14/10 and 103.99/10 in rural areas, respectively. Female breast cancer and colorectal cancer occurred more frequently in urban than in rural areas, quite in contrast to liver cancer and cervical cancer. Cancers of lung and bronchus, liver, stomach, and colon and rectum were the leading causes of cancer death in both areas. Age-standardized incidence of female breast cancer and colorectal cancer in urban areas increased while gastric cancer and liver cancer decreased in both areas. Age-standardized mortalities of cancers of breast, esophagus, stomach, colon and rectum, liver, and lung and bronchus decreased in both areas. For all cancers combined, the 5-year observed and relative survivals of cancer patients were higher in urban than in rural areas. The 5-year observed and relative survivals of cancers of liver, pancreas, stomach, brain and central nervous system (CNS), and prostate were higher in urban than in rural areas. The 5-year observed and relative survivals of cervical cancer were higher in rural than in urban areas. Factors promoting female breast cancer and colorectal cancer in urban areas and liver cancer and cervical cancer in rural areas should be specifically intervened in cancer prophylaxis. Improved medical services can greatly prolong the survival of major cancers in rural areas.
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http://dx.doi.org/10.3389/fonc.2018.00579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287035PMC
December 2018

Efficacy and safety of antiviral treatment on blocking the mother-to-child transmission of hepatitis B virus: A meta-analysis.

J Viral Hepat 2019 03 11;26(3):397-406. Epub 2018 Dec 11.

Department of Epidemiology, Second Military Medical University, Shanghai, China.

Nucleo(t)side analogues (NAs) have been administered as adjunctive therapy to interrupt the mother-to-child transmission (MTCT) of hepatitis B virus (HBV). The efficacy and safety of this method remain controversial. A meta-analysis was conducted to evaluate the efficacy and safety of NAs treatment during pregnancy. The differences among different agents and initiation trimesters were analysed. A total of 9228 mother-infant pairs in 59 studies (32 RCTs and 27 non-RCTs) were included in this meta-analysis. NAs significantly reduced the risk of MTCT, as indicated by seropositivity of hepatitis B surface antigen (HBsAg) (risk ratio (RR) = 0.51, 95% confidence interval (CI) 0.45-0.57) and HBV DNA in newborns (RR = 0.22, 95% CI 0.18-0.26). No differences in the efficacy of interrupting HBV MTCT were evident among lamivudine, telbivudine and tenofovir disoproxil fumarate. NA was more effective when administered from the second than from the third trimester as indicated by HBV DNA (RR: the second vs the third 0.08 vs 0.22, P = 0.010), but this effect was not evident as indicated by HBsAg (RR: the second vs the third 0.46 vs 0.53, P = 0.596). Antiviral treatment initiated from the second trimester did not confer a higher risk of safety problems in the newborns compared with treatment from the third trimester, as indicated by weight (P = 0.064), length (P = 0.491) and malformation rate (P = 0.635) of newborns. CONCLUSIONS: Lamivudine, telbivudine and tenofovir disoproxil fumarate are equally effective in blocking HBV MTCT. Antiviral treatment can be applied from the second trimester, without obvious safety concerns.
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http://dx.doi.org/10.1111/jvh.13036DOI Listing
March 2019

Influence of socioeconomic events on cause-specific mortality in urban Shanghai, China, from 1974 to 2015: a population-based longitudinal study.

CMAJ 2018 10;190(39):E1153-E1161

Department of Epidemiology (Wang, Du, Yang, M. Li, Zhang, Liu, Song, Cao), Second Military Medical University; Department of Chronic Diseases (Han, Zhao, H. Li), Center for Disease Control and Prevention of Yangpu District, Shanghai, China

Background: Understanding how socioeconomic events influence cause-specific mortality is essential for optimizing disease-control strategies. We characterized long-term trends in cause-specific mortality in a stable population from a very large urban centre.

Methods: We derived population data from 1974 to 2015 on vital status, demographics and causes of death from the death registration system in Yangpu District, Shanghai, China. We examined temporal trends in mortality and assessed the effects of age, period and birth cohort.

Results: Over 41 879 864 person-years of follow-up, we analyzed 290 332 deaths: 3.80% from communicable conditions (group 1), 86.50% from noncommunicable diseases (group 2), and 5.56% from injuries (group 3). Age-standardized mortality decreased after 1988 for group 1 (average annual percentage change [AAPC] -6.7, 95% confidence interval [CI] -9.3 to -4.1), after 1995 for group 2 (AAPC -2.9, 95% CI -3.5 to -2.3), and after 1994 for group 3 (AAPC -5.4, 95% CI -6.3 to -4.5), after improvements in public health and clinical service infrastructure and the removal of polluting industries during the 1980s. We observed increased mortality from group 2 and group 3 causes in those born between 1955 and 1965, a period that included the Great Chinese Famine. Cause-specific mortality risks increased in those born after 1949 for cancer and diabetes only.

Interpretation: Birth cohorts exposed to extreme starvation in early life had increased premature cause-specific mortality in later life. Decreased cause-specific mortality followed improvements in public health, medical infrastructure and pollution control, but not for cancer or diabetes, likely because of exposure to new risk factors.
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http://dx.doi.org/10.1503/cmaj.180272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6167223PMC
October 2018

Follistatin-like protein 1 plays a tumor suppressor role in clear-cell renal cell carcinoma.

Chin J Cancer 2018 01 22;37(1). Epub 2018 Jan 22.

Department of Epidemiology, Second Military Medical University, Shanghai, 200433, P. R. China.

Background: We previously showed that the expression of follistatin-like protein 1 (FSTL1) was significantly down-regulated in metastatic clear-cell renal cell carcinoma (ccRCC). In this study, we aimed to characterize the role of FSTL1 in the development of ccRCC.

Methods: The effects of FSTL1 on cell activity and cell cycle were investigated in ccRCC cell lines with altered FSTL1 expression. Gene expression microarray assays were performed to identify the major signaling pathways affected by FSTL1 knockdown. The expression of FSTL1 in ccRCC and its effect on postoperative prognosis were estimated in a cohort with 89 patients.

Results: FSTL1 knockdown promoted anchorage-independent growth, migration, invasion, and cell cycle of ccRCC cell lines, whereas FSTL1 overexpression attenuated cell migration. FSTL1 knockdown up-regulated nuclear factor-κB (NF-κB) and hypoxia-inducible factor (HIF) signaling pathways, increased epithelial-to-mesenchymal transition, up-regulated interleukin-6 expression, and promoted tumor necrosis factor-α-induced degradation of NF-κB inhibitor (IκBα) in ccRCC cell lines. FSTL1 immunostaining was selectively positive in epithelial cytoplasm in the loop of Henle, and positive rate of FSTL1 was significantly lower in ccRCC tissues than in adjacent renal tissues (P < 0.001). The multivariate Cox regression analysis showed that the intratumoral FSTL1 expression conferred a favorable independent prognosis with a hazard ratio of 0.325 (95% confidence interval 0.118-0.894). HIF-2α expression was negatively correlated with FSTL1 expression in ccRCC specimens (r = - 0.229, P = 0.044). Intratumoral expression of HIF-2α, rather than HIF-1α, significantly predicted an unfavorable prognosis in ccRCC (log-rank, P = 0.038).

Conclusions: FSTL1 plays a tumor suppression role possibly via repressing the NF-κB and HIF-2α signaling pathways. To increase FSTL1 expression might be a candidate therapeutic strategy for metastatic ccRCC.
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http://dx.doi.org/10.1186/s40880-018-0267-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5778637PMC
January 2018

Enzalutamide and CXCR7 inhibitor combination treatment suppresses cell growth and angiogenic signaling in castration-resistant prostate cancer models.

Int J Cancer 2018 05 30;142(10):2163-2174. Epub 2018 Jan 30.

Division of Cancer Medicine, Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX.

Previous studies have shown that increased levels of chemokine receptor CXCR7 are associated with the increased invasiveness of prostate cancer cells. We now show that CXCR7 expression is upregulated in VCaP and C4-2B cells after enzalutamide (ENZ) treatment. ENZ treatment induced apoptosis (sub-G1) in VCaP and C4-2B cells, and this effect was further increased after combination treatment with ENZ and CCX771, a specific CXCR7 inhibitor. The levels of p-EGFR (Y1068), p-AKT (T308) and VEGFR2 were reduced after ENZ and CCX771 combination treatment compared to single agent treatment. In addition, significantly greater reductions in migration were shown after combination treatment compared to those of single agents or vehicle controls, and importantly, similar reductions in the levels of secreted VEGF were also demonstrated. Orthotopic VCaP xenograft growth and subcutaneous MDA133-4 patient-derived xenograft (PDX) tumor growth was reduced by single agent treatment, but significantly greater suppression was observed in the combination treatment group. Although overall microvessel densities in the tumor tissues were not different among the different treatment groups, a significant reduction in large blood vessels (>100 μm ) was observed in tumors following combination treatment. Apoptotic indices in tumor tissues were significantly increased following combination treatment compared with vehicle control-treated tumor tissues. Our results demonstrate that significant tumor suppression mediated by ENZ and CXCR7 combination treatment may be due, in part, to reductions in proangiogenic signaling and in the formation of large blood vessels in prostate cancer tumors.
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http://dx.doi.org/10.1002/ijc.31237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5867246PMC
May 2018

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

Oncotarget 2017 Nov 30;8(54):92470-92482. Epub 2017 Sep 30.

Department of Epidemiology, Second Military Medical University, Shanghai 200433, China.

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 (153.1/10. 88.8/10, 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.
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http://dx.doi.org/10.18632/oncotarget.21419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5696197PMC
November 2017

Meteorological factors affect the epidemiology of hemorrhagic fever with renal syndrome via altering the breeding and hantavirus-carrying states of rodents and mites: a 9 years' longitudinal study.

Emerg Microbes Infect 2017 Nov 29;6(11):e104. Epub 2017 Nov 29.

Department of Epidemiology, Second Military Medical University, Shanghai, China.

The incidence of hemorrhagic fever with renal syndrome (HFRS) in Qingdao, China was three times higher than that of the average national level. Here we characterized the epidemiology, ecological determinants and pathogen evolution of HFRS in Qingdao during 2007-2015. In this longitudinal study, a total of 1846 HFRS patients and 41 HFRS-related deaths were reported. HFRS in Qingdao peaked once a year in the fourth quarter. We built a time series generalized additive model, and found that meteorological factors in the previous quarter could accurately predict HFRS occurrence. To explore how meteorological factors influenced the epidemic of HFRS, we analyzed the relationship between meteorological factors and hantavirus-carrying states of the hosts (including rodents and shrews). Comprehensive analysis showed humidity was correlated to high host densities in the third quarter and high hantavirus-carrying rates of animal hosts in the third to fourth quarters, which might contribute to HFRS peak in the fourth quarter. We further compared the L segments of hantaviruses from HFRS patients, animal hosts and ectoparasites. Phylogenetic analysis showed that hantaviruses in gamasid and trombiculid mites were the same as those from the hosts. This indicated mites also contributed to the transmission of hantavirus. Furthermore, Hantaan virus from HFRS patients, hosts and mites in Qingdao formed a distinct phylogenetic cluster. A new clade of Seoul virus was also identified in the hosts. Overall, meteorological factors increase HFRS incidence possibly via facilitating hosts' reproduction and consequent mite-mediated hantavirus transmission. New hantavirus subtypes evolved in Qingdao represent new challenges of fighting against HFRS.
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http://dx.doi.org/10.1038/emi.2017.92DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5717093PMC
November 2017

HGF/R-spondin1 rescues liver dysfunction through the induction of Lgr5 liver stem cells.

Nat Commun 2017 10 27;8(1):1175. Epub 2017 Oct 27.

Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China.

Induction of endogenous adult stem cells by administering soluble molecules provides an advantageous approach for tissue damage repair, which could be a clinically applicable and cost-effective alternative to transplantation of embryonic or pluripotent stem cell-derived tissues for the treatment of acute organ failures. Here, we show that HGF/Rspo1 induce liver stem cells and rescue liver dysfunction. Carbon tetrachloride treatment promotes both fibrosis and Lgr5 liver stem cell proliferation, whereas Lgr5 knockdown worsens fibrosis. Injection of HGF in combination with Rspo1 increases the number of Lgr5 liver stem cells and improves liver function by attenuating fibrosis. We observe Lgr5 liver stem cells in human liver fibrosis tissues, and once they are isolated, these cells are able to form organoids, and treatment with HGF/Rspo1 promotes their expansion. We suggest that Lgr5 liver stem cells represent a valuable target for liver damage treatment, and that HGF/Rspo1 can be used to promote liver stem cell expansion.
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http://dx.doi.org/10.1038/s41467-017-01341-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5660090PMC
October 2017

Nontyphoidal Salmonella Gastroenteritis in Baoshan, Shanghai, China, 2010 to 2014: An Etiological Surveillance and Case-Control Study.

J Food Prot 2017 03;80(3):482-487

2 Department of Epidemiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, 800 Xiangyin Road, Yangpu District, Shanghai 200433, People's Republic of China.

Nontyphoidal Salmonella (NTS) gastroenteritis is a widespread global foodborne disease. To identify the epidemiologic characteristics, sources of food contamination, and risk factors of NTS gastroenteritis, epidemiologic data and stool specimens of diarrheal patients were collected from sentinel hospitals in Baoshan, Shanghai, People's Republic of China, between 2010 and 2014. Food products from nearby farmers' markets and animal feces from live poultry markets and livestock farms were sampled to identify the pathogen; a case-control study was conducted to characterize risk factors of NTS gastroenteritis. Of 3,906 diarrheal patients examined, 266 (6.8%) were positive for Salmonella. The positive rates were higher in summer than in the other seasons. Salmonella Typhimurium (36.1%) and Salmonella Enteritidis (30.8%) were the dominant serovars in the patients. Salmonella was detected in 26.2% pork samples, 7.1 to 7.8% poultry meats, and 3.3 to 8.9% poultry feces. Salmonella Typhimurium was the major serovar in contaminated food and animal feces. Multivariate conditional logistic regression analysis indicated that consumption of pork and quickly cooked eggs increased, whereas separating kitchen knives for cooked and raw food decreased the risk of NTS gastroenteritis, independently. We believe that NTS in poultry feces contaminated the meat products in the same markets and then infected humans if these foods were not sufficiently cooked. To prevent NTS gastroenteritis, it is necessary to survey Salmonella in meats and poultry feces, to cook eggs and pork sufficiently, to separate kitchen knives for cooked and raw food, and to prohibit live poultry trade in fresh meat markets.
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http://dx.doi.org/10.4315/0362-028X.JFP-16-309DOI Listing
March 2017

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

Sci Rep 2016 05 26;6:26689. Epub 2016 May 26.

Department of Epidemiology, Second Military Medical University, Shanghai, China.

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.
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http://dx.doi.org/10.1038/srep26689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4880907PMC
May 2016

Pancreatic cancer risk variant in LINC00673 creates a miR-1231 binding site and interferes with PTPN11 degradation.

Nat Genet 2016 07 23;48(7):747-57. Epub 2016 May 23.

Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Genome-wide association studies have identified several loci associated with pancreatic cancer risk; however, the mechanisms by which genetic factors influence the development of sporadic pancreatic cancer remain largely unknown. Here, by using genome-wide association analysis and functional characterization, we identify a long intergenic noncoding RNA (lincRNA), LINC00673, as a potential tumor suppressor whose germline variation is associated with pancreatic cancer risk. LINC00673 is able to reinforce the interaction of PTPN11 with PRPF19, an E3 ubiquitin ligase, and promote PTPN11 degradation through ubiquitination, which causes diminished SRC-ERK oncogenic signaling and enhanced activation of the STAT1-dependent antitumor response. A G>A change at rs11655237 in exon 4 of LINC00673 creates a target site for miR-1231 binding, which diminishes the effect of LINC00673 in an allele-specific manner and thus confers susceptibility to tumorigenesis. These findings shed new light on the important role of LINC00673 in maintaining cell homeostasis and how its germline variation might confer susceptibility to pancreatic cancer.
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http://dx.doi.org/10.1038/ng.3568DOI Listing
July 2016

A genetic study and meta-analysis of the genetic predisposition of prostate cancer in a Chinese population.

Oncotarget 2016 Apr;7(16):21393-403

Department of Urology, Changhai Hospital, The Second Military Medical University, Shanghai, 200433, China.

Prostate cancer predisposition has been extensively investigated in European populations, but there have been few studies of other ethnic groups. To investigate prostate cancer susceptibility in the under-investigated Chinese population, we performed single-nucleotide polymorphism (SNP) array analysis on a cohort of Chinese cases and controls and then meta-analysis with data from the existing Chinese prostate cancer genome-wide association study (GWAS). Genotyping 211,155 SNPs in 495 cases and 640 controls of Chinese ancestry identified several new suggestive Chinese prostate cancer predisposition loci. However, none of them reached genome-wide significance level either by meta-analysis or replication study. The meta-analysis with the Chinese GWAS data revealed that four 8q24 loci are the main contributors to Chinese prostate cancer risk and the risk alleles from three of them exist at much higher frequencies in Chinese than European populations. We also found that several predisposition loci reported in Western populations have different effect on Chinese men. Therefore, this first extensive single-nucleotide polymorphism study of Chinese prostate cancer in comparison with European population indicates that four loci on 8q24 contribute to a great risk of prostate cancer in a considerable large proportion of Chinese men. Based on those four loci, the top 10% of the population have six- or two-fold prostate cancer risk compared with men of the bottom 10% or median risk respectively, which may facilitate the design of prostate cancer genetic risk screening and prevention in Chinese men. These findings also provide additional insights into the etiology and pathogenesis of prostate cancer.
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http://dx.doi.org/10.18632/oncotarget.7250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5008293PMC
April 2016
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