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1.  Polymorphisms of estrogen receptors and risk of biliary tract cancers and gallstones: a population-based study in Shanghai, China 
Carcinogenesis  2010;31(5):842-846.
Biliary tract cancer encompasses tumors of the gallbladder, bile duct and ampulla of Vater. Gallbladder cancer is more common in women, whereas bile duct cancer is more common in men, suggesting that sex hormones may play a role in the etiology of these cancers. The intracellular action of estrogens is regulated by the estrogen receptor (ESR); thus, we examined the role of common genetic variants in ESR genes on the risk of biliary tract cancers and stones in a population-based case–control study in Shanghai, China (411 cancer cases, 895 stone cases and 786 controls). We genotyped six single-nucleotide polymorphisms (SNPs), four in ESR1 (rs2234693, rs3841686, rs2228480 and rs1801132) and two in ESR2 (rs1256049 and rs4986938). In all participants, the ESR1 rs1801132 (P325P) G allele was associated with excess risks of bile duct [odds ratio (OR) = 1.7, 95% confidence interval (CI) 1.1–2.8] and ampulla of Vater cancers (OR = 2.1, 95% CI 0.9–4.9) compared with the CC genotype. The association with bile duct cancer was apparent among men (OR = 2.8, 95% CI 1.4–5.7) but not among women (P-heterogeneity = 0.01). Also, the ESR2 rs4986938 (38 bp 3′ of STP) GG genotype was associated with a higher risk of bile duct cancer (OR = 3.3, 95% CI 1.3–8.7) compared with the AA genotype, although this estimate was based on a small number of subjects. None of the other SNPs examined was associated with biliary tract cancers or stones. False discovery rate-adjusted P-values were not significant (P > 0.1). No association was found for ESR1 haplotype based on four SNPs. These preliminary results suggest that variants in ESR genes could play a role in the etiology of biliary tract cancers, especially bile duct cancer in men.
PMCID: PMC2864412  PMID: 20172949
2.  Variants in Inflammation Genes and the Risk of Biliary Tract Cancers and Stones: A Population-based Study in China 
Cancer research  2008;68(15):6442-6452.
To evaluate the role of chronic inflammation in the development of gallstones and biliary tract cancer, we examined the risk associated with 62 single nucleotide polymorphisms (SNPs), including 22 inflammation-related genes, based on a population-based case-control study conducted in Shanghai, China, where the incidence of biliary tract cancer has been increasing in recent decades. The study included 411 cases with biliary tract cancer (237 gallbladder, 127 extrahepatic bile duct, and 47 ampulla of Vater), 895 with biliary stones, and 786 controls randomly selected from the population. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the association of individual single nucleotide polymorphisms (SNPs) and haplotypes with biliary stones and biliary tract cancer. Of the 62 SNPs examined, 14 were related to the risk of biliary cancer and stones. Specifically, variants in the IL8, IL8RB, RNASEL, and NOS2 genes were associated with biliary stones, while VEGF variants were associated with gallbladder cancer. Of the 10 genes with multiple SNPs from which we inferred haplotypes, only one IL8RB haplotype, consisting of 3 SNPs (rs2230054, rs1126579, rs1126580), was associated with the risk of bile duct cancer (p=0.003) and biliary stones (p=0.02), relative to the most frequent haplotype. In summary, common variants in genes that influence inflammatory responses may predispose to gallstones and biliary tract cancer, suggesting the need for future studies into the immunologic and inflammatory pathways that contribute to biliary diseases, including cancer.
PMCID: PMC2860726  PMID: 18676870
gallstones; biliary tract cancer; inflammation; genetic susceptibility
3.  Variants of DNA Repair Genes and the Risk of Biliary Tract Cancers and Stones: A population-based study in China 
Biliary tract cancers, encompassing tumors of the gallbladder, extrahepatic ducts, and ampulla of Vater, are relatively rare tumors with a high fatality rate. Other than a close link with gallstones, the etiology of biliary tract cancers is poorly understood. We conducted a population-based case-control study in Shanghai, China, to examine whether genetic variants in several DNA repair genes are associated with biliary tract cancers or biliary stones. Genomic DNA from 411 patients with biliary tract cancers (237 gallbladder, 127 bile duct, and 47 ampulla of Vater), 891 patients with biliary stones, and 786 healthy subjects randomly selected from the Shanghai population, was genotyped for 6 single nucleotide polymorphisms (SNPs) in 4 DNA repair genes (MGMT, RAD23B, CCNH, and XRCC3). Of the 6 SNPs, only one (MGMT EX5-25C>T, rs12917) was associated with biliary tract cancer. Independent of gallstones, subjects carrying the CT genotype of the MGMT EX5-25C>T marker had a significantly reduced risk of gallbladder cancer (odds ratio (OR)=0.63; 95% confidence interval (CI): 0.41-0.97; Ptrend = 0.02) and non-significant reduced risks of bile duct (OR=0.61; 95% CI: 0.35-1.06) and ampulla of Vater (OR=0.85; 95% CI: 0.39-1.87) cancers. However, this marker was not associated with biliary stones, and the other markers examined were not significantly associated with either biliary tract cancers or stones. Findings from this population-based study in Shanghai suggest that MGMT gene variants may alter susceptibility to biliary tract cancer, particularly gallbladder cancer. Confirmation in future studies, however, is required.
PMCID: PMC2860746  PMID: 18708406
Biliary tract cancers; gallbladder; extrahepatic bile duct; ampulla of Vater; DNA repair; polymorphism; China
4.  Prospective comparison of three predictive rules for assessing severity of community‐acquired pneumonia in Hong Kong 
Thorax  2006;62(4):348-353.
Community‐acquired pneumonia (CAP) is a leading infectious cause of death throughout the world, including Hong Kong.
To compare the ability of three validated prediction rules for CAP to predict mortality in Hong Kong: the 20 variable Pneumonia Severity Index (PSI), the 6‐point CURB65 scale adopted by the British Thoracic Society and the simpler CRB65.
A prospective observational study of 1016 consecutive inpatients with CAP (583 men, mean (SD) age 72 (17) years) was performed in a university hospital in the New Territories of Hong Kong in 2004. The patients were classified into three risk groups (low, intermediate and high) according to each rule. The ability of the three rules to predict 30 day mortality was compared.
The overall mortality and intensive care unit (ICU) admission rates were 8.6% and 4.0%, respectively. PSI, CURB65 and CRB65 performed similarly, and the areas under the receiver operating characteristic (ROC) curve were 0.736 (95% CI 0.687 to 0.736), 0.733 (95% CI 0.679 to 0.787) and 0.694 (95% CI 0.634 to 0.753), respectively. All three rules had high negative predictive values but relatively low positive predictive values at all cut‐off points. Larger proportions of patients were identified as low risk by PSI (47.2%) and CURB65 (43.3%) than by CRB65 (12.6%).
All three predictive rules have a similar performance in predicting the severity of CAP, but CURB65 is more suitable than the other two for use in the emergency department because of its simplicity of application and ability to identify low‐risk patients.
PMCID: PMC2092476  PMID: 17121867
5.  IκBα polymorphism at promoter region (rs2233408) influences the susceptibility of gastric cancer in Chinese 
BMC Gastroenterology  2010;10:15.
Nuclear factor of kappa B inhibitor alpha (IκBα) protein is implicated in regulating a variety of cellular process from inflammation to tumorigenesis. The objective of this study was to investigate the susceptibility of rs2233408 T/C genotype in the promoter region of IκBα to gastric cancer and the association of this polymorphism with clinicopathologic variables in gastric cancer patients.
A population-based case-control study was conducted between 1999 and 2006 in Guangdong Province, China. A total of 564 gastric cancer patients and 566 healthy controls were enrolled in this study. rs2233408 genotypes in IκBα were analyzed by TaqMan SNP genotyping assay.
Both rs2233408 T homozygote (TT) and T heterozygotes (TC and TT) had significantly reduced gastric cancer risk (TT: OR = 0.250, 95% CI = 0.069-0.909, P = 0.035; TC and TT: OR = 0.721, 95% CI = 0.530-0.981, P = 0.037), compared with rs2233408 C homozygote (CC). rs2233408 T heterozygotes were significantly associated with reduced risk of intestinal-type gastric cancer with ORs of 0.648 (95% CI = 0.459-0.916, P = 0.014), but not with the diffuse or mix type of gastric cancer. The association between rs2233408 T heterozygotes and gastric cancer appeared more apparent in the older patients (age>40) (OR = 0.674, 95% CI = 0.484-0.939, P = 0.02). rs2233408 T heterozygotes was associated with non-cardiac gastric cancer (OR = 0.594, 95% CI = 0.411-0.859, P = 0.006), but not with cardiac gastric cancer. However, rs2233408 polymorphism was not associated with the prognosis of gastric cancer patients.
IκBα rs2233408 T heterozygotes were associated with reduced risk of gastric cancer, especially for the development of certain subtypes of gastric cancer in Chinese population.
PMCID: PMC2829487  PMID: 20132559
6.  MBL2 and Hepatitis C Virus Infection among Injection Drug Users 
Genetic variations in MBL2 that reduce circulating levels and alter functional properties of the mannose binding lectin (MBL) have been associated with many autoimmune and infectious diseases. We examined whether MBL2 variants influence the outcome of hepatitis C virus (HCV) infection.
Participants were enrolled in the Urban Health Study of San Francisco Bay area injection drug users (IDU) during 1998 through 2000. Study subjects who had a positive test for HCV antibody were eligible for the current study. Participants who were positive for HCV RNA were frequency matched to those who were negative for HCV RNA on the basis of ethnicity and duration of IDU. Genotyping was performed for 15 single nucleotide polymorphisms in MBL2. Statistical analyses of European American and African American participants were conducted separately.
The analysis included 198 study subjects who were positive for HCV antibody, but negative for HCV RNA, and 654 IDUs who were positive for both antibody and virus. There was no significant association between any of the genetic variants that cause MBL deficiency and the presence of HCV RNA. Unexpectedly, the MBL2 -289X promoter genotype, which causes MBL deficiency, was over-represented among European Americans who were HCV RNA negative (OR = 1.65, 95% CI 1.05–2.58), although not among the African Americans.
This study found no association between genetic variants that cause MBL deficiency and the presence of HCV RNA. The observation that MBL2 -289X was associated with the absence of HCV RNA in European Americans requires validation.
PMCID: PMC2413243  PMID: 18452612
7.  Lymphocyte subsets in hemophilic patients with hepatitis C virus infection with or without human immunodeficiency virus co-infection: a nested cross-sectional study 
With chronic infection, hepatitis C virus (HCV) RNA can be detected in B cells and associated with B-cell disorders, but these are not well defined.
The relationship between HCV infection and lymphocyte subpopulations was evaluated rigorously in 120 asymptomatic hemophilic patients, randomly selected from a prospective cohort study. CD4+ T cells, CD8+ T cells, CD19+ B cells, and CD56+ NK cells were quantified by flow cytometry using cryopreserved peripheral blood mononuclear cells of 24 hemophilic patients in each of five age-matched groups [uninfected; chronic HCV with or without human immunodeficiency virus (HIV); and cleared HCV with or without HIV].
As expected, patients with HIV had significantly reduced CD4+ and increased CD8+ T cells. Irrespective of HIV, patients with chronic HCV infection had approximately 25% fewer CD19+ B cells than those without chronic HCV infection.
These data support the hypothesis that asymptomatic patients with chronic HCV infection have an altered B-lymphocyte population.
PMCID: PMC546217  PMID: 15656905
8.  Hepatitis C Virus Infection, Linxian, China1 
Emerging Infectious Diseases  2005;11(1):17-21.
The prevalence of HCV infection was high among older citizens of Linxian, China, in 2000.
Bloodborne viruses may have spread in rural China during the past 25 years, but population-based prevalence estimates are lacking. We examined the frequency of hepatitis C virus (HCV) and HIV type 1 (HIV-1) among residents of Linxian, a rural community in Henan Province. In 2000, blood was collected from participants (>55 years of age) who had enrolled in a population-based nutritional intervention trial in 1985. We randomly selected 500 participants for HCV testing and 200 participants for HIV-1 testing. For HCV, 48 (9.6%) of 500 participants were positive by enzyme immunoassay and recombinant immunoblot assay (95% confidence interval [CI], 7.0%–12.2%), and prevalence was lowest in the most geographically isolated participants. Among the HCV-infected participants, 42 had a specimen available from1985, of which 16 (38.1%) were positive for HCV. For HIV-1, 0/200 participants were positive. We conclude that HCV is now a common infection among older adults in Linxian, China.
PMCID: PMC3294338  PMID: 15705317
AIDS; China; epidemiology; hepatitis B virus (HBV); hepatitis C virus (HCV); human immunodeficiency virus type 1 (HIV-1); liver cancer; prevalence; research
9.  A Functional NSP4 Enterotoxin Peptide Secreted from Rotavirus-Infected Cells 
Journal of Virology  2000;74(24):11663-11670.
Previous studies have shown that the nonstructural glycoprotein NSP4 plays a role in rotavirus pathogenesis by functioning as an enterotoxin. One prediction of the mechanism of action of this enterotoxin was that it is secreted from virus-infected cells. In this study, the media of cultured (i) insect cells infected with a recombinant baculovirus expressing NSP4, (ii) monkey kidney (MA104) cells infected with the simian (SA11) or porcine attenuated (OSU-a) rotavirus, and (iii) human intestinal (HT29) cells infected with SA11 were examined to determine if NSP4 was detectable. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis–Western blotting, immunoprecipitation and N-terminal amino acid sequencing identified, in the early media from virus-infected cells, a secreted, cleavage product of NSP4 with an apparent molecular weight of 7,000 that represented amino acids 112 to 175 (NSP4 aa112–175). The secretion of NSP4 aa112–175 was not affected by treatment of cells with brefeldin A but was abolished by treatment with nocodazole and cytochalasin D, indicating that secretion of this protein occurs via a nonclassical, Golgi apparatus-independent mechanism that utilizes the microtubule and actin microfilament network. A partial gene fragment coding for NSP4 aa112–175 was cloned and expressed using the baculovirus-insect cell system. Purified NSP4 aa112–175 increased intracellular calcium mobilization in intestinal cells when added exogenously, and in insect cells when expressed endogenously, similarly to full-length NSP4. NSP4 aa112–175 caused diarrhea in neonatal mice, as did full-length NSP4. These results indicate that NSP4 aa112–175 is a functional NSP4 enterotoxin peptide secreted from rotavirus-infected cells.
PMCID: PMC112448  PMID: 11090165
10.  Mutations in Rotavirus Nonstructural Glycoprotein NSP4 Are Associated with Altered Virus Virulence 
Journal of Virology  1998;72(5):3666-3672.
Rotaviruses are major pathogens causing life-threatening dehydrating gastroenteritis in children and animals. One of the nonstructural proteins, NSP4 (encoded by gene 10), is a transmembrane, endoplasmic reticulum-specific glycoprotein. Recently, our laboratory has shown that NSP4 causes diarrhea in 6- to 10-day-old mice by functioning as an enterotoxin. To confirm the role of NSP4 in rotavirus pathogenesis, we sequenced gene 10 from two pairs of virulent and attenuated porcine rotaviruses, the OSU and Gottfried strains. Comparisons of the NSP4 sequences from these two pairs of rotaviruses suggested that structural changes between amino acids (aa) 131 and 140 are important in pathogenesis. We next expressed the cloned gene 10 from the OSU virulent (OSU-v) and OSU attenuated (OSU-a) viruses by using the baculovirus expression system and compared the biological activities of the purified proteins. NSP4 from OSU-v virus increased intracellular calcium levels over 10-fold in intestinal cells when added exogenously and 6-fold in insect cells when expressed endogenously, whereas NSP4 from OSU-a virus had little effect. NSP4 from OSU-v caused diarrhea in 13 of 23 neonatal mice, while NSP4 from OSU-a caused disease in only 4 of 25 mice (P < 0.01). These results suggest that avirulence is associated with mutations in NSP4. Results from site-directed mutational analyses showed that mutated OSU-v NSP4 with deletion or substitutions in the region of aa 131 to 140 lost its ability to increase intracellular calcium levels and to induce diarrhea in neonatal mice, confirming the importance of amino acid changes from OSU-v NSP4 to OSU-a NSP4 in the alteration of virus virulence.
PMCID: PMC109587  PMID: 9557647

Results 1-10 (10)