Xiaohua Man

Epidemiology of Peptic Ulcer Disease: Endoscopic Results of the Systematic Investigation of Gastrointestinal Disease in China

OBJECTIVES:Complications of peptic ulcer disease (PUD) are common in China. Population-based estimates of the prevalence of PUD are needed to quantify and characterize the population at risk of these complications.METHODS:As part of a large epidemiological study, 3,600 randomly selected residents of Shanghai (aged 18–80 years) were asked to undergo endoscopy and to provide blood samples for Helicobacter pylori serology. All participants also completed a general information questionnaire and Chinese versions of the reflux disease questionnaire (RDQ) and Rome II questionnaire. Associations between PUD and other factors were analyzed using a multiple logistic regression model.RESULTS:In total, 3,153 individuals (87.6%) completed the survey. All underwent blood tests, and 1,030 patients (32.7%) agreed to undergo endoscopy. Results from 1,022 patients were suitable for analysis. In all, 176 participants (17.2%) had PUD (62 with gastric ulcer; 136 with duodenal ulcer). The prevalence of H. pylori infection was 73.3% in the total population and 92.6% among those with PUD. H. pylori infection was associated with the presence of PUD (odds ratio (OR), 6.77; 95% confidence interval (CI), 2.85–16.10). The majority (72.2%) of individuals with PUD had none of the upper gastrointestinal symptoms assessed by the RDQ. PUD was not significantly associated with symptom-defined gastroesophageal reflux disease (GERD) (OR, 0.80; 95% CI, 0.32–2.03), reflux esophagitis (OR, 1.46; 95% CI, 0.76–2.79) or dyspepsia (OR, 1.69; 95% CI, 0.94–3.04).CONCLUSIONS:The prevalence of endoscopically confirmed PUD in this Shanghai population (17.2%) is substantially higher than in Western populations (4.1%). The majority of individuals with PUD were asymptomatic.

Diagnostic value of mucins (MUC1, MUC2 and MUC5AC) expression profile in endoscopic ultrasound-guided fine-needle aspiration specimens of the pancreas.

Mucins are aberrantly expressed in various malignancies. We immunohistochemistrically tested mucins expression (MUC1, MUC2 and MUC5AC) in EUS‐FNA samples from pancreatic occupying lesions for the diagnostic utility. The prevalence of MUC1, MUC2 and MUC5AC expression in pancreatic cancers were 77.5% (31/40), 10.0% (4/40) and 80.0% (32/40), respectively, and in the benign pancreatic diseases 25% (4/16), 31.3% (5/16) and 43.8% (7/16). MUC1 and MUC5AC significantly overexpressed in pancreatic cancer, and MUC1 negatively related with tumor differentiation degree (p < 0.05). The prevalence of MUC1, MUC2 and MUC5AC expression in pancreatic mucinous neoplasms were 66.7% (12/18), 38.9% (7/18) and 88.9% (16/18), respectively, and in the pancreatic nonmucinous neoplasms 60.5% (23/38), 5.3% (2/38) and 57.9% (22/38). MUC2 and MUC5AC significantly overexpressed in pancreatic mucinous neoplasms, especially MUC2 in benign mucinous neoplasms (p < 0.05). Compared with cytology alone, the combination test of MUC1+cytology, and MUC5AC+cytology could achieve higher sensitivity (85 vs. 65%, 100 vs. 65%) and accuracy (89.3% vs. 73.2%, 91.1% vs. 73.2%) for pancreatic cancer diagnosis; the combination test of MUC2 + cytology, and MUC5AC + cytology could achieve higher sensitivity (77.8% vs. 38.9%, 100% vs. 38.9%), and specificity (97.4% vs. 60.5%, 71.1% vs. 60.5%) accuracy (100% vs. 51.8%, 80.4% vs. 51.8%) for mucinous neoplasm diagnosis. The panel MUC1+/MUC2−/MUC5AC+/ was higher specific in pancreatic cancer diagnosis, as well as MUC1−/MUC2+/MUC5AC+/ in pancreatic mucinous neoplasms. Our observations suggest the mucins expression profile in EUS‐FNA specimens has higher value for the diagnosis of pancreatic cancer and mucinous neoplasms.

Epidemiology of symptom-defined gastroesophageal reflux disease and reflux esophagitis: the systematic investigation of gastrointestinal diseases in China (SILC).

Abstract Objective. Gastroesophageal reflux disease (GERD) is thought to be less prevalent in China than in Western countries. However, essential population-based endoscopy data are lacking for this country. Material and methods. As part of a wider study, 3600 individuals selected randomly from the Shanghai region were asked to undergo endoscopy. Participants completed a general information questionnaire and a Chinese version of the Reflux Disease Questionnaire. When sufficient numbers were available, associations were assessed using multiple logistic regression or the Wilcoxon rank-sum test. Results. Of 3153 (87.6%) individuals who completed the survey, 1030 (32.7%) agreed to endoscopy and 1029 endoscopies were suitable for analysis. Symptom-defined GERD was more prevalent in the endoscopy group (4.7%) than in the non-endoscopy group (1.7%). Prevalence estimates were 6.4% for reflux esophagitis, 1.8% for endoscopically suspected esophageal metaplasia and 0.7% for hiatus hernia. Reflux esophagitis was more prevalent in patients with symptom-defined GERD than in those without (12.5% [6/48] vs. 6.1% [60/981]), and was significantly associated with reflux symptoms of any frequency or severity (OR = 2.10, 95% CI 1.13–3.89) and with negative Helicobacter pylori infection (OR = 0.44, 95% CI 0.25–0.80). Only 28.8% of participants with reflux esophagitis had heartburn and/or regurgitation symptoms. Epigastric burning was significantly more severe and frequent in participants with reflux esophagitis than in those without (p = 0.05). Conclusions. Reflux esophagitis is less prevalent in China than reported in Western countries. Further work is needed to establish why reflux esophagitis appears less symptomatic in China than in Western countries.

Dyspepsia and irritable bowel syndrome in China: a population‐based endoscopy study of prevalence and impact

Aliment Pharmacol Ther 2010; 32: 562–572

Aberrant DNA methyltransferase expression in pancreatic ductal adenocarcinoma development and progression

BackgroundAltered gene methylation, regulated by DNA methyltransferases (DNMT) 1, 3a and 3b, contributes to tumorigenesis. However, the role of DNMT in pancreatic ductal adenocarcinoma (PDAC) remains unknown.MethodsExpression of DNMT 1, 3a and 3b was detected in 88 Pancreatic ductal adenocarcinoma (PDAC) and 10 normal tissue samples by immunohistochemistry. Changes in cell viability, cell cycle distribution, and apoptosis of PDAC cell lines (Panc-1 and SW1990) were assessed after transfection with DNMT1 and 3b siRNA. Levels of CDKN1A, Bcl-2 and Bax mRNA were assessed by qRT-PCR, and methylation of the Bax gene promoter was assayed by methylation-specific PCR (MSP).ResultsDNMT1, 3a and 3b proteins were expressed in 46.6%, 23.9%, and 77.3% of PDAC tissues, respectively, but were not expressed in normal pancreatic tissues. There was a co-presence of DNMT3a and DNMT3b expression and an association of DNMT1 expression with alcohol consumption and poor overall survival. Moreover, knockdown of DNMT1 and DNMT3b expression significantly inhibited PDAC cell viability, decreased S-phase but increased G1-phase of the cell cycle, and induced apoptosis. Molecularly, expression of CDKN1A and Bax mRNA was upregulated, and the Bax gene promoter was demethylated. However, a synergistic effect of combined DNMT1 and 3b knockdown was not observed.ConclusionExpression of DNMT1, 3a and 3b proteins is increased in PDAC tissues, and DNMT1 expression is associated with poor prognosis of patients. Knockdown of DNMT1 and 3b expression arrests tumor cells at the G1 phase of the cell cycle and induces apoptosis. The data suggest that DNMT knockdown may be a novel treatment strategy for PDAC.

E1B-55kD-deleted oncolytic adenovirus armed with canstatin gene yields an enhanced anti-tumor efficacy on pancreatic cancer

Conditionally-replicating adenovirus (CRAd) therapy is currently being tested against pancreatic cancer and has shown some promise. To improve the efficacy, a novel virus CRAd-Cans was designed by deletion of E1B-55kDa gene for selective replication in tumor cells, as well as carrying a new angiogenesis inhibitor gene, canstatin. CRAd-Cans mediated higher expression of canstatin in BxPC-3 pancreatic cancer cell line compared to the replication-deficient adenovirus Ad5-Cans. The modified CRAd-Cans manifested the same selective replication and cytocidal effects in pancreatic cancer cells as ONYX-015 in vitro, yet showed greater reduction of tumor growth in nude mice with markedly prolonged survival rate in vivo (P<0.05), compared to that of either ONYX-015 or Ad5-Cans. Pathological examination revealed viral replication, decreased microvessel density and increased cancer cell apoptosis in CRAd-Cans-treated xenografts. The results suggest that the novel oncolytic virus CRAd-Cans, showing synergistic effects of oncolytic therapy and anti-angiogenesis therapy, is a new promising therapeutics for pancreatic cancer.

Adenovirus vector-mediated Gli1 siRNA induces growth inhibition and apoptosis in human pancreatic cancer with Smo-dependent or Smo-independent Hh pathway activation in vitro and in vivo.

Activation of Hedgehog (Hh) signaling pathway is a core molecular mechanism in pancreatic carcinogenesis. However, the inhibition of upstream Hh signals does not inhibit the growth of a subset of pancreatic cancer (PC). This study was to examine the effect of siRNA targeting Gli1, the downstream component of Hh pathway, on PC cells and to provide some insight into the underlying mechanisms. A Gli1siRNA-expressing adenovirus (Ad-U6-Gli1siRNA) was constructed, and its effect on PC cells was investigated in vitro and in vivo. Gli1 was expressed in 83.3% (20/24) PC tissues, whereas no expression was found in normal pancreatic ductal epithelium. Gli1 was expressed in SW1990 and CFPAC cells in which Smo was completely absent, as well as in PaTu8988, Panc-1 and BxPC-3 cells in which Smo was concomitantly present. Ad-U6-Gli1siRNA induced cell growth inhibition, strong G0/G1 cell cycle arrest and apoptosis in all five human PC cell lines. Meanwhile, Ad-U6-Gli1siRNA significantly suppressed the expression of Gli1, Ptch1 and two target genes, Cyclin D2 and Bcl-2, in all five lines. Furthermore, two tumor xenograft nude mice models were established by subcutaneously injecting Smo-positive Panc-1 cells or Smo-negative SW1990 cells. The in vivo experimental results demonstrated that Ad-U6-Gli1siRNA inhibited the growth of both Panc1-derived and SW1990-derived tumors and induced cell apoptosis. Our study indicates that Gli1-targeting siRNA could induce growth inhibition and apoptosis in PC through knockdown of Gli1 and its target genes; and this method may represent a more effective therapeutic strategy for PC with Smo-dependent or Smo-independent Hh pathway activation.

Toll-like receptor 4 promotes angiogenesis in pancreatic cancer via PI3K/AKT signaling.

Deregulation of Toll-like receptor 4 (TLR4) is closely associated with the progression of various types of cancers, but its role in pancreatic carcinogenesis is unclear. This study aimed to investigate the role of TLR4 in the angiogenesis of pancreatic cancer and the underlying molecular mechanisms. The culture supernatant (conditioned medium) of PANC-1 cells after appropriate treatment was used for the treatment of HUVECs. The proliferation, migration and tube formation of HUVECs were assessed by MTT, Transwell and Matrigel, respectively. In pancreatic cancer tissues, TLR4, VEGF and CD31 were upregulated as determined by immunohistochemistry and the expression of TLR4 and VEGF was positively correlated with microvessel density as detected by CD31 staining. Activation of TLR4 signaling by LPS in PANC-1 cells resulted in increased VEGF and phosphorylation of AKT, which were abolished by TLR4 silencing with siRNA and PI3K/AKT signaling inhibitor LY294002. The conditioned medium from PANC-1 cells treated with LY294002 or transfected with TRL4 siRNA reduced the proliferation, migration and tube formation of HUVECs. In contrast, the conditioned medium from PANC-1 cells treated with LPS stimulated the proliferation, migration and tube formation of HUVECs, which was however significantly inhibited by pretreatment of PANC-1 cells with LY294002 or transfection with TRL4 siRNA. Our findings suggest TLR4 may promote angiogenesis in pancreatic cancer by activating the PI3K/AKT signaling pathway to induce VEGF expression.

Helicobacter pylori infection and gastritis: The Systematic Investigation of gastrointestinaL diseases in China (SILC)

Background and Aim:  Helicobacter pylori infection remains common in East Asia, though its prevalence is decreasing in Western countries. H. pylori‐related atrophic gastritis (AG) may reduce the likelihood of gastroesophageal reflux disease (GERD). We investigated the prevalence of H. pylori infection and AG and their association with endoscopic findings and symptom‐defined GERD in Shanghai.

A Novel Approach for Treatment of Unresectable Pancreatic Cancer: Design of Radioactive Stents and Trial Studies on Normal Pigs

Purpose: Patients diagnosed with pancreatic cancer typically have a poor prognosis. The aims of these studies were to design radioactive stents and to evaluate the feasibility and safety of the stents in animals. Experimental Design: To combine the effects of stents and brachytherapy, plastic stents with inserted iodine-125 seeds were designed and tested in 18 normal pigs. The pigs were divided into five groups on the basis of radiation dose. The estimated radiation dose at a 5-mm radial distance from the axis of the seeds was 50 Gy in group A, 100 Gy in group B, 150 Gy in group C, and 200 Gy in group D, with four pigs in each group. In the control group (n = 2), the same plastic stents with non-radioactive seeds were implanted in the pancreatic duct. Results: The procedures were successfully done on 14 of 18 (78%) pigs, whereas pancreatic duct perforation occurred in four pigs (22%). The thickened wall of the dilated pancreatic duct was clearly observed in the control group. However, the normal morphologic structure of the pancreatic duct wall disappeared in the experimental groups. Histopathologic examination revealed that the stents were surrounded with necrotic tissues and lateral fibrous tissues. During the follow-up period, the width of outside fibrous tissues gradually increased. Conclusions: These results indicate that the radioactive stents are safe in all dose groups, and it is feasible to design a special radioactive stent for each patient according to the size, shape, and position of the pancreatic tumor.