Objective: To develop and validate a clinical risk score predictive of risk for colorectal advanced neoplasia for Asia. Methods: A prospective, cross-sectional and multicentre study was carried out in tertiary hospitals in 11 Asian cities. The subjects comprise 2752 asymptomatic patients undergoing screening colonoscopy. From a development set of 860 asymptomatic subjects undergoing screening colonoscopy, multiple logistic regression was applied to identify significant risk factors for advanced colorectal neoplasia defined as invasive carcinoma or advanced adenoma. The ORs for significant risk factors were utilised to develop a risk score ranging from 0 to 7 (Asia-Pacific Colorectal Screening (APCS) score). Three tiers of risk were arbitrarily defined: 0-1 'average risk' (AR); 2-3 'moderate risk' (MR); and 4-7 'high risk' (HR). Subjects undergoing screening colonoscopy between July 2006 and December 2007 were prospectively enrolled to form an independent validation group. Each subject had a personal APCS score calculated by summing the points attributed from the presence of risk factors in the individuals. The performance of the APCS score in predicting risk of advanced neoplasia was evaluated. Results: There were 860 subjects in the derivation set and 1892 subjects in the validation set, with a baseline prevalence of advanced neoplasia of 4.5% and 3%, respectively. Applying the APCS stratification in the validation set, 559 subjects (29.5%) were in the AR tier, 966 subjects (51.1%) in the MR tier and 367 (19.4%) subjects in the HR tier. The prevalence of advanced neoplasia in the AR, MR and HR groups was 1.3, 3.2 and 5.2%, respectively. The subjects in the MR and HR tiers had 2.6-fold (95% CI 1.1 to 6.0) and 4.3-fold (95% CI 1.8 to 10.3) increased prevalence of advanced neoplasia, respectively, than those in the AR tier. Conclusions: The APCS score based on age, gender, family history and smoking is useful in selecting asymptomatic Asian subjects for priority of colorectal screening.

Khay guan Yeoh    Khek yu Ho    Hanmo Chiu    Zhu Feng    Jessica Ching    Deng chyang Wu    Matsuda    Byeon Jeong-Sik    Sang kil il Lee    Khean lee Goh    José Sollano    Rerknimitr    Leong    Kelvin kf Tsoi    Jawtown Lin    沈祖堯    

Gut

2011

As there is currently a lack of consensus on the most appropriate dose and duration of peginterferon alfa-2a (PEG-IFNα-2a) therapy in hepatitis B e antigen (HBeAg)-positive patients, the efficacy and safety of either 24 or 48 weeks' duration and 90 μg/week or 180 μg/week doses were compared. HBeAg-positive patients (n = 544; 34% genotype B, 51% genotype C) were randomized to receive PEG-IFNα-2a (2 × 2 factorial design) for 24 or 48 weeks and at 90 μg/week or 180 μg/week and included in the per-protocol population. The primary efficacy endpoint of the noninferiority study was HBeAg seroconversion 6 months posttreatment. The prespecified odds ratio (OR) noninferiority margin was 1.88 with a one-sided significance level of 0.025. The highest rates of HBeAg seroconversion 6 months posttreatment were in the 180/48 arm (36.2% versus 14.1%-25.8% in the other arms). When the dose and duration arms were pooled, the OR for noninferiority of 24 weeks versus 48 weeks was 2.17 (95% confidence interval [CI] 1.43, 3.31; P = 0.749) and for 90 μg versus 180 μg was 1.79 (95% CI 1.18, 2.72; P = 0.410). As the upper limit of the 95% CI of the ORs were >1.88, 24 weeks were inferior to 48 weeks and 90 μg/week was inferior to 180 μg/week. The highest rates of response in the 180/48 arm were achieved by patients with HBsAg <1,500 IU/mL at Week 12 (58%) or Week 24 (57%), whereas patients with HBsAg >20,000 IU/mL did not respond. Adverse events were typical of those associated with PEG-IFNα-2a. Conclusion: Compared with lower doses and shorter durations, the licensed PEG-IFNα-2a treatment regimen (180μg/48 weeks) was the most efficacious and beneficial for HBeAg-positive patients predominantly infected with hepatitis B virus genotypes B or C. © 2011 American Association for the Study of Liver Diseases.

Liaw Yun-Fan    Jidong Jia    Henry lik yuen Chan    Kwanghyub Han    Tanwandee Tawesak    Chuang Wanlong    Tan De-ming    Xinyue Chen    Edward Gane    Teerha Piratvisuth    Lixiang Chen    谢青    沈祖堯     Wat    Bernaards    Cui    Patrick Marcellin   

Hepatology

2011

Objectives: Functional constipation (FC) is a common clinical complaint. Despite a lack of consolidated evidence, Chinese herbal medicine (CHM) has become a popular alternative treatment for this condition. The aim of this study was to assess, with a rigidly designed study, the efficacy and safety of a CHM proprietary medicine, Hemp Seed Pill (HSP), in optimal dosage for treating FC. Methods: This study comprised two parts: trial I, a dose determination study, and trial II, a placebo-controlled clinical study. In trial I, the optimal dosage of HSP was first determined from among three doses (2.5, 5.0, and 7.5 g b.i.d.). In trial II, a randomized double-blind study, the efficacy and safety of HSP for FC patients (Rome III criteria) in excessive syndrome as defined by traditional Chinese medicine (TCM) theory were compared with placebo. All participants in trials underwent a 2-week run-in, an 8-week treatment, and an 8-week follow-up. The primary end point was the responder rate for complete spontaneous bowel movement (CSBM) during treatment. Participants with a mean increase of CSBM 1/week compared with their baselines were defined as responders. Secondary outcome measures included responder rate during follow-up, individual and global symptom assessments, and reported adverse effects (AEs). Results: The dose of 7.5 g b.i.d. showed better therapeutic effect than that of 2.5 and 5.0 g b.i.d. among 96 subjects (32 per arm) in trial I and was therefore selected for comparison with placebo in trial II. In trial II, 120 subjects were randomized into two arms (60 per arm). Responder rates for the HSP and placebo groups were 43.3 and 8.3% during treatment and 30.0 and 15.0% in the follow-up period, respectively (P<0.05). Those in the HSP group showed benefit in terms of increased CSBM, relief in the severity of constipation and straining of evacuation, and effective reduction in the use of rescue therapy when compared with placebo. No serious AE was reported. Conclusions: HSP (7.5 g b.i.d.) is safe and effective for alleviating FC for subjects in excessive syndrome. Optimal dose determination may be crucial for all CHM studies. © 2011 by the American College of Gastroenterology.

Chungwah Cheng    Zhaoxiang Bian    朱力行    胡志    沈祖堯    

American Journal of Gastroenterology

2011

Colon carcinogenesis represents a stepwise progression from benign polyps to invasive adenocarcinomas and distant metastasis. It is believed that these pathologic changes are contributed by aberrant activation or inactivation of protein-coding proto-onco genes and tumor suppressor genes. However, recent discoveries in microRNA (miRNA) research have reshaped our understanding of the role of non-protein-coding genes in carcinogenesis. In this regard, a remarkable number of miRNAs exhibit differential expression in colon cancer tissues. These miRNAs alter cell proliferation, apoptosis and metastasis through their interactions with intracellular signaling networks. From a clinical perspective, polymorphisms within miRNA-binding sites are associated with the risk for colon cancer, whereas miRNAs isolated from feces or blood may serve as biomarkers for early diagnosis. Altered expression of miRNA or polymorphisms in miRNA-related genes have also been shown to correlate with patient survival or treatment outcome. With further insights into miRNA dysregulation in colon cancer and the advancement of RNA delivery technology, it is anticipated that novel miRNA-based therapeutics will emerge. © The Author 2010. Published by Oxford University Press. All rights reserved.

William ka kei Wu    Yin Law Priscilla Tak    Chungwa Lee    Chihin Cho    樊代明    Kaichun Wu    Jun Yu    沈祖堯    

Carcinogenesis

2011

Aim: Nuclear factor-kappa B inhibitor alpha (IκBα) polymorphisms were found to be associated with inflammatory diseases. However, the association between IκBα polymorphisms with gastric cancer is still unknown. We aim to investigate the association between IκBα polymorphisms and gastric cancer risk in a large population-based case-control study among southern Chinese. Main methods: A population-based case-control study was conducted between 1999 and 2006 in Guangdong Province, China. A total of 1010 gastric cancer patients and 1500 healthy controls were enrolled in this study. IκBα polymorphisms were identified by sequencing of IκBα gene ranging from the 2 kb promoter region to the 3.5 kb genomic region. Polymorphisms in IκBα were analyzed by TaqMan SNP genotyping assay. Key findings: rs17103265 deletion homozygote (-/-) had significantly increased gastric cancer risk (OR = 2.11, 95% CI = 1.17-3.83, P = 0.01), compared with rs17103265 T homozygote (TT). rs17103265 (-/-) genotype was significantly associated with increased risk of intestinal-type gastric cancer with (OR = 2.21, 95% CI = 1.19-4.08, P = 0.01), but not with the diffuse or mix type of gastric cancer. rs17103265 (-/-) was associated with poorly differentiated gastric cancer (OR = 2.05, 95% CI = 1.07-3.94, P = 0.03), but not with moderately or well differentiated gastric cancer. A significant decrease in luciferase activity was observed in rs17103265 deletion allele as compared with the vector containing the rs17103265 T allele (P < 0.0001). rs17103265 polymorphism was not associated with the prognosis of gastric cancer patients. Significance: IκBα rs17103265 deletion homozygote is a novel genetic risk factor for gastric carcinogenesis, especially for the development of certain subtypes of gastric cancer in southern Chinese population. © 2011 Elsevier Inc.

Shiyan Wang    Zhang Mingdong    曾志荣    Linwei Tian    Kaichun Wu    Chu Jian-Hong    樊代明    Pinjin Hu    沈祖堯     Jun Yu   

Life Sciences

2011

Purpose: Yes-associated protein 1 (YAP1) is a multifunctional protein that can interact with different transcription factors to activate gene expression. The role of YAP1 in tumorigenesis is unclear. We aimed to investigate the functional role of YAP1 in tumorigenesis of gastric cancer. Experimental Design: YAP1 expresson in gastric adenocarcinoma was evaluated. The biological function was determined by proliferation assay, colony formation, cell invasion, and flow cytometric analysis through knocking down or ectopic expressing YAP1 in gastric cancer cell lines coupled with in vivo study. The possible downstream effectors of YAP1 were investigated by expression microarray. Results: YAP1 protein expression was upregulated in gastric cancer. Nuclear accumulation of YAP1 was associated with poor disease-specific survival (P = 0.021), especially in patients with early-stage diseases (P < 0.001). Knockdown YAP1 resulted in a significant reduction in proliferation, anchoragedependent colony formation, cell invasion, and cell motility. Ectopic YAP1 expression promoted anchorage-independent colony formation, induced a more invasive phenotype, and accelerated cell growth both in vitro and in vivo. Microarray analysis highlighted the alteration of MAPK (mitogenactivated protein kinase) pathway by YAP1. We confirmed a constitutive activation of RAF/MEK/ERK (extracellular signal-regulated kinase) in YAP1-expressing MKN45 cells and further showed that YAP1 enhanced serum/epidermal growth factor-induced c-Fos expression in gastric cancer cells. Conclusions: Our findings supported that YAP1 exhibits oncogenic property in gastric cancer. We provided the first evidence that YAP1 exerted the oncogenic function by enhancing the capacity to activate the early-response gene pathway. YAP1 could be a prognostic biomarker and potential therapeutic target for gastric cancer. © 2011 American Association for Cancer Research.

Wei Kang    Tong Joanna H.M.    Anthony wing hong Chan    Tinlap Lee    Raymond wai ming Lung    Leung Patrick P. S.    So Ken K. Y.    Kaichun Wu    樊代明    Jun Yu    沈祖堯     Kafai To   

Clinical Cancer Research

2011

Chungwah Cheng    Zhaoxiang Bian    朱力行    Wu Justin C.Y.    沈祖堯    

American Journal of Gastroenterology

2011

Ethnopharmacological relevance: Coptis chinensis rhizomes (Coptidis Rhizoma, CR), also known as "Huang Lian", is a common component of traditional Chinese herbal formulae used for the relief of abdominal pain and diarrhea. Yet, the action mechanism of CR extract in the treatment of irritable bowel syndrome is unknown. Thus, the aim of our present study is to investigate the effect of CR extract on neonatal maternal separation (NMS)-induced visceral hyperalgesia in rats and its underlying action mechanisms. Materials and methods: Male Sprague-Dawley rats were subjected to 3-h daily maternal separation from postnatal day 2 to day 21 to form the NMS group. The control group consists of unseparated normal (N) rats. From day 60, rats were administrated CR (0.3, 0.8 and 1.3 g/kg) or vehicle (Veh; 0.5% carboxymethylcellulose solution) orally for 7 days for the test and control groups, respectively. Results: Electromyogram (EMG) signals in response to colonic distension were measured with the NMS rats showing lower pain threshold and increased EMG activity than those of the unseparated (N) rats. CR dose-dependently increased pain threshold response and attenuated EMG activity in the NMS rats. An enzymatic immunoassay study showed that CR treatment significantly reduced the serotonin (5HT) concentration from the distal colon of NMS rats compared to the Veh (control) group. Real-time quantitative PCR and Western-blotting studies showed that CR treatment substantially reduced NMS induced cholecystokinin (CCK) expression compared with the Veh group. Conclusions: These results suggest that CR extract robustly reduces visceral pain that may be mediated via the mechanism of decreasing 5HT release and CCK expression in the distal colon of rats. © 2011 Elsevier Ireland Ltd. All rights reserved.

Tjong Yung-Wui    Siupo Ip    Lixing Lao    Fong Harry H. S.    沈祖堯     Berman Brian    Chuntao Che   

Journal of Ethnopharmacology

2011

Background Nitric oxide (NO) is implicated in the pathogenesis of irritable bowel syndrome (IBS) but the underlying mechanism is unclear. Thus, the aim of the present study is to examine the role of NO synthase (NOS) expression in the distal colon of neonatal maternal separation (NMS) model rats employed in IBS studies. Methods Male neonates of Sprague-Dawley rats were randomly assigned into NMS and normal control (N) groups. Rats of NMS group were subjected to 3h daily maternal separation on postnatal day 2-21. Rats were administrated non-selective NOS inhibitor l-NAME (100mgkg ), selective neuronal NOS (nNOS) inhibitor 7-NINA (10mgkg ), selective inducible NOS (iNOS) inhibitor, endothelial NOS (eNOS) inhibitor (10mgkg ) or Vehicle (Veh; distilled water) intraperitoneally 1h prior to the experiment for the test and control groups, respectively. Key Results The amount of NO was significantly higher in the NMS Veh rats compared with unseparated N rats. Western-blotting and real-time quantitative PCR studies showed that protein and mRNA expression of nNOS were higher in the NMS group than that in the N rats; whereas no significant change in iNOS and eNOS was found in either groups. Neonatal maternal separation Veh rats showed low pain threshold and increased electromyogram (EMG) activity in response to colonic distension stimuli. l-NAME and 7-Nitroindazole monosodium salt (7-NINA) increased pain threshold pressure and attenuated EMG activity in the NMS rats. In addition, l-NAME and 7-NINA substantially reduced oxidative marker malondialdehyde level in NMS rats. Conclusions & Inferences Neonatal maternal separation increased the NO generation by nNOS upregulation that interact with reactive oxygen species contributing to the visceral hypersensitivity in IBS. © 2011 Blackwell Publishing Ltd.

Tjong Yung-Wui    Siupo Ip    Lixing Lao    胡志    Fong Harry H. S.    沈祖堯     Berman Brian    Chuntao Che   

Neurogastroenterology and Motility

2011

Background & Aims: Computed tomography colonography (CTC) is a recommended screening modality for colorectal cancer (CRC). It is not known whether polyps 6-9 mm based on CRC are likely to have advanced histologic features in Asian patients. We estimated the risk of advanced colonic neoplasia (ACN) from polyps <10 mm and the risk of ACN detection failure if patients with polyps <10 mm are not referred for colonoscopy. Methods: The study included 1457 subjects from the Asia-Pacific Working Group on CRC screening and the Hong Kong CRC screening program. Polyps and ACN found during colonoscopy examinations were classified by size and histology. Results: Of the subjects, 38.2% had polyps; 16.7% of these were ACN, 5.4% of ACN were ≤5 mm, and 24.7% of the ACN were 6-9 mm. Adopting the policy of reporting polyps found by CTC of <5 mm as normal and repeating CTC in patients with polyps of 6-9 mm, 5.4% of subjects with ACN, 4.5% of male subjects, and 11.5% of subjects with family history of CRC would be classified as normal. In referring patients with polyps of 6-9 mm for CTC surveillance, 20.4% of those with ACN, 22.4% of those that are male, and 23.1% of those with family histories of CRC would have polypectomies delayed by at least 3 years. Conclusions: A substantial proportion of polyps <10 mm have advanced histologic features in Asia, so patients with a polyp of 6 mm or more at CTC should be offered colonoscopies with polypectomies, rather than CTC surveillance of polyps. © 2011 AGA Institute.

沈祖堯     Luo    Simon siu man Ng    James Lau    Kelvin kf Tsoi   

Clinical Gastroenterology and Hepatology

2011