Background There is as yet no ideal design of a plastic biliary stent with the longest patency period. Objective To study the safety and effective patency period of a new plastic antireflux biliary stent in the clinical setting. Design We conducted a prospective, randomized trial to compare the patency of 2 similar plastic biliary stents, one of which has an antiduodenobiliary reflux property. Setting The study was conducted at 2 separate tertiary centers in 2 countries. Patients Patients with inoperable distal malignant biliary obstruction were recruited. Interventions One of the 2 types of plastic stents under study was randomly chosen and inserted in the common bile duct of the study subjects. The subjects were followed until the end of study or occlusion occurrence. Main Outcome Measurements Our primary endpoint was the time to stent occlusion in days, with stent-related adverse events and all-cause mortality the secondary endpoints. Results A total of 16 subjects were recruited for the study; 7 were allocated to group A (ordinary Tannenbaum stent) and 9 to group B (antireflux biliary stent). Five of 7 subjects (71%) in group B had stent occlusion within 8 days, and the primary end point was reached in all 7 subjects within 30 days, whereas the primary endpoint was not reached within 30 days in any of the subjects in group A. Our data showed a significantly shorter stent patency period in group B compared with group A (P <.003). Limitations Small sample size. Conclusion Routine use of antireflux plastic biliary stents in the palliative management of malignant biliary obstructions cannot be recommended at present. (Clinical trial registration number: NCT01142921.)

Leong Quan Wai    Shen Mira L.    Au Kim    Luo Derek    Lau James Y.W.    Wu Justin C. Y.    Francis Chan    沈祖堯    

Gastrointestinal Endoscopy

2016

Kyaw Moe    沈祖堯    

Medical Journal of Australia

2016

Acute bleeding from esophageal varices (EV) is a potentially lethal complication in patients with portal hypertension and cirrhosis. Advances in medical and intensive care support, use of antibiotic prophylaxis and vasoactive drugs, and more effective endoscopic therapy have contributed to a decrease in mortality in patients with bleeding EV, although the mortality rate remains significant at about 20 %. Adequate resuscitation of the bleeding patient is vital in the initial management of esophageal variceal hemorrhage. The use of antibiotic prophylaxis has led to reduced bacterial infections and mortality in cirrhotic patients with variceal bleeding. The combination of vasoactive drugs and endoscopic therapy improves control of initial bleeding and 5-day hemostasis. Endoscopic band ligation is the preferred endoscopic therapy. In patients who fail vasoactive drugs and endoscopic therapy, rescue modalities, such as balloon tamponade, transjugular intrahepatic portosystemic shunt, and shunt surgery, can be considered in selected patients. This chapter includes supplementary videos.

Tang    沈祖堯    

GI Endoscopic Emergencies

2016

microRNA-29b (miR-29b) is known to be associated with TGF-β-mediated fibrosis, but the mechanistic action of miR-29b in liver fibrosis remains unclear and is warranted for investigation. We found that miR-29b was significantly downregulated in human and mice fibrotic liver tissues and in primary activated HSCs. miR-29b downregulation was directly mediated by Smad3 through binding to the promoter of miR-29b in hepatic stellate cell (HSC) line LX1, whilst miR-29b could in turn suppress Smad3 expression. miR-29b transduction in the liver of mice prevented CCl4 induced-fibrogenesis, concomitant with decreased expression of α-SMA, collagen I and TIMP-1. Ectopic expression of miR-29b in activated HSCs (LX-1, HSC-T6) inhibited cell viability and colony formation, and caused cell cycle arrest in G1 phase by downregulating cyclin D1 and p21^cip1. Further, miR-29b induced apoptosis in HSCs mediated by caspase-9 and PARP. miR-29b inhibited its downstream effectors of PIK3R1 and AKT3 through direct targeting their 3′UTR regions. Moreover, knockdown of PIK3R1 or AKT3 suppressed α-SMA and collagen I and induced apoptosis in both HSCs and in mice. In conclusion, miR-29b prevents liver fibrogenesis by inhibiting HSC activation and inducing HSC apoptosis through inhibiting PI3K/AKT pathway. These results provide novel mechanistic insights for the anti-fibrotic effect of miR-29b.

Wang Jia    Chu Eagle S.H.    Haiyong Chen    Kwan Man    Minnieyy Go    Huang Xiao Ru    Huiyao Lan    沈祖堯     Jun Yu   

Oncotarget

2015

Although surgery remains the mainstay of curative treatment for colorectal cancer (CRC), many patients still have high chance to experience disease relapse. It is therefore imperative to identify prognostic markers that can help predict the clinical outcomes of CRC. Aberrant microRNA expression holds great potential as diagnostic and prognostic biomarker for CRC. Here we aimed to investigate clinical potential of miR-34a-5p as a prognostic marker for CRC recurrence and its functional significance. First, we validated that miR-34a-5p was downregulated in CRC tumour tissues (P<0.05). The expression level of tissue miR-34a-5p was then evaluated in two independent cohorts of 268 CRC patients. miR-34a-5p expression was positively correlated with disease-free survival in two independent cohorts (cohort I: n=205, P<0.001; cohort II: n=63, P=0.006). Moreover, the expression of miR-34a-5p was an independent prognostic factor for CRC recurrence by multivariate analysis (P<0.001 for cohort I, P=0.007 for cohort II). Ectopic expression of miR-34a-5p in p53 wild-type colon cancer cell HCT116 significantly inhibited cell growth, migration, invasion and metastasis. miR-34a-5p induced cell apoptosis, cell cycle arrest at G1 phase and p53 transcription activity in HCT116 cells, but not in the HCT116 p53 knockout (p53) cells. miR-34a-5p significantly suppressed the HCT116 growth in vivo, whereas it showed no effect on the HCT116 p53 xenograft, indicating that the growth-inhibiting effect by miR-34a-5p was dependent on p53. In addition, the expression level of miR-34a-5p in patients with p53-positive expression was higher than that in patients with p53-negative expression (P<0.01). In conclusion, miR-34a-5p inhibits recurrence of CRC through inhibiting cell growth, migration and invasion, inducing cell apoptosis and cell cycle arrest in a p53-dependent manner.

高景    Li Na    Dong    Li Shan    Xu Lixia    Xiangchun Li    Yanyan Li    Zhongwu Li    Simon siu man Ng    沈祖堯     Shen    Jun Yu   

Oncogene

2015

Chromatin remodeling has emerged as a hallmark of gastric cancer, but the regulation of chromatin regulators other than genetic change is unknown. Helicobacter pylori causes epigenetic dysregulation to promote gastric carcinogenesis, but the roles and functions of microRNAs (miRNA) in this multistage cascade are not fully explored. In this study, miRNA expression in preneoplastic and neoplastic lesions in murine stomachs induced by H. pylori and N -methyl- N-nitrosourea (MNU) was pro filed by miRNA expression array. miR-490-3p exhibited progressive downregulation in gastritis, intestinal metaplasia, and adenocarcinoma during H. pylori and MNU-induced gastric carcinogenesis. Signifi cant downregulation of miR-490-3p was con fi rmed in human gastric cancer tissues in which its regulatory region was found to be hypermethylated. miR-490-3p exerted growth- and metastasis-suppressive effects on gastric cancer cells through directly targeting SMARCD1, a SWItch/ Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex subunit. Knockdown of SMARCD1 signi ficantly attenuated the protumorigenic effects of miR-490-3p inhibitor, whereas enforced expression of SMARCD1 promoted in vitro and in vivo oncogenic phenotypes of gastric cancer cells. SMARCD1 was markedly upregulated in gastric cancer in which its high expression was associated with shortened patients' survival independent of TNM staging. In conclusion, hyper-methylation-mediated silencing of miR-490-3p reactivates SMARCD1 to confer malignant phenotypes, mechanistically linking H. pylori , chromatin remodeling, and gastric carcinogenesis. Cancer Res; 75(4); 754-65.

Shen Jing    Xiao Zhangang    William ka kei Wu    Wang Maggie H.    To Ka F.    Chen Yangchao    Yang    Li May S.    Shin Vivian Y.    Joanna Tong    Wei Kang    Zhang Lin    Li Minxing    Lin Wang    Lu    Chan Ruby L.Y.    Sunny Wong    Jun Yu    Matthew Chan    Francis Chan    沈祖堯     Alfred Cheng    Chihin Cho   

Cancer Research

2015

Assessment of mucosal inflammation is important in the management of patients with ulcerative colitis (UC). Colon capsule endoscopy (CCE) has recently been shown to be effective in colorectal polyp detection. However, its role in the evaluation of mucosal inflammation in UC is unclear. This systematic review aims to clarify the state of the art with an evidence-based summary of current studies on the utility of CCE in UC. The overall results show that the accuracy of CCE for assessment of mucosal inflammation in UC appeared to be comparable with that of colonoscopy. Long-term follow-up studies with larger sample size are needed to further validate the utility of CCE in the management of UC subjects in clinical practice.

Shi Hai Yun    Siew Ng    Kelvin kf Tsoi    Wu Justin C.Y.    沈祖堯     Francis Chan   

Expert Review of Gastroenterology and Hepatology

2015

Background: Mucosal healing (MH) has been associated with improved outcomes in ulcerative colitis but factors associated with MH are not well defined. Methods: Consecutive patients with ulcerative colitis in clinical remission (Mayo symptomatic subscore 0) who had at least 1 colonoscopy since diagnosis from 6 centers were included. For patients who had at least 2 colonoscopies during follow-up, each colonoscopy was reviewed to define whether they had early MH (Mayo endoscopic subscore reduced to 0 within 3 yr of clinical remission). Factors associated with MH and early MH were determined using logistic regression. Results: Two hundred thirty-seven patients with ulcerative colitis (mean age 50.39 ± 14.10 yr; 56.5% male) were included. Independent factors for MH were clinical remission >3 years (odds ratio [OR] 4.0; 95% confidence interval [CI], 1.2-13.1), mild/moderate mucosal inflammation (OR 3.3; 95% CI, 1.3-8.5), and immunosuppressant use (OR 4.6; 95% CI, 1.5-14.6). Among patients who had ≥2 of above factors, 74% achieved MH, whereas only 39% with <2 factors achieved MH (P < 0.001). Of patients in clinical remission <1 year, 1 to 3 years and >3 years, 30%, 45.9%, and 62.9% achieved MH, respectively. Immunosuppressant therapy was associated with early MH (P 0.025). In multivariate analysis, patients with previous mild inflammation were more likely to achieve early MH than those with moderate/severe inflammation (OR 2.8; 95% CI, 1.2-6.2). Conclusions: A longer disease remission, previous less severe mucosal inflammation, and immunosuppressant use are associated with MH. Severity of mucosal inflammation and use of immunosuppressant are also associated with early MH.

Shi Hai Yun    Francis Chan    Tsang Steven W. C.    Hui Yee Tak    Sze Shun Fung    Ching Jessica Y.L.    Chung Tiffany    Iu Catherine Y. Y.    Lo Fu Hang    Shan Edwin H. S.    Li    Wu Justin C.Y.    沈祖堯     Siew Ng   

Inflammatory Bowel Diseases

2015

Background & Aims Aberrant chromatin modification is a key feature of hepatocellular carcinoma (HCC), which is characterized by strong sexual dimorphism. Both enhancer of zeste homolog 2 (EZH2) and cell cycle-related kinase (CCRK) contribute to hepatocarcinogenesis, yet whether the two oncogenic factors have functional crosstalk is unknown. Methods Cellular proliferation and tumorigenicity upon transgenic expression and RNA interference were determined by colony formation and soft agar assays, xenograft, orthotopic and diethylnitrosamine-induced HCC models. Gene regulation was assessed by chromatin immunoprecipitation, site-directed mutagenesis, luciferase reporter, co-immunoprecipitation and expression analyses. Protein levels in clinical specimens were correlated with clinicopathological parameters and patient survival rates. Results Ectopic CCRK expression in immortalized human liver cells increased EZH2 and histone H3 lysine 27 trimethylation (H3K27me3) to stimulate proliferation and tumor formation. Conversely, knockdown of CCRK reduced EZH2/H3K27me3 levels and decreased HCC cell growth, which could be rescued by EZH2 over-expression. Mechanistically, GSK-3β phosphorylation by CCRK activated a β-catenin/TCF/E2F1/EZH2 transcriptional feedback loop to epigenetically enhance androgen receptor (AR) signaling. Simultaneously, the phosphorylation of AKT/EZH2 by CCRK facilitated the co-occupancy of CCRK promoter by EZH2-AR and its subsequent transcriptional activation, thus forming a self-reinforcing circuitry. Lentiviral-mediated knockdown of CCRK, which abrogated the phosphorylation-transcriptional network, prevented diethylnitrosamine-induced tumorigenicity. More importantly, the hyperactivation of the CCRK-EZH2 circuitry in human HCCs correlated with tumor recurrence and poor survival. Conclusions These findings uncover an epigenetic vicious cycle in hepatocarcinogenesis that operates through reciprocal regulation of CCRK and EZH2, providing novel therapeutic strategy for HCC.

Feng Hai    Yu Zhuo    Tian Yuan    Lee Ying-Ying    Li May S.    Minnieyy Go    Cheung Yue-Sun    Lai Paul B.S.    Chan Andrew M.L.    To Ka Fai    Henry lik yuen Chan    沈祖堯     Alfred Cheng   

Journal of Hepatology

2015

OBJECTIVES:Serrated polyps of the colon comprise a heterogeneous group of lesions with distinct histological and malignant features. The presence of serrated polyps has been associated with synchronous advanced neoplasia, although the magnitude of this relationship is unclear.METHODS:Using studies identified from systematic literature search up to February 2014, we performed a systematic review and meta-analysis to estimate the pooled prevalence of serrated polyps and their association with synchronous advanced neoplasia. Random-effects models were used to combine estimates from heterogeneous studies, and odds ratios (ORs) with 95% confidence intervals (CIs) were presented.RESULTS:Nine studies with 34,084 participants were included. The mean age of subjects was 59.9±6.6 years and 52.5% of the subjects were male. Pooled prevalence of serrated polyps was 15.6% (95% CI, 10.3-22.9%). The pooled OR of advanced neoplasia in individuals with serrated polyps was 2.05 (95% CI, 1.38-3.04). Pooled analysis showed that the presence of proximal serrated polyps (OR=2.77, 95% CI, 1.71-4.46) and large serrated polyps (OR=4.10, 95% CI, 2.69-6.26) was associated with an increased risk of synchronous advanced neoplasia. The pooled OR for advanced neoplasia in individuals with proximal and large serrated polyps was 3.35 (95% CI, 2.51-4.46). Considerable heterogeneity was observed in most analyses.CONCLUSIONS:Our meta-analysis showed that serrated polyps are associated with a more than twofold increased risk of detection of synchronous advanced neoplasia. Individuals with proximal and large serrated polyps have the highest risk. These individuals deserve surveillance colonoscopy.

Gao    Kelvin kf Tsoi    Hirai Hoyee W.    黄至生    Francis Chan    Wu Justin C.Y.    Lau James Y.W.    沈祖堯     Siew Ng   

American Journal of Gastroenterology

2015