沈祖堯    

Endoscopy

2011

Background/Aims: The incidence of uncomplicated peptic ulcer has decreased in recent years. It is unclear what the impact of this has been on the epidemiology of peptic ulcer complications. This systematic review aimed to determine the incidence, recurrence and mortality of complicated peptic ulcer and the risk factors associated with these events. Methods: Systematic PubMed searches. Results: Overall, 93 studies were identified. Annual incidence estimates of peptic ulcer hemorrhage and perforation were 19.4-57.0 and 3.8-14 per 100,000 individuals, respectively. The average 7-day recurrence of hemorrhage was 13.9% (95% CI: 8.4-19.4), and the average long-term recurrence of perforation was 12.2% (95% CI: 2.5-21.9). Risk factors for peptic ulcer complications and their recurrence included nonsteroidal anti-inflammatory drug and/or acetylsalicylic acid use, Helicobacter pylori infection and ulcer size ≥1 cm. Proton pump inhibitor use reduced the risk of peptic ulcer hemorrhage. Average 30-day mortality was 8.6% (95% CI: 5.8-11.4) after hemorrhage and 23.5% (95% CI: 15.5-31.0) after perforation. Older age, comorbidity, shock and delayed treatment were associated with increased mortality. Conclusions: Complicated peptic ulcer remains a substantial healthcare problem which places patients at a high risk of recurrent complications and death. Copyright © 2011 S. Karger AG, Basel.

James Lau    沈祖堯     Catherine jane Hill    Henderson    Howden    David Metz   

Digestion

2011

Vincent Wong    沈祖堯    

Alimentary Pharmacology and Therapeutics

2011

The Hong Kong HIV Cohort Database is an observational cohort including all patients enrolled in 2 HIV specialist clinical services in Hong Kong. Basic demographics, HIV transmission category, and the diagnoses of AIDS were captured using a standardized template. As of December 2006, 2132 HIV cases had been registered in the database, representing two thirds of all reports submitted to the government's surveillance system. Non-Chinese and young females ≥24 years were less represented in the cohort. Description of cohort cases was, however, more complete in terms of transmission category and presentation with AIDS-defining illnesses. Overall, Pneumocystis jirovecci, tuberculosis, and systemic mycosis accounted for a majority of AIDS cases within 3 months of HIV diagnosis. There was a gradual rise of HIV positive men having sex with men in the cohort, notably after 2002, an observation also made in other Asian countries. © 2011 APJPH.

Lee Shui Shan    Lee Krystal C.K.    Lee Man Po    Tse Ian C.T.    Mak Wai Lai    Li    Wong    沈祖堯    

Asia-Pacific Journal of Public Health

2011

In cancer cells, glucose is often converted into lactic acid, which is known as the Warburg effect. The reason that cancer cells have a higher rate of aerobic glycolysis, but not oxidative phosphorylation, remains largely unclear. Herein, we proposed an epigenetic mechanism of the Warburg effect. Fructose-1,6-bisphosphatase-1 (FBP1), which functions to antagonize glycolysis was downregulated through NF-kappaB pathway in Ras-transformed NIH3T3 cells. Restoration of FBP1 expression suppressed anchorage-independent growth, indicating the relevance of FBP1 downregulation in carcinogenesis. Indeed, FBP1 was downregulated in gastric carcinomas (P<0.01, n22) and gastric cancer cell lines (57%, 4/7). Restoration of FBP1 expression reduced growth and glycolysis in gastric cancer cells. Moreover, FBP1 downregulation was reversed by pharmacological demethylation. Its promoter was hypermethylated in gastric cancer cell lines (57%, 4/7) and gastric carcinomas (33%, 33/101). Inhibition of NF-kappaB restored FBP1 expression, partially through demethylation of FBP1 promoter. Notably, Cox regression analysis revealed FBP1 promoter methylation as an independent prognosis predicator for gastric cancer (hazard ratio: 3.60, P0.010). In summary, we found that NF-kappaB functions downstream of Ras to promote epigenetic downregulation of FBP1. Promoter methylation of FBP1 can be used as a new biomarker for prognosis prediction of gastric cancer. Such an important epigenetic link between glycolysis and carcinogenesis partly explains the Warburg effect. © 2010 Macmillan Publishers Limited All rights reserved.

Liu    Xian Wang    Jianbin Zhang    Emily Lam    Vivian yvonne Shin    Alfred Cheng    Jieping Yu    Francis Chan    沈祖堯     Hongchuan Jin   

Oncogene

2010

Background: Peptic ulcer bleeding (PUB) is a serious and sometimes fatal condition. The outcome of PUB strongly depends on the risk of rebleeding. A recent multinational placebo-controlled clinical trial (ClinicalTrials.gov identifier: NCT00251979) showed that high-dose intravenous (IV) esomeprazole, when administered after successful endoscopic haemostasis in patients with PUB, is effective in preventing rebleeding. From a policy perspective it is important to assess the cost efficacy of this benefit so as to enable clinicians and payers to make an informed decision regarding the management of PUB. Objective: Using a decision-tree model, we compared the cost efficacy of highdose IV esomeprazole versus an approach of no-IV proton pump inhibitor for prevention of rebleeding in patients with PUB. Method: The model adopted a 30-day time horizon and the perspective of third-party payers in the USA and Europe. The main efficacy variable was the number of averted rebleedings. Healthcare resource utilization costs (physician fees, hospitalizations, surgeries, pharmacotherapies) relevant for the management of PUB were also determined. Data for unit costs (prices) were primarily taken from official governmental sources, and data for other model assumptions were retrieved from the original clinical trial and the literature. After successful endoscopic haemostasis, patients received either highdose IV esomeprazole (80mg infusion over 30 min, then 8mg/hour for 71.5 hours) or no-IV esomeprazole treatment, with both groups receiving oral esomeprazole 40mg once daily from days 4 to 30. Results: Rebleed rates at 30 days were 7.7% and 13.6%, respectively, for the high-dose IV esomeprazole and no-IV esomeprazole treatment groups (equating to a number needed to treat of 17 in order to prevent one additional patient from rebleeding). In the US setting, the average cost per patient for the high-dose IV esomeprazole strategy was $US14 290 compared with $US14 239 for the no-IV esomeprazole strategy (year 2007 values). For the European setting, Sweden and Spain were used as examples. In the Swedish setting the corresponding respective figures were Swedish kronor (SEK)67 862 ($US9220 at average 2006 interbank exchange rates) and SEK67 807 ($US9212) [year 2006 values]. Incremental cost-effectiveness ratios were $US866 and SEK938 ($US127), respectively, per averted rebleed when using IV esomeprazole. For the Spanish setting, the high-dose IV esomeprazole strategy was dominant (more effective and less costly than the no-IV esomeprazole strategy) [year 2008 values]. All results appeared robust to univariate/threshold sensitivity analysis, with high-dose IV esomeprazole becoming dominant with small variations in assumptions in the US and Swedish settings, while remaining a dominant approach in the Spanish scenario across a broad range of values. Sensitivity variables with prespecified ranges included lengths of stay and per diem assumptions, rebleeding rates and, in some cases, professional fees. Conclusion: In patients with PUB, high-dose IV esomeprazole after successful endoscopic haemostasis appears to improve outcomes at a modest increase in costs relative to a no-IV esomeprazole strategy from the US and Swedish thirdparty payer perspective. Whereas, in the Spanish setting, the high-dose IV esomeprazole strategy appeared dominant, being more effective and less costly. © 2010 Adis Data Information BV. All rights reserved.

Alan Barkun    Adam Viviane    沈祖堯     Ernst johan Kuipers    Joachim Mossner    Jensen    Stuart    James Lau    Nauclér Emma    Kilhamn Jan    Granstedt Helena    Liljas Bengt    Tore Lind   

PharmacoEconomics

2010

AIM: To investigate the pharmacological effect of JCM-16021, a Chinese herbal formula, and its underlying mechanisms. METHODS: JCM-16021 is composed of seven herbal plant materials. All raw materials of the formula were examined according to the quality control criteria listed in the Chinese Pharmacopeia (2005). In a neonatal maternal separation (NMS) model, male Sprague-Dawley rats were submitted to daily maternal separation from postnatal day 2 to day 14, or no specific handling (NH). Starting from postnatal day 60, rats were administered JCM-16021 (2, 4, 8 g/kg per day) orally twice a day for 28 d. Pain threshold pressure and electromyographic activities of external oblique muscles in response to colorectal distention recorded with a Power Lab System (AD Instruments International), were tested as pain indices. Changes in serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations in the colon of rats were analyzed; the enterochromaffin cell numbers and serotonin transporter in the colon of rats were also evaluated with an immunohistochemistry method. RESULTS: NMS treatment significantly reduced pain threshold pressure (37.4 ± 1.4 mmHg), as compared to that of NH rats (57.7 ± 1.9 mmHg, P < 0.05). After JCM-16021 treatment, the pain threshold pressure significantly increased when compared to that before treatment (34.2 ± 0.9 mmHg vs 52.8 ± 2.3 mmHg in the high dose group, 40.2 ± 1.6 mmHg vs 46.5 ± 1.3 mmHg in the middle dose group, and 39.3 ± 0.7 mmHg vs 46.5 ± 1.6 mmHg in the low dose group, P < 0.05). Also JCM-16021 significantly and dose-dependently decreased electromyographic activity to the graded colorectal distension (CRD), (the mean ΔAUC values were: 0.17 ± 0.03, 0.53 ± 0.15, 1.06 ± 0.18, 1.22 ± 0.24 in the high dose group; 0.23 ± 0.04, 0.68 ± 0.17, 1.27 ± 0.26, 1.8 ± 0.3 in the middle dose group; and 0.29 ± 0.06, 0.8 ± 0.16, 1.53 ± 0.24, 2.1 ± 0.21 in the low dose group for the pressures 20, 40, 60, 80 mmHg), as compared to the NMS vehicle group. The mean ΔAUC values were: 0.57 ± 0.12, 1.33 ± 0.18, 2.57 ± 0.37, 3.08 ± 0.37 for the pressures 20, 40, 60, 80 mmHg (P < 0.05). JCM-16021 treatment significantly reduced the 5-HT concentrations (from high, middle and low dosage groups: 60.25 ± 5.98 ng/100 mg, 60.32 ± 4.22 ng/100 mg, 73.31 ± 7.65 ng/100 mg), as compared to the NMS vehicle groups (93.11 ± 9.85 ng/100 mg, P < 0.05); and increased the 5-HIAA concentrations (after treatment, from high, middle and low dosage groups: 54.24 ± 3.27 ng/100 mg, 50.34 ± 1.26 ng/100 mg, 51.37 ± 2.13 ng/100 mg) when compared to that in the NMS vehicle group (51.75 ± 1.98 ng/100 mg, P < 0.05); but did not change the enterochromaffin cell numbers in the colon of rats. In addition, NMS rats had higher SERT expression (n = 10) than NH rats (n = 8, P < 0.05). JCM-16021 treatment significantly decreased SERT expression when compared to the NMS group (P < 0.01-0.001). CONCLUSION: JCM-16021 can attenuate visceral hypersensitivity, and this analgesic effect may be mediated through the serotonin signaling pathway in the colon of rats. © 2010 Baishideng. All rights reserved.

Zhaoxiang Bian    Zhang Man    Quanbin bing Han    徐宏喜    沈祖堯    

World Journal of Gastroenterology

2010

Purpose: Hepatitis B virus (HBV) infection is an important etiology for hepatocellular carcinoma (HCC). We aim to develop a simple clinical score in predicting the risk of HCC among HBV carriers. Patients and Methods: We first evaluated 1,005 patients and found that the following five factors independently predicted HCC development: age, albumin, bilirubin, HBV DNA, and cirrhosis. These variables were used to construct a prediction score ranging from 0 to 44.5. The score was validated in another prospective cohort of 424 patients. Results: During a median follow-up of 10 years, 105 patients (10.4%) in the training cohort and 45 patients (10.6%) in the validation cohort developed HCC. Cutoff values of 5 and 20 best discriminated HCC risk. By applying the cutoff value of 5, the score excluded future HCC development with high accuracy (negative predictive value = 97.8% and 97.3% in the training and validation cohorts, respectively). In the validation cohort, the 5-year HCC-free survival rates were 98.3%, 90.5%, and 78.9% in the low-, medium-, and high-risk groups, respectively. The hazard ratios for HCC in the medium- and high-risk groups were 12.8 and 14.6, respectively. Conclusion: A simple prediction score constructed from routine clinical and laboratory parameters is accurate in predicting HCC development in HBV carriers. Future prospective validation is warranted. © 2010 by American Society of Clinical Oncology.

Vincent Wong    Stephenlam Chan    Frankie Mo    Chan Tung-Ching    Loong Herbert Ho-Fung    Grace Wong    Lui Yanni Yan-Ni    Anthony Chan    沈祖堯     Winnie Yeo    Henry lik yuen Chan    Tony Mok   

Journal of Clinical Oncology

2010

H19 is an imprinted oncofetal non-coding RNA recently shown to be the precursor of miR-675. The pathophysiological roles of H19 and its mature product miR-675 to carcinogenesis have, however, not been defined. By quantitative reverse transcription-polymerase chain reaction, both H19 and miR-675 were found to be upregulated in human colon cancer cell lines and primary human colorectal cancer (CRC) tissues compared with adjacent noncancerous tissues. Subsequently, the tumor suppressor retinoblastoma (RB) was confirmed to be a direct target of miR-675 as the microRNA suppressed the activity of the luciferase reporter carrying the 3′-untranslated region of RB messenger RNA that contains the miR-675-binding site. Suppression of miR-675 by transfection with anti-miR-675 increased RB expression and at the same time, decreased cell growth and soft agar colony formation in human colon cancer cells. Reciprocally, enhanced miR-675 expression by transfection with miR-675 precursor decreased RB expression, increased tumor cell growth and soft agar colony formation. Moreover, the inverse relationship between the expressions of RB and H19/miR-675 was also revealed in human CRC tissues and colon cancer cell lines. Our findings demonstrate that H19-derived miR-675, through downregulation of its target RB, regulates the CRC development and thus may serve as a potential target for CRC therapy. © The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org.

Wingpui Tsang    Kaion Ng    Simon siu man Ng    Hongchuan Jin    Jun Yu    沈祖堯     Timtak Kwok   

Carcinogenesis

2010

Nicotine is shown to be one of the carcinogenic agents for gastric cancer. Perturbation of epithelial-mesenchymal transition (EMT) results in loss of intracellular adhesions leading to tumor progression. In this study, we examined the underlying mechanism of the long-term effects of nicotine on tumor progression in human gastric cancer cells. Nicotine activated 5-lipoxygenase (5-LOX) in three gastric cancer cell lines (MKN-45, MKN-28 and AGS). Cells treated with nicotine dose- and time-dependently induced cell proliferation, invasion and suppressed apoptosis. In addition, cell cycle progression analysis revealed that activation of 5-LOX modulated the G1/S phase transition regulatory proteins and caused cell proliferation. MK886 (5-LOX activating protein inhibitor) mediated the induction of apoptosis by elevation of caspase-3 and Bax/Bcl2 ratio. Abrogation of 5-LOX repressed featured molecular markers of EMT (inactivation of E-cadherin and activation of transcriptional repressor Snail). Blockade of 5-LOX signaling resulted in downregulation of cyclin D1, matrix metalloproteinase (MMP-7, -9), urokinase plasminogen activator (uPA) and its receptor (uPAR), and pro-apoptotic proteins. Furthermore, suppression of Snail and induction of E-cadherin is extracellular signal-regulated kinase (Erk)-dependent. Thus, we conclude that the promotion effect of nicotine on cancer cell progression and EMT is mediated by Erk/5-LOX signaling pathway. © 2009 Elsevier Ireland Ltd.

Vivian yvonne Shin    Hongchuan Jin    Kaion Ng    沈祖堯     Kent man Chu    Chihin Cho   

Cancer Letters

2010