Background & Aims Perpetuate liver inflammation is crucial in the pathogenesis of non-alcoholic steatohepatitis (NASH). Expression of CXCL10, a pro-inflammatory cytokine, correlates positively with obesity and type 2 diabetes. Whether CXCL10 plays a role in NASH was unknown. We aimed to investigate the functional and clinical impact of CXCL10 in NASH. Methods Cxcl10 gene-deleted (Cxcl10^-/-) and C57BL/6 wild type (WT) mice were fed a methionine- and choline-deficient (MCD) diet for 4 or 8 weeks. In other experiments, we injected neutralizing anti-CXCL10 mAb into MCD-fed WT mice. Human serum was obtained from 147 patients with biopsy-proven non-alcoholic fatty liver disease and 73 control subjects. Results WT mice, fed the MCD diet, developed steatohepatitis with higher hepatic CXCL10 expression. Cxcl10^-/- mice were refractory to MCD-induced steatohepatitis. We further revealed that CXCL10 was associated with the induction of important pro-inflammatory cytokines (TNF-α, IL-1β, and MCP-1) and activation of the NF-κB pathway. CXCL10 was linked to steatosis through upregulation of the lipogenic factors SREBP-1c and LXR, and also to oxidative stress (upregulation of CYP2E1 and C/EBPβ). Blockade of CXCL10 protected against hepatocyte injury in vitro and against steatohepatitis development in mice. We further investigated the clinical impact of CXCL10 and found circulating and hepatic CXCL10 levels were significantly higher in human NASH. Importantly, the circulating CXCL10 level was correlated with the degree of lobular inflammation and was an independent risk factor for NASH patients. Conclusions We demonstrate for the first time that CXCL10 plays a pivotal role in the pathogenesis of experimental steatohepatitis. CXCL10 maybe a potential non-invasive biomarker for NASH patients.

Xiang Zhang    Jiayun Shen    Kwan Man    Chu Eagle S.H.    Yau Tung On    Sung Joanne C.Y.    Minnieyy Go    Deng Jun    Liwei Lu    Vincent Wong    沈祖堯     Geoffrey Farrell    Jun Yu   

Journal of Hepatology

2014

Background: Screening for latent tuberculosis (TB) is mandatory in inflammatory bowel disease (IBD) before starting anti-tumor necrosis factor therapy. Data on the utility of screening tests in populations with moderate background risk of TB are limited. This study aims to evaluate the performance of interferon-gamma release assay (IGRA) with QuantiFERON-TB Gold in IBD patients in a TB endemic region. Methods: Two hundred sixty-eight consecutive adult IBD patients and 234 healthy controls were prospectively recruited. Detailed clinical history, chest x-ray findings, and IGRA results were documented for all individuals. The IGRA positive rates between IBD patients, with or without immunosuppressant, and healthy controls were compared. Results: The IGRA result was positive in 21.9% of IBD patients and 19.2% of healthy controls (P = 0.535). IBD patients on immunosuppressive therapy had a significantly lower IGRA positive rate (13.0% versus 29.6%; P = 0.002) compared with immunosuppressant-naive IBD patients. This difference seemed to be most prominent for patients taking azathioprine (11.8% versus 27.3%, P = 0.006). Conclusions: IGRA results are negatively impacted by immunosuppressive therapy. Current guidelines suggesting TB screening before anti-tumor necrosis factor therapy may be inadequate in patients already on immunosuppressive drugs. Latent TB testing seems best performed before the initiation of immunosuppressive therapies in IBD patients.

Sunny Wong    Margaret Ip    Tang Whitney    Lin Zheng    Kee Carmen    Hung Esther    Lui Grace    Lee Nelson    Francis Chan    Wu Justin C.Y.    沈祖堯     Siew Ng   

Inflammatory Bowel Diseases

2014

Dapper homolog (DACT) 2 is one of the Dact gene family members, which are important modulators of Wnt signaling pathway. We aim to clarify its epigenetic inactivation, biological function and clinical implication in colon cancer. DACT2 was silenced in five out of eight colon cancer cell lines, but robustly expressed in normal colon tissues. The loss of DACT2 expression was regulated by promoter hypermethylation. Restoring DACT2 expression in colon cancer cell lines suppressed tumor cell growth by inducing cell apoptosis and inhibiting cell proliferation both in vitro and in vivo. Moreover, DACT2 overexpression effectively reduced lung metastasis of colon cancer cells in nude mice. These effects by DACT2 were attributed to inhibition of Wnt/β-catenin signaling. Reexpression of DACT2 significantly suppressed the transcriptional activity of both wild-type β-catenin and degradation-resistant form mutant β-catenin (S33Y). DACT2 could actively shuttle into and out of nuclei, with its predominant steady-state localization in the cytoplasm dependent on its nuclear export signal. Co-immunoprecipitation results indicated that DACT2 strongly associated β-catenin as well as lymphoid enhancer-binding factor 1 (LEF1) and directly disrupted the formation of the β-catenin-LEF1 complex in the nucleus. Whereas in the cytoplasm, DACT2 restored junctional localization of E-cadherin-β-catenin complexes and prevented β-catenin nuclear translocation through direct interaction with β-catenin. DACT2 methylation was detected in 43.3% (29/67) of colon cancer tissues, but none in normal controls. Multivariate analysis revealed that patients with DACT2 methylation had a significant decrease in overall survival (P=0.006). Kaplan-Meier survival curves showed that DACT2 methylation was significantly associated with shortened survival in stage I-III colon cancer patients. In conclusion, DACT2 acts as a functional tumor suppressor in colon cancer through inhibiting Wnt/β-catenin signaling. Its methylation at early stages of colon carcinogenesis is an independent prognostic factor.

Shiyan Wang    Dong Yeping    Zhang    Xiaojuan Wang    Xu Lixia    Yang    Xiangchun Li    Dong Hui-Ming    Liping Xu    Ling Su    Simon siu man Ng    Zhijie Chang    沈祖堯     Xueji Zhang    Yu   

Oncogene

2014

Background and objective: About 9% of gastric carcinomas have Epstein-Barr virus (EBV) in the tumour cells, but it is unclear whether viral presence influences clinical progression. We therefore examined a large multicentre case series for the association of tumour EBV status with survival after gastric cancer diagnosis, accounting for surgical stage and other prognostic factors. Methods: We combined individual-level data on 4599 gastric cancer patients diagnosed between 1976 and 2010 from 13 studies in Asia (n=8), Europe (n=3), and Latin America (n=2). EBV positivity of tumours was assessed by in situ hybridisation. Mortality HRs for EBV positivity were estimated by Cox regression models stratified by study, adjusted for distributions of sex (71% male), age (mean 58 years), stage (52% tumour-node-metastasis stages III or IV), tumour histology (49% poorly differentiated, 57% Lauren intestinal-type), anatomic subsite (70% non-cardia) and year of diagnosis. Variations by study and continent were assessed using study-specific HRs for EBV positivity. Results: During median 3.0 years follow-up, 49% of patients died. Stage was strongly predictive of mortality, with unadjusted HRs (vs stage I) of 3.1 for stage II, 8.1 for stage III and 13.2 for stage IV. Tumour EBV positivity was 8.2% overall and inversely associated with stage (adjusted OR: 0.79 per unit change). Adjusted for stage and other confounders, EBV positivity was associated with lower mortality (HR, 0.72; 95% CI 0.61 to 0.86), with low heterogeneity among the study populations (p=0.2). The association did not significantly vary across patient or tumour characteristics. There was no significant variation among the three continent-specific HRs (p=0.4). Conclusions: Our findings suggest that tumour EBV positivity is an additional prognostic indicator in gastric cancer. Further studies are warranted to identify the mechanisms underlying this protective association.

Constanza Camargo María    Wooho Kim    Chiaravalli Anna M.    Kyoung mee Kim    Corvalan    Keitaro Matsuo    Jun Yu    沈祖堯     Herrera-Goepfert Roberto    Meneses-Gonzalez Fernando    Kijima Yuko    Natsugoe Shoji    Linda Liao    Lissowska    Kim Sung    Hu Nan    Gonzalez    Yatabe Yashushi    Koriyama Chihaya    Stephen Hewitt    Akiba Suminori    Margaret Gulley    Philip Taylor    Rabkin   

Gut

2014

沈祖堯    

Gut

2014

In November 2004, the very first issue of this journal featured articles on the pathogenesis of ulcerative colitis, mechanisms leading to chronic pancreatitis, and treatment of recurrent Clostridium-difficile-associated diarrhoea. Although those topics might seem familiar, much has changed in the intervening years in our understanding, diagnosis and treatment of many different diseases across the field of gastroenterology and hepatology. Nonetheless, many challenges remain. Here, we have asked five of our Advisory Board members - international experts across different subspecialties in gastroenterology and hepatology - to reflect on the progress and frustrations of the past 10 years. They also comment on where effort and money should be invested now, as well as their predictions for progress in the next 10 years.

Scott laurence Friedman    Eamonn Quigley    Keith Sharkey    沈祖堯     Whitcomb David C.   

Nature Reviews Gastroenterology and Hepatology

2014

Upper gastrointestinal hemorrhage, which is generally subdivided as variceal or nonvariceal, is a common clinical presentation associated with significant mortality and considerable healthcare expenditure. Nonvariceal hemorrhage is most commonly due to peptic ulceration or erosions, which are themselves frequently due to NSAIDs or aspirin, though Helicobacter pylori remains an important cause. Increased use of antiplatelet and anticoagulation combinations in heart disease are associated with higher risks of such bleeding. Variceal hemorrhage is mainly a complication of cirrhosis but is not increasing despite rising liver disease, possibly because preventive measures in cirrhotic patients are improving. Mortality risk for gastrointestinal hemorrhage is greatest among the old, with comorbid conditions, and those who present with shock or ongoing bleeding. The increasing age and comorbidity amongst patients with nonvariceal upper gastrointestinal bleeding may well explain a failure to greatly reduce mortality despite proven improvements in care. This edition first published 2014

Crooks    沈祖堯     Timothy Card   

GI Epidemiology: Diseases and Clinical Methodology: Second Edition

2014

Background & Aims: Deregulation of forkhead box (Fox) proteins, an evolutionarily conserved family of transcriptional regulators, leads to tumorigenesis. Little is known about their regulation or functions in the pathogenesis of gastric cancer. Promoter hypermethylation occurs during Helicobacter pylori-induced gastritis. We investigated whether the deregulated genes contribute to gastric tumorigenesis. Methods: We used integrative genome-wide scans to identify concomitant hypermethylated genes in mice infected with H pylori and human gastric cancer samples. We also analyzed epigenetic gene silencing in gastric tissues from patients with H pylori infection and gastritis, intestinal metaplasia, gastric tumors, or without disease (controls). Target genes were identified by chromatin immunoprecipitation microarrays and expression and luciferase reporter analyses. Results: Methylation profile analyses identified the promoter of FOXD3 as the only genomic region with increased methylation in mice and humans during progression of H pylori-associated gastric tumors. FOXD3 methylation also correlated with shorter survival times of patients with gastric cancer. Genome demethylation reactivated FOXD3 expression in gastric cancer cell lines. Transgenic overexpression of FOXD3 significantly inhibited gastric cancer cell proliferation and invasion, and reduced growth of xenograft tumors in mice, at least partially, by promoting tumor cell apoptosis. FOXD3 bound directly to the promoters of, and activated transcription of, genes encoding the cell death regulators CYFIP2 and RARB. Levels of FOXD3, CYFIP2, and RARB messenger RNAs were reduced in human gastric tumor samples, compared with control tissues. Conclusions: FOXD3-mediated transcriptional control of tumor suppressors is deregulated by H pylori infection-induced hypermethylation; this could perturb the balance between cell death and survival. These findings identify a pathway by which epigenetic changes affect gastric tumor suppression. © 2013 AGA Institute.

Alfred Cheng    Li May S.    Wei Kang    Vicky Cheng    Chou Jian-Liang    Lau Suki Shuk-Kei    Minnieyy Go    Lee Ching C.    Thomas Ling    Kaion Ng    Jun Yu    Huang Tim H.-M.    Kafai To    Michaelwy Chan    沈祖堯     Francis Chan   

Gastroenterology

2013

Background & Aims: Colorectal cancer (CRC) is the second-most common cancer in Hong Kong. Relatives of patients with CRC have an increased risk of colorectal neoplasm. We assessed the prevalence of advanced neoplasms among asymptomatic siblings of patients with CRC. Methods: Patients with CRC were identified from the Prince of Wales Hospital CRC Surgery Registry from 2001 to 2011. Colonoscopies were performed for 374 siblings of patients (age, 52.6 ± 7.4 y) and 374 age- and sex-matched siblings of healthy subjects who had normal colonoscopies and did not have a family history of CRC (controls, 52.7 ± 7.4 y). We identified individuals with advanced neoplasms (defined as cancers or adenomas of at least 10 mm in diameter, high-grade dysplasia, with villous or tubulovillous characteristics). Results: The prevalence of advanced neoplasms was 7.5% among siblings of patients and 2.9% among controls (matched odds ratio [mOR], 3.07; 95% confidence interval [CI], 1.5-6.3; P =.002). The prevalence of adenomas larger than 10 mm was higher among siblings of patients than in controls (5.9% vs 2.1%; mOR, 3.34; 95% CI, 1.45-7.66; P =.004), as was the presence of colorectal adenomas (31.0% vs 18.2%; mOR, 2.19; 95% CI, 1.52-3.17; P <.001). Six cancers were detected among siblings of patients; no cancers were detected in controls. The prevalence of advanced neoplasms among siblings of patients was higher when their index case was female (mOR, 4.95; 95% CI, 1.81-13.55) and had distally located CRC (mOR, 3.10; 95% CI, 1.34-7.14). Conclusions: In Hong Kong, siblings of patients with CRC have a higher prevalence of advanced neoplasms, including CRC, than siblings of healthy individuals. Screening is indicated in this high-risk population. ClinicalTrials.gov number: NCT00164944. © 2013 AGA Institute.

Ng Siew C.    James Lau    Francis Chan    张保亭    Wai keung Leung    Yeekit Tse    吴兆文    Janet Lee    Kafai To    Justin cy Wu    沈祖堯    

Gastroenterology

2013

Background: The human gut microbiota has profound influence on host metabolism and immunity. This study characterized the fecal microbiota in patients with nonalcoholic steatohepatitis (NASH). The relationship between microbiota changes and changes in hepatic steatosis was also studied. Methods: Fecal microbiota of histology-proven NASH patients and healthy controls was analyzed by 16S ribosomal RNA pyrosequencing. NASH patients were from a previously reported randomized trial on probiotic treatment. Proton-magnetic resonance spectroscopy was performed to monitor changes in intrahepatic triglyceride content (IHTG). Results: A total of 420,344 16S sequences with acceptable quality were obtained from 16 NASH patients and 22 controls. NASH patients had lower fecal abundance of Faecalibacterium and Anaerosporobacter but higher abundance of Parabacteroides and Allisonella. Partial least-square discriminant analysis yielded a model of 10 genera that discriminated NASH patients from controls. At month 6, 6 of 7 patients in the probiotic group and 4 of 9 patients in the usual care group had improvement in IHTG (P = 0.15). Improvement in IHTG was associated with a reduction in the abundance of Firmicutes (R = 0.4820, P = 0.0028) and increase in Bacteroidetes (R = 0.4366, P = 0.0053). This was accompanied by corresponding changes at the class, order and genus levels. In contrast, bacterial biodiversity did not differ between NASH patients and controls, and did not change with probiotic treatment. Conclusions: NASH patients have fecal dysbiosis, and changes in microbiota correlate with improvement in hepatic steatosis. Further studies are required to investigate the mechanism underlying the interaction between gut microbes and the liver. © 2013 Wong et al.

Vincent Wong    谢志恒    Tommy tsan yuk Lam    Grace Wong    Angel mei ling Chim    Winnie cw Chu    David Yeung    Law Patrick Tik Wan    Kwan Hoi Shan    Jun Yu    沈祖堯     Henry lik yuen Chan   

PLoS ONE

2013