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  • Bacteriophage transfer during faecal microbiota transplantation in Clostridium difficile infection is associated with treatment outcome

    • 摘要:

      Objective Faecal microbiota transplantation (FMT) is effective for the treatment of recurrent Clostridium difficile infection (CDI). Studies have shown bacterial colonisation after FMT, but data on viral alterations in CDI are scarce. We investigated enteric virome alterations in CDI and the association between viral transfer and clinical outcome in patients with CDI. Design Ultra-deep metagenomic sequencing of virus-like particle preparations and bacterial 16S rRNA sequencing were performed on stool samples from 24 subjects with CDI and 20 healthy controls. We longitudinally assessed the virome and bacterial microbiome changes in nine CDI subjects treated with FMT and five treated with vancomycin. Enteric virome alterations were assessed in association with treatment response. Results Subjects with CDI demonstrated a significantly higher abundance of bacteriophage Caudovirales and a lower Caudovirales diversity, richness and evenness compared with healthy household controls. Significant correlations were observed between bacterial families Proteobacteria, Actinobacteria and Caudovirales taxa in CDI. FMT treatment resulted in a significant decrease in the abundance of Caudovirales in CDI. Cure after FMT was observed when donor-derived Caudovirales contigs occupied a larger fraction of the enteric virome in the recipients (p=0.024). In treatment responders, FMT was associated with alterations in the virome and the bacterial microbiome, while vancomycin treatment led to alterations in the bacterial community alone. Conclusions In a preliminary study, CDI is characterised by enteric virome dysbiosis. Treatment response in FMT was associated with a high colonisation level of donor-derived Caudovirales taxa in the recipient. Caudovirales bacteriophages may play a role in the efficacy of FMT in CDI. Trial registration number NCT02570477

    • 作者:

      Zuo Tao    Sunny Wong    Lam    Lui Rashid N.S.    Cheung    Tang Whitney    Jessica Ching    Paul Chan    陈子蔚    胡志    Francis ka leung Chan    Jun Yu    沈祖堯     Ng Siew C.   

    • 刊名:

      Gut

    • 在线出版时间:

      2018

  • A modified colorectal screening score for prediction of advanced neoplasia: A prospective study of 5744 subjects

    • 摘要:

      Background and Aim: We validated a modified risk algorithm based on the Asia-Pacific Colorectal Screening (APCS) score that included body mass index (BMI) for prediction of advanced neoplasia. Methods: Among 5744 Chinese asymptomatic screening participants undergoing a colonoscopy in Hong Kong from 2008 to 2012, a random sample of 3829 participants acted as the derivation cohort. The odds ratios for significant risk factors identified by binary logistic regression analysis were used to build a scoring system ranging from 0 to 6, divided into “average risk” (AR): 0; “moderate risk” (MR): 1–2; and “high risk” (HR): 3–6. The other 1915 subjects formed a validation cohort, and the performance of the score was assessed. Results: The prevalence of advanced neoplasia in the derivation and validation cohorts was 5.4% and 6.0%, respectively (P = 0.395). Old age, male gender, family history of colorectal cancer, smoking, and BMI were significant predictors in multivariate regression analysis. A BMI cut-off at > 23 kg/m had better predictive capability and lower number needed to screen than that of > 25 kg/m. Utilizing the score developed, 8.4%, 57.4%, and 34.2% in the validation cohort were categorized as AR, MR, and HR, respectively. The corresponding prevalence of advanced neoplasia was 3.8%, 4.3%, and 9.3%. Subjects in the HR group had 2.48-fold increased prevalence of advanced neoplasia than the AR group. The c-statistics of the modified score had better discriminatory capability than that using predictors of APCS alone (c-statistics = 0.65 vs 0.60). Conclusions: Incorporating BMI into the predictors of APCS score was found to improve risk prediction of advanced neoplasia and reduce colonoscopy resources.

    • 作者:

      沈祖堯     黄至生    Lam Thomas Y.T.    Kelvin kf Tsoi    Chan Victor Y. W.    Cheung Wilson    Jessica yl Ching   

    • 刊名:

      Journal of Gastroenterology and Hepatology (Australia)

    • 在线出版时间:

      2018

  • Association between investigator-measured body-mass index and colorectal adenoma: a systematic review and meta-analysis of 168,201 subjects

    • 摘要:

      The objective of this meta-analysis is to evaluate the odds of colorectal adenoma (CRA) in colorectal cancer screening participants with different body mass index (BMI) levels, and examine if this association was different according to gender and ethnicity. The EMBASE and MEDLINE were searched to enroll high quality observational studies that examined the association between investigator-measured BMI and colonoscopy-diagnosed CRA. Data were independently extracted by two reviewers. A random-effects meta-analysis was conducted to estimate the summary odds ratio (SOR) for the association between BMI and CRA. The Cochran’s Q statistic and I analyses were used to assess the heterogeneity. A total of 17 studies (168,201 subjects) were included. When compared with subjects having BMI < 25, individuals with BMI 25–30 had significantly higher risk of CRA (SOR 1.44, 95% CI 1.30–1.61; I = 43.0%). Subjects with BMI ≥ 30 had similarly higher risk of CRA (SOR 1.42, 95% CI 1.24–1.63; I = 18.5%). The heterogeneity was mild to moderate among studies. The associations were significantly higher than estimates by previous meta-analyses. There was no publication bias detected (Egger’s regression test, p = 0.584). Subgroup analysis showed that the magnitude of association was significantly higher in female than male subjects (SOR 1.43, 95% CI 1.30–1.58 vs. SOR 1.16, 95% CI 1.07–1.24; different among different ethnic groups (SOR 1.72, 1.44 and 0.88 in White, Asians and Africans, respectively) being insignificant in Africans; and no difference exists among different study designs. In summary, the risk conferred by BMI for CRA was significantly higher than that reported previously. These findings bear implications in CRA risk estimation.

    • 作者:

      黄至生    Chan Chun hei    Cheung Wilson    Fung Din hei    Liang Miaoyin    Huang Jason Li wen    Wang Yanhong    Johnnyyu Jiang    Yu Chun pong    Wang Harry H. X    胡志    Francis ka leung Chan    沈祖堯    

    • 刊名:

      European Journal of Epidemiology

    • 在线出版时间:

      2018

  • Defective lysosomal clearance of autophagosomes and its clinical implications in nonalcoholic steatohepatitis

    • 摘要:

      Autophagic impairment is implicated in nonalcoholic fatty liver disease (NAFLD), but the molecular mechanism is unclear. We found that autophagic flux was significantly inhibited in 3 murine models of NAFLD. Interestingly, the number of acidic organelles and the level of mature cathepsin D were reduced, suggesting defective lysosome acidification. Asparagine synthetase (ASNS) was induced by endoplasmic reticulum stress, leading to the generation of asparagine, which inhibited lysosome acidification. Both steatotic- and asparagine-treated hepatocytes showed reduced lysosomal acidity and retention of lysosomal calcium. Knockdown of ASNS in steatotic hepatocytes restored autophagic flux. As a potential biomarker, increased serum p62/sequestosome 1 (SQSTM1) level was an independent risk factor for patients with steatosis and lobular inflammation. Impaired autophagy in NAFLD is elicited by defective lysosome acidification, which is caused by ASNS-induced asparagine synthesis under endoplasmic reticulum stress and subsequent retention of lysosomal calcium. p62/SQSTM1 could be used as a noninvasive biomarker in the diagnosis of NAFLD patients.

    • 作者:

      Xiaojuan Wang    Xiang Zhang    Eagle Chu    Chen Xiaoting    Wei Kang    Wu Feng    Kafai To    Wong Vincent W.S.    Henry lik yuen Chan    Matthew Chan    沈祖堯     William ka kei Wu    Jun Yu   

    • 刊名:

      FASEB Journal

    • 在线出版时间:

      2018

  • A novel susceptibility locus in MST1 and gene-gene interaction network for Crohn's disease in the Chinese population

    • 摘要:

      The incidence of Crohn's disease is increasing in many Asian countries, but considerable differences in genetic susceptibility have been reported between Western and Asian populations. This study aimed to fine-map 23 previously reported Crohn's disease genes and identify their interactions in the Chinese population by Illumina-based targeted capture sequencing. Our results showed that the genetic polymorphism A>G at rs144982232 in MST1 showed the most significant association (P = 1.78 × 10; odds ratio = 4.87). JAK2 rs1159782 (T>C) was also strongly associated with Crohn's disease (P = 2.34 × 10; odds ratio = 3.72). Gene-gene interaction analysis revealed significant interactions between MST1 and other susceptibility genes, including NOD2, MUC19 and ATG16L1 in contributing to Crohn's disease risk. Main genetic associations and gene-gene interactions were verified using ImmunoChip data set. In conclusion, a novel susceptibility locus in MST1 was identified. Our analysis suggests that MST1 might interact with key susceptibility genes involved in autophagy and bacterial recognition. These findings provide insight into the genetic architecture of Crohn's disease in Chinese and may partially explain the disparity of genetic signals in Crohn's disease susceptibility across different ethnic populations by highlighting the contribution of gene-gene interactions.

    • 作者:

      William ka kei Wu    Sun Rui    Zuo Tao    Tian Yuanyuan    曾志荣    Ho Jeffery    Justin cy Wu    Francis ka leung Chan    Matthew Chan    Jun Yu    沈祖堯     Sunny Wong    Maggie haitian Wang    Ng Siew C.   

    • 刊名:

      Journal of Cellular and Molecular Medicine

    • 在线出版时间:

      2018

  • Genomic analysis of liver cancer unveils novel driver genes and distinct prognostic features

    • 摘要:

      Objective: Hepatocellular carcinoma (HCC) is a highly heterogeneous disease with a dismal prognosis. However, driver genes and prognostic markers in HCC remain to be identified. It is hoped that in-depth analysis of HCC genomes in relation to available clinicopathological information will give rise to novel molecular prognostic markers. Methods: We collected genomic data of 1,061 HCC patients from previous studies, and performed integrative analysis to identify significantly mutated genes and molecular prognosticators. We employed three MutSig algorithms (MutSigCV, MutSigCL and MutSigFN) to identify significantly mutated genes. The GISTIC2 algorithm was used to delineate focally amplified and deleted genomic regions. Nonnegative matrix factorization (NMF) was utilized to decipher mutational signatures. Kaplan-Meier survival and Cox regression analyses were used to associate gene mutation and copy number alteration with survival outcome. Logistic regression model was applied to test association between gene mutation and mutational signatures. Results: We discovered 11 novel driver genes, including RNF213, VAV3 and TNRC6B, with mutational prevalence ranging from 1% to 3%. Seven mutational signatures were also identified in HCC, some of which were associated with mutations of classical driver genes (e.g., TP53, TERT) as well as alcohol consumption. Focal amplifications of TERT and other druggable targets, including AURKA, were also revealed. Targeting AURKA by a small-molecule inhibitor potently induced apoptosis in HCC cells. We further demonstrated that HCC patients with TERT amplification displayed shortened overall survival independent of other clinicopathological parameters. In conclusion, our study identified novel cancer driver genes and prognostic markers in HCC, reiterating the translational importance of omics data in the precision medicine era.

    • 作者:

      Xiangchun Li    Xu Weiqi    Wei Kang    Sunny Wong    Wang Mengyao    Zhou Yong    Xiaodong Fang    Xiuqing Zhang    杨焕明    Wong Chi Hang    Kafai To    Stephenlam Chan    Matthew Chan    沈祖堯     William ka kei Wu    Jun Yu   

    • 刊名:

      Theranostics

    • 在线出版时间:

      2018

  • Responses are durable for up to 5 years after completion of peginterferon alfa-2a treatment in hepatitis B e antigen-positive patients

    • 摘要:

      Background: In the large randomised NEPTUNE study, peginterferon alfa-2a 180 μg/wk for 48 weeks produced higher hepatitis B e antigen (HBeAg) seroconversion rates 24 weeks post-treatment (36%) than a lower dose (90 μg/wk) and/or shorter duration (24 weeks) (range 14%-26%). Aim: To determine seroconversion rates 5 years after completion of treatment in NEPTUNE. Methods: HBeAg-positive patients who completed 24 weeks’ follow-up in NEPTUNE (with peginterferon alfa-2a 90 μg/wk × 24 weeks [group 1]; 180 μg/wk × 24 weeks [2]; 90 μg/wk × 48 weeks [3] or 180 μg/wk × 48 weeks [4]) were followed up. Results: Three hundred and eighty three of the 544 patients in the original study were enrolled in the long-term follow-up study. Many patients (196 overall; more in groups 1-3 than 4) received nucleos(t)ide analogues or immunomodulators during follow-up, and more patients had missing data at year 5 in groups 2 and 4 (48 weeks, 50/112) than in groups 1 and 3 (24 weeks, 23/103), which confounds the planned per-protocol analysis. HBeAg seroconversion rates in groups 1, 2, 3 and 4 at year 5 were 47.5%, 50.7%, 52.2% and 67.1%, respectively, (odds ratio for group 4 versus 1-3: 2.02; 95% CI 1.21, 3.38), using multiple imputation methods for missing measurements. Conclusion: Seroconversion rates are durable for up to 5 years after completion of peginterferon alfa-2a therapy and, consistent with NEPTUNE, the results suggest that the licensed regimen (180 μg × 48 weeks) is more efficacious for HBeAg-positive patients than a lower dose and/or shorter treatment duration.

    • 作者:

      Wanlong Chuang    Jidong Jia    Henry lik yuen Chan    Han K. H.    Tanwandee Tawesak    Tan De-ming    Xinyue Chen    Edward Gane    Teerha Piratvisuth    Liang Chen    Qing Xie    沈祖堯     Diethelm Messinger    Wat    Bakalos Georgios    Liaw Yun-Fan   

    • 刊名:

      Alimentary Pharmacology and Therapeutics

    • 在线出版时间:

      2018

  • DEAD-box helicase 27 promotes colorectal cancer growth and metastasis and predicts poor survival in CRC patients

    • 摘要:

      Copy number alterations (CNAs) are crucial for colorectal cancer (CRC) development. In this study, DEAD box polypeptide 27 (DDX27) was identified to be highly amplified in both TCGA CRC (474/615) and primary CRC (47/103), which was positively correlated with its mRNA overexpression. High DDX27 mRNA (N = 199) and protein expression (N = 260) predicted poor survival in CRC patients. Ectopic expression of DDX27 increased CRC cells proliferation, migration and invasion, but suppressed apoptosis. Conversely, silencing of DDX27 exerted opposite effects in vitro and significantly inhibited murine xenograft tumor growth and lung metastasis in vivo. Up-regulation of DDX27 enhanced and prolonged TNF-α-mediated NF-κB signaling. Nucleophosmin (NPM1) was identified as a binding partner of DDX27. DDX27 increased nuclear NPM1 and NF-κB-p65 interaction to enhance DNA binding activity of NF-κB. Silencing NPM1 abrogated DDX27-activating NF-κB signaling and its tumor-promoting function. Together, DDX27 is overexpressed and plays a pivotal oncogenic role in CRC.

    • 作者:

      Tang Jieting    Chen Huarong    Chichun Wong    Liu Dabin    Li Tong    Wang Xiao-Hong    季加孚    沈祖堯     房静远    Jun Yu   

    • 刊名:

      Oncogene

    • 在线出版时间:

      2018

  • CREPT facilitates colorectal cancer growth through inducing Wnt/β-catenin pathway by enhancing p300-mediated β-catenin acetylation

    • 摘要:

      Using whole genome sequencing, we identified gene amplification of CREPT in colorectal cancer (CRC). In this study, we aim to clarify its clinical significance, biological effects, and mechanism in CRC. CREPT was upregulated in CRC cell lines and in 47.37% (72/152) of primary CRC tumors. Amplification of CREPT was detected in 48.28% (56/116) of primary CRC tumors, which was positively correlated with its overexpression (P < 0.001). Multivariate analysis showed that CRC patients with CREPT protein overexpression were significantly associated with poor disease-free survival (P < 0.05). CREPT significantly accelerated CRC cell proliferation and metastasis both in vitro and in vivo. RNA-sequencing (seq) analysis uncovered that the tumor-promoting effect by CREPT was attributed to enhancing Wnt/β-catenin signaling. Using co-immunoprecipitation coupled with mass spectroscopy, we identified p300 protein was a novel CREPT interacting partner. CREPT greatly increased the interaction between p300 and β-catenin, thus promoting p300-mediated β-catenin acetylation and stabilization. Moreover, CREPT cooperated with p300, leading to elevated active histone acetylation markers H3K27ac and H4Ac and decreased repressive histone marker H3K9me3 at the promoters of Wnt downstream targets. In summary, CREPT plays a pivotal oncogenic role in colorectal carcinogenesis through promoting Wnt/β-catenin pathway via cooperating with p300. CREPT may serve as a prognostic biomarker of patients with CRC.

    • 作者:

      Zhang Yanquan    Shiyan Wang    Wei Kang    Liu Chunxiao    Yujuan Dong    Ren Fangli    Wang Yin-Yin    Jinglin Zhang    Wang Guoping    Kafai To    Xueji Zhang    沈祖堯     Zhijie Chang    Jun Yu   

    • 刊名:

      Oncogene

    • 在线出版时间:

      2018

  • Global Incidence and mortality of oesophageal cancer and their correlation with socioeconomic indicators temporal patterns and trends in 41 countries

    • 摘要:

      Oesophageal cancers (adenocarcinomas [AC] and squamous cell carcinomas [SCC]) are characterized by high incidence/mortality in many countries. We aimed to delineate its global incidence and mortality, and studied whether socioeconomic development and its incidence rate were correlated. The age-standardized rates (ASRs) of incidence and mortality of this medical condition in 2012 for 184 nations from the GLOBOCAN database; national databases capturing incidence rates, and the WHO mortality database were examined. Their correlations with two indicators of socioeconomic development were evaluated. Joinpoint regression analysis was used to generate trends. The ratio between the ASR of AC and SCC was strongly correlated with HDI (r = 0.535 [men]; r = 0.661 [women]) and GDP (r = 0.594 [men]; r = 0.550 [women], both p < 0.001). Countries that reported the largest reduction in incidence in male included Poland (Average Annual Percent Change [AAPC] =-7.1, 95%C.I. =-12,-1.9) and Singapore (AAPC =-5.8, 95%C.I. =-9.5,-1.9), whereas for women the greatest decline was seen in Singapore (AAPC =-12.3, 95%C.I. =-17.3,-6.9) and China (AAPC =-5.6, 95%C.I. =-7.6,-3.4). The Philippines (AAPC = 4.3, 95%C.I. = 2,6.6) and Bulgaria (AAPC = 2.8, 95%C.I. = 0.5,5.1) had a significant mortality increase in men; whilst Columbia (AAPC =-6.1, 95%C.I. =-7.5,-4.6) and Slovenia (AAPC =-4.6, 95%C.I. =-7.9,-1.3) reported mortality decline in women. These findings inform individuals at increased risk for primary prevention.

    • 作者:

      Wong Martin C.S.    Hamilton    David Whiteman    Johnnyyu Jiang    Qiao Youlin    Fung Franklin D.H.    Wang Harry H. X    赵伟仁    Enders kwok wai Ng    Justin cy Wu    Jun Yu    Francis ka leung Chan    沈祖堯    

    • 刊名:

      Scientific Reports

    • 在线出版时间:

      2018

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