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  • The effect of off-hours hospital admission on mortality and clinical outcomes for patients with upper gastrointestinal hemorrhage: A systematic review and meta-analysis of 20 cohorts

    • 摘要:

      Objective: The objective of this article is to evaluate the relationship between off-hours hospital admission (weekends, public holidays or nighttime) and mortality for upper gastrointestinal hemorrhage (UGIH). Methods: Medline, Embase, Scopus, and the Chinese Biomedical Literature were searched through December 2016 to identify eligible records for inclusion in this meta-analysis. A random-effects model was applied. Results: Twenty cohort studies were included for analysis. Patients with UGIH who were admitted during off-hours had a significantly higher mortality and were less likely to receive endoscopy within 24 hours of admission. In comparison to variceal cases, patients with nonvariceal bleeding showed a higher mortality when admitted during off-hours. However, for studies conducted in hospitals that provided endoscopy outside normal hours, off-hours admission was not associated with an increased risk of mortality. Conclusion: Our study showed a higher mortality for patients with nonvariceal UGIH who were admitted during off-hours, while this effect might be offset in hospitals with a formal out-of-hours endoscopy on-call rotation.

    • 作者:

      Xia Xian Feng    赵伟仁    Kelvin kf Tsoi    Francis ka leung Chan    沈祖堯     James Lau   

    • 刊名:

      United European Gastroenterology Journal

    • 在线出版时间:

      2018

  • Non-variceal upper gastrointestinal bleeding

    • 摘要:

      Non-variceal upper gastrointestinal bleeding (NVUGIB) is bleeding that develops in the oesophagus, stomach or proximal duodenum. Peptic ulcers, caused by Helicobacter pylori infection or use of NSAIDs and low-dose aspirin (LDA), are the most common cause. Although the incidence and mortality associated with NVUGIB have been decreasing owing to considerable advances in the prevention and management of NVUGIB over the past 20 years, it remains a common clinical problem with an annual incidence of ∼67 per 100,000 individuals in the United States in 2012. NVUGIB is a medical emergency, and mortality is in the range ∼1-5%. After resuscitation and initial assessment, early (within 24 hours) diagnostic and therapeutic endoscopy together with intragastric pH control with proton pump inhibitors (PPIs) form the basis of treatment. With a growing ageing population treated with antiplatelet and/or anticoagulant medications, the clinical management of NVUGIB is complex as the risk between gastrointestinal bleeding events and adverse cardiovascular events needs to be balanced. The best clinical approach includes identification of risk factors and prevention of bleeding; available strategies include continuous treatment with PPIs or H. pylori eradication in those at increased risk of developing NVUGIB. Treatment with PPIs and/or use of cyclooxygenase-2-selective NSAIDs should be implemented in those patients at risk of NVUGIB who need NSAIDs and/or LDA.

    • 作者:

      Lanas Ángel    Jean marc Dumonceau    Hunt    Mitsuhiro Fujishiro    James Scheiman    Ian mark Gralnek    Campbell Helen    Rostom    Villanueva Càndid    沈祖堯    

    • 刊名:

      Nature Reviews Disease Primers

    • 在线出版时间:

      2018

  • Squalene epoxidase drives NAFLD-induced hepatocellular carcinoma and is a pharmaceutical target

    • 摘要:

      Nonalcoholic fatty liver disease (NAFLD)–induced hepatocellular carcinoma (HCC) is an emerging malignancy in the developed world; however, mechanisms that contribute to its formation are largely unknown, and targeted therapy is currently not available. Our RNA sequencing analysis of NAFLD-HCC samples revealed squalene epoxidase (SQLE) as the top outlier metabolic gene overexpressed in NAFLD-HCC patients. Hepatocyte-specific Sqle transgenic expression in mice accelerated the development of high-fat, high-cholesterol diet–induced HCC. SQLE exerts its oncogenic effect via its metabolites, cholesteryl ester and nicotinamide adenine dinucleotide phosphate (NADP). Increased SQLE expression promotes the biosynthesis of cholesteryl ester, which induces NAFLD-HCC cell growth. SQLE increased the NADP/NADPH (reduced form of NADP) ratio, which triggered a cascade of events involving oxidative stress–induced DNA methyltransferase 3A (DNMT3A) expression, DNMT3A-mediated epigenetic silencing of PTEN, and activation of AKT-mTOR (mammalian target of rapamycin). In human NAFLD-HCC and HCC, SQLE is overexpressed and its expression is associated with poor patient outcomes. Terbinafine, a U.S. Food and Drug Administration–approved antifungal drug targeting SQLE, markedly inhibited SQLE-induced NAFLD-HCC cell growth in NAFLD-HCC and HCC cells and attenuated tumor development in xenograft models and in Sqle transgenic mice. Suppression of tumor growth by terbinafine is associated with decreased cholesteryl ester concentrations, restoration of PTEN expression, and inhibition of AKT-mTOR, consistent with blockade of SQLE function. Collectively, we established SQLE as an oncogene in NAFLD-HCC and propose that repurposing SQLE inhibitors may be a promising approach for the prevention and treatment of NAFLD-HCC.

    • 作者:

      Liu Dabin    Chichun Wong    Fu Li    Chen Huarong    Zhao Liuyang    Li Chuangen    Zhou Yunfei    Zhang Yanquan    Xu Weiqi    Yang Yi-Dong    Bin Wu    Cheng Gong    Paul Lai    王昭春    沈祖堯     Jun Yu   

    • 刊名:

      Science Translational Medicine

    • 在线出版时间:

      2018

  • Hepatoma-intrinsic CCRK inhibition diminishes myeloid-derived suppressor cell immunosuppression and enhances immune-checkpoint blockade efficacy

    • 摘要:

      Objective: Myeloid-derived suppressor cells (MDSCs) contribute to tumour immunosuppressive microenvironment and immune-checkpoint blockade resistance. Emerging evidence highlights the pivotal functions of cyclin-dependent kinases (CDKs) in tumour immunity. Here we elucidated the role of tumour-intrinsic CDK20, or cell cycle-related kinase (CCRK) on immunosuppression in hepatocellular carcinoma (HCC). Design: Immunosuppression of MDSCs derived from patients with HCC and relationship with CCRK were determined by flow cytometry, expression analyses and co-culture systems. Mechanistic studies were also conducted in liver-specific CCRK-inducible transgenic (TG) mice and Hepa1-6 orthotopic HCC models using CRISPR/Cas9-mediated Ccrk depletion and liver-targeted nanoparticles for interleukin (IL) 6 trapping. Tumorigenicity and immunophenotype were assessed on single or combined antiprogrammed death-1-ligand 1 (PD-L1) therapy. Results: Tumour-infiltrating CD11bCD33HLA-DR MDSCs from patients with HCC potently inhibited autologous CD8T cell proliferation. Concordant overexpression of CCRK and MDSC markers (CD11b/CD33) positively correlated with poorer survival rates. Hepatocellular CCRK stimulated immunosuppressive CD11bCD33HLA-DR MDSC expansion from human peripheral blood mononuclear cells through upregulating IL-6. Mechanistically, CCRK activated nuclear factor-κB (NF-κB) via enhancer of zeste homolog 2 (EZH2) and facilitated NF-κB-EZH2 co-binding to IL-6 promoter. Hepatic CCRK induction in TG mice activated the EZH2/NF-κB/IL-6 cascade, leading to accumulation of polymorphonuclear (PMN) MDSCs with potent T cell suppressive activity. In contrast, inhibiting tumorous Ccrk or hepatic IL-6 increased interferon γ tumour necrosis factor-αCD8T cell infiltration and impaired tumorigenicity, which was rescued by restoring PMN-MDSCs. Notably, tumorous Ccrk depletion upregulated PD-L1 expression and increased intratumorous CD8 T cells, thus enhancing PD-L1 blockade efficacy to eradicate HCC. Conclusion: Our results delineate an immunosuppressive mechanism of the hepatoma-intrinsic CCRK signalling and highlight an overexpressed kinase target whose inhibition might empower HCC immunotherapy.

    • 作者:

      Zhou Jingying    Liu Man    Sun Hanyong    Feng Yu    Liangliang Xu    Chan Anthony W.H.    Joanna Tong    John Wong    Chong Charing C. N.    Paul Lai    Wang Hector Kwong Sang    Tsang Shun Wa    Goodwin Tyler    Rihe Liu    黄力夫    Chen Zhiwei    沈祖堯     Chow King L.    Kafai To    Alfred Cheng   

    • 刊名:

      Gut

    • 在线出版时间:

      2018

  • Forkhead box F2 suppresses gastric cancer through a novel FOXF2–IRF2BPL–b-Catenin signaling axis

    • 摘要:

      DNA methylation has been identified as a hallmark of gastric cancer (GC). Identifying genes that are repressed by DNA promoter methylation is essential in providing insights into the molecular pathogenesis of gastric cancer. Using genome-wide methylation studies, we identified that transcription factor forkhead box F2 (FOXF2) was preferentially methylated in gastric cancer. We then investigated the functional significance and clinical implication of FOXF2 in gastric cancer. FOXF2 was silenced in gastric cancer cell lines and cancer tissues by promoter methylation, which was negatively associated with mRNA expression. Ectopic expression of FOXF2 inhibited proliferation, colony formation, G–S cell-cycle transition, induced apoptosis of gastric cancer cell lines, and suppressed growth of xenograft tumors in nude mice; knockdown of FOXF2 elicited opposing effects. FOXF2 inhibited Wnt signaling by inducing b-catenin protein ubiquitination and degradation independently of GSK-3b. FOXF2 directly bound the promoter of E3 ligase interferon regulatory factor 2-binding protein-like (IRF2BPL) and induced its transcriptional expression. IRF2BPL in turn interacted with b-catenin, increasing its ubiquitination and degradation. Multivariate Cox regression analysis identified FOXF2 hypermethylation as an independent prognostic factor of poor survival in early-stage gastric cancer patients. In conclusion, FOXF2 is a critical tumor suppressor in gastric carcinogenesis whose methylation status serves as an independent prognostic factor for gastric cancer patients. Significance: FOXF2-mediated upregulation of the E3 ligase IRF2BPL drives ubiquitylation and degradation of b-catenin in gastric cancer, blunting Wnt signaling and suppressing carcinogenesis.

    • 作者:

      Higashimori Akira    Yujuan Dong    Zhang Yanquan    Wei Kang    Nakatsu Geicho    吴兆文    Arakawa Tetsuo    沈祖堯     Francis ka leung Chan    Jun Yu   

    • 刊名:

      Cancer Research

    • 在线出版时间:

      2018

  • RNF6 promotes colorectal cancer by activating the Wnt/b-catenin pathway via ubiquitination of TLE3

    • 摘要:

      Gene amplification is a hallmark of cancer and is frequently observed in colorectal cancer. Previous whole-genome sequencing of colorectal cancer clinical specimens identified amplification of Ring finger protein 6 (RNF6), a RING-domain E3 ubiquitin ligase. In this study, we showed that RNF6 is upregulated in 73.5% (147/200) of patients with colorectal cancer and was positively associated with RNF6 gene amplification. Furthermore, RNF6 expression and its gene amplification were independent prognostic factors for poor outcome of patients with colorectal cancer. RNF6 promoted cell growth, cell-cycle progression, and epithelial-to-mesenchymal transition in colorectal cancer cells; RNF6 also promoted colorectal tumor growth and lung metastasis in mouse models. Mechanistic investigations revealed that RNF6 bound and ubiquitylated transducin-like enhancer of split 3 (TLE3), a transcriptional repressor of the b-catenin/TCF4 complex. RNF6-mediated degradation of TLE3 significantly suppressed the association of TLE3 with TCF4/LEF, which in turn led to recruitment of b-catenin to TCF4/LEF, triggering Wnt/b-catenin activation. Restoration of TLE3 expression abolished the oncogenic effects of RNF6. Taken together, these results demonstrate that RNF6 plays a pivotal oncogenic role in colorectal tumorigenesis. Significance: RNF6-mediated ubiquitination and degradation of TLE3 activates the Wnt/b-catenin pathway in colorectal carcinogenesis.

    • 作者:

      Liu Lei    Zhang Yanquan    Chichun Wong    Zhang Jingwan    Yujuan Dong    Xiangchun Li    Wei Kang    Francis ka leung Chan    沈祖堯     Jun Yu   

    • 刊名:

      Cancer Research

    • 在线出版时间:

      2018

  • Prophylactic angiographic embolisation after endoscopic control of bleeding to high-risk peptic ulcers: A randomised controlled trial

    • 摘要:

      Objectives: In the management of patients with bleeding peptic ulcers, recurrent bleeding is associated with high mortality. We investigated if added angiographic embolisation after endoscopic haemostasis to high-risk ulcers could reduce recurrent bleeding. Design: After endoscopic haemostasis to their bleeding gastroduodenal ulcers, we randomised patients with at least one of these criteria (ulcers≥20 mm in size, spurting bleeding, hypotensive shock or haemoglobin<9 g/dL) to receive added angiographic embolisation or standard treatment. Our primary endpoint was recurrent bleeding within 30 days. Results: Between January 2010 and July 2014, 241 patients were randomised (added angiographic embolisation n=118, standard treatment n=123); 22 of 118 patients (18.6%) randomised to angiography did not receive embolisation. In an intention-to-treat analysis, 12 (10.2%) in the embolisation and 14 (11.4%) in the standard treatment group reached the primary endpoint (HR 1.14, 95% CI 0.53 to 2.46; p=0.745). The rate of reinterventions (13 vs 17; p=0.510) and deaths (3 vs 5, p=0.519) were similar. In a per-protocol analysis, 6 of 96 (6.2%) rebled after embolisation compared with 14 of 123 (11.4%) in the standard treatment group (HR 1.89, 95% CI 0.73 to 4.92; p=0.192). None of 96 patients died after embolisation compared with 5 (4.1%) deaths in the standard treatment group (p=0.108). In a posthoc analysis, embolisation reduced recurrent bleeding only in patients with ulcers≥15 mm in size (2 (4.5%) vs 12 (23.1%); p=0.027). Conclusions: After endoscopic haemostasis, added embolisation does not reduce recurrent bleeding. Trial registration number: NCT01142180.

    • 作者:

      James Lau    Pittayanon Rapat    Katak Wong    Pinjaroen Nutcha    赵伟仁    Rerknimitr    Holster Ingrid L.    Kuipers Ernst J.    Kaichun Wu    Au Kim    Francis ka leung Chan    沈祖堯    

    • 刊名:

      Gut

    • 在线出版时间:

      2018

  • Asia-Pacific working group consensus on non-variceal upper gastrointestinal bleeding: An update 2018

    • 摘要:

      Non-variceal upper gastrointestinal bleeding remains an important emergency condition, leading to significant morbidity and mortality. As endoscopic therapy is the 'gold standard' of management, treatment of these patients can be considered in three stages: pre-endoscopic treatment, endoscopic haemostasis and post-endoscopic management. Since publication of the Asia-Pacific consensus on non-variceal upper gastrointestinal bleeding (NVUGIB) 7 years ago, there have been significant advancements in the clinical management of patients in all three stages. These include pre-endoscopy risk stratification scores, blood and platelet transfusion, use of proton pump inhibitors; during endoscopy new haemostasis techniques (haemostatic powder spray and over-the-scope clips); and post-endoscopy management by second-look endoscopy and medication strategies. Emerging techniques, including capsule endoscopy and Doppler endoscopic probe in assessing adequacy of endoscopic therapy, and the pre-emptive use of angiographic embolisation, are attracting new attention. An emerging problem is the increasing use of dual antiplatelet agents and direct oral anticoagulants in patients with cardiac and cerebrovascular diseases. Guidelines on the discontinuation and then resumption of these agents in patients presenting with NVUGIB are very much needed. The Asia-Pacific Working Group examined recent evidence and recommends practical management guidelines in this updated consensus statement.

    • 作者:

      沈祖堯     Chiu Philip C.Y.    Francis ka leung Chan    James Lau    Goh Khean Lee    Ho Lawrence H.Y.    Jung Hwoon Young    José Sollano    Gotoda Takuji    Nageshwar duvvuru Reddy    Singh    Sugano Kentaro    Kaichun Wu    Wu Chun Yin    Bjorkman    Jensen    Kuipers Ernst J.    Lanas Ángel   

    • 刊名:

      Gut

    • 在线出版时间:

      2018

  • Association Between Bacteremia From Specific Microbes and Subsequent Diagnosis of Colorectal Cancer

    • 摘要:

      Background & Aims: Colorectal cancer (CRC) development has been associated with increased proportions of Bacteroides fragilis and certain Streptococcus, Fusobacterium, and Peptostreptococcus species in the intestinal microbiota. We investigated associations between bacteremia from specific intestinal microbes and occurrence of CRC. Methods: We performed a retrospective study after collecting data on 13,096 adult patients (exposed group) in Hong Kong hospitalized with bacteremia (identified by blood culture test) without a previous diagnosis of cancer from January 1, 2006 through December 31, 2015. We collected data on intestinal microbes previously associated with CRC (genera Bacteroides, Clostridium, Filifactor, Fusobacterium, Gemella, Granulicatella, Parvimonas, Peptostreptococcus, Prevotella, Solobacterium, and Streptococcus). Clinical information, including patient demographics, comorbid medical conditions, date of bacteremia, and bacterial species identified, were collected. The incidence of biopsy-proved CRC was compared between the exposed and unexposed (patients without bacteremia matched for age, sex, and comorbidities) groups. Results: The risk of CRC was increased in patients with bacteremia from B fragilis (hazard ratio [HR] = 3.85, 95% CI = 2.62–5.64, P = 5.5 × 10) or Streptococcus gallolyticus (HR = 5.73, 95% CI = 2.18–15.1, P = 4.1 × 10) compared with the unexposed group. In addition, the risk of CRC was increased in patients with bacteremia from Fusobacterium nucleatum (HR = 6.89, 95% CI = 1.70–27.9, P =.007), Peptostreptococcus species (HR = 3.06, 95% CI = 1.47–6.35, P =.003), Clostridium septicum (HR = 17.1, 95% CI = 1.82–160, P =.013), Clostridium perfringens (HR = 2.29, 95% CI = 1.16–4.52, P =.017), or Gemella morbillorum (HR = 15.2, 95% CI = 1.54–150, P =.020). We observed no increased risk in patients with bacteremia caused by microbes not previously associated with colorectal neoplasms. Conclusions: In a retrospective analysis of patients hospitalized for bacteremia, we associated later diagnosis of CRC with B fragilis and S gallolyticus and other intestinal microbes. These bacteria might have entered the bloodstream from intestinal dysbiosis and perturbed barrier function. These findings support a model in which specific members of the intestinal microbiota promote colorectal carcinogenesis. Clinicians should evaluate patients with bacteremia from these species for neoplastic lesions in the colorectum.

    • 作者:

      Kwong Thomas    Wang Xiansong    Nakatsu Geicho    Chow Tai Cheong    Tipoe Timothy    Dai Rudin Z.W.    Tsoi Kelvin K.K.    黄至生    Gary Tse    Chan Matthew T.V.    Francis ka leung Chan    Ng Siew C.    Justin cy Wu    William ka kei Wu    Jun Yu    沈祖堯     Wong Sunny H.   

    • 刊名:

      Gastroenterology

    • 在线出版时间:

      2018

  • Alterations in Enteric Virome Are Associated With Colorectal Cancer and Survival Outcomes

    • 摘要:

      Background & Aims: Patients with colorectal cancer (CRC) have a different gut microbiome signature than individuals without CRC. Little is known about the viral component of CRC-associated microbiome. We aimed to identify and validate viral taxonomic markers of CRC that might be used in detection of the disease or predicting outcome. Methods: We performed shotgun metagenomic analyses of viromes of fecal samples from 74 patients with CRC (cases) and 92 individuals without CRC (controls) in Hong Kong (discovery cohort). Viral sequences were classified by taxonomic alignment against an integrated microbial reference genome database. Viral markers associated with CRC were validated using fecal samples from 3 separate cohorts: 111 patients with CRC and 112 controls in Hong Kong, 46 patients with CRC and 63 controls in Austria, and 91 patients with CRC and 66 controls in France and Germany. Using abundance profiles of CRC-associated virome genera, we constructed random survival forest models to identify those associated with patient survival times. Results: The diversity of the gut bacteriophage community was significantly increased in patients with CRC compared with controls. Twenty-two viral taxa discriminated cases from controls with an area under the receiver operating characteristic curve of 0.802 in the discovery cohort. The viral markers were validated in 3 cohorts, with area under the receiver operating characteristic curves of 0.763, 0.736, and 0.715, respectively. Clinical subgroup analysis showed that dysbiosis of the gut virome was associated with early- and late-stage CRC. A combination of 4 taxonomic markers associated with reduced survival of patients with CRC (log-rank test, P = 8.1 × 10) independently of tumor stage, lymph node metastases, or clinical parameters. We found altered interactions between bacteriophages and oral bacterial commensals in fecal samples from patients with CRC compared with controls. Conclusions: In a metagenomic analysis of fecal samples from patients and controls, we identified virome signatures associated with CRC. These data might be used to develop tools to identify individuals with CRC or predict outcomes.

    • 作者:

      Nakatsu Geicho    Zhou Haokui    William ka kei Wu    Wong Sunny H.    Coker Olabisi Oluwabukola    Dai Zhenwei    Xiangchun Li    Szeto Chun Ho    Sugimura Naoki    Lam Thomas Yuen Tung    Yu Allen C. S.    Wang Xiansong    Zigui Chen    黄至生    Ng Siew C.    Chan Matthew T.V.    Paul Chan    Francis ka leung Chan    沈祖堯     Jun Yu   

    • 刊名:

      Gastroenterology

    • 在线出版时间:

      2018

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