ORCID Profile
0000-0003-3125-5199
Current Organisation
Nanyang Technological University
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Publisher: Elsevier BV
Date: 12-2004
Publisher: BMJ
Date: 10-2020
DOI: 10.1136/GUTJNL-2020-322368
Abstract: A global consensus meeting was held to review current evidence and knowledge gaps and propose collaborative studies on population-wide screening and eradication of Helicobacter pylori for prevention of gastric cancer (GC). 28 experts from 11 countries reviewed the evidence and modified the statements using the Delphi method, with consensus level predefined as ≥80% of agreement on each statement. The Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach was followed. Consensus was reached in 26 statements. At an in idual level, eradication of H. pylori reduces the risk of GC in asymptomatic subjects and is recommended unless there are competing considerations. In cohorts of vulnerable subjects (eg, first-degree relatives of patients with GC), a screen-and-treat strategy is also beneficial. H. pylori eradication in patients with early GC after curative endoscopic resection reduces the risk of metachronous cancer and calls for a re-examination on the hypothesis of ‘the point of no return’. At the general population level, the strategy of screen-and-treat for H. pylori infection is most cost-effective in young adults in regions with a high incidence of GC and is recommended preferably before the development of atrophic gastritis and intestinal metaplasia. However, such a strategy may still be effective in people aged over 50, and may be integrated or included into national healthcare priorities, such as colorectal cancer screening programmes, to optimise the resources. Reliable locally effective regimens based on the principles of antibiotic stewardship are recommended. Subjects at higher risk of GC, such as those with advanced gastric atrophy or intestinal metaplasia, should receive surveillance endoscopy after eradication of H. pylori . Evidence supports the proposal that eradication therapy should be offered to all in iduals infected with H. pylori . Vulnerable subjects should be tested, and treated if the test is positive. Mass screening and eradication of H. pylori should be considered in populations at higher risk of GC.
Publisher: Springer Science and Business Media LLC
Date: 10-2012
Publisher: BMJ
Date: 09-04-2214
Abstract: The aim of this study was to investigate factors affecting clinical outcomes of adults hospitalised with severe seasonal influenza. A prospective, observational cohort study was conducted over 24 months (2007-2008) in two acute, general hospitals. Consecutive, hospitalised adult patients were recruited and followed once their laboratory diagnosis of influenza A/B was established (based on viral antigen detection and virus isolation from nasopharyngeal aspirates collected per protocol). Outcomes studied included in-hospital death, length of stay and duration of oxygen therapy. Factors affecting outcomes were analysed using multivariate Cox proportional hazards models. Sequencing analysis on the neuraminidase gene was performed for available H1N1 isolates. 754 patients were studied (influenza A, n=539 >75% H3N2). Their mean age was 70+/-18 years co-morbidities and serious complications were common (61-77%). Supplemental oxygen and ventilatory support was required in 401 (53.2%) and 41 (5.4%) patients, respectively. 39 (5.2%) patients died pneumonia, respiratory failure and sepsis were the causes. 395 (52%) patients received antiviral (oseltamivir) treatment. Omission of antiviral treatment was associated with delayed presentation or negative antigen detection results. The mortality rate was 4.56 and 7.42 per 1000 patient-days in the treated and untreated patients, respectively among those with co-morbidities, it was 5.62 and 11.64 per 1000 patient-days, respectively. In multivariate analysis, antiviral use was associated with reduced risk of death (adjusted HR (aHR) 0.27 (95% CI 0.13 to 0.55) p<0.001). Improved survival was observed with treatment started within 4 days from onset. Earlier hospital discharge (aHR 1.28 (95% CI 1.04 to 1.57) p=0.019) and faster discontinuation of oxygen therapy (aHR 1.30 (95% CI 1.01 to 1.69) p=0.043) was associated with early treatment within 2 days. Few (n=15) H1N1 isolates in this cohort had the H275Y mutation. Antiviral treatment for severe influenza is associated with reduced mortality and improved clinical outcomes.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2019
DOI: 10.1038/S41395-018-0233-2
Abstract: Living in an urban environment may increase the risk of developing inflammatory bowel disease (IBD). It is unclear if this observation is seen globally. We conducted a population-based study to assess the relationship between urbanization and incidence of IBD in the Asia-Pacific region. Newly diagnosed IBD cases between 2011 and 2013 from 13 countries or regions in Asia-Pacific were included. Incidence was calculated with 95% confidence interval (CI) and pooled using random-effects model. Meta-regression analysis was used to assess incidence rates and their association with population density, latitude, and longitude. We identified 1175 ulcerative colitis (UC), 656 Crohn's disease (CD), and 37 IBD undetermined (IBD-U). Mean annual IBD incidence per 100 000 was 1.50 (95% CI: 1.43-1.57). India (9.31 95% CI: 8.38-10.31) and China (3.64 95% CI, 2.97-4.42) had the highest IBD incidence in Asia. Incidence of overall IBD (incidence rate ratio [IRR]: 2.19 95% CI: 1.01-4.76]) and CD (IRR: 3.28 95% CI: 1.83-9.12) was higher across 19 areas of Asia with a higher population density. In China, incidence of IBD (IRR: 2.37 95% CI: 1.10-5.16) and UC (IRR: 2.63 95% CI: 1.2-5.8) was positively associated with gross domestic product. A south-to-north disease gradient (IRR: 0.94 95% CI: 0.91-0.98) was observed for IBD incidence and a west-to-east gradient (IRR: 1.14 95% CI: 1.05-1.24) was observed for CD incidence in China. This study received IRB approval. Regions in Asia with a high population density had a higher CD and UC incidence. Coastal areas within China had higher IBD incidence. With increasing urbanization and a shift from rural areas to cities, disease incidence may continue to climb in Asia.
Publisher: BMJ
Date: 08-2017
DOI: 10.1136/GUTJNL-2017-314281
Abstract: We aimed to characterise the microbial changes associated with histological stages of gastric tumourigenesis. We performed 16S rRNA gene analysis of gastric mucosal s les from 81 cases including superficial gastritis (SG), atrophic gastritis (AG), intestinal metaplasia (IM) and gastric cancer (GC) from Xi’an, China, to determine mucosal microbiome dysbiosis across stages of GC. We validated the results in mucosal s les of 126 cases from Inner Mongolia, China. We observed significant mucosa microbial dysbiosis in IM and GC subjects, with significant enrichment of 21 and depletion of 10 bacterial taxa in GC compared with SG (q .05). Microbial network analysis showed increasing correlation strengths among them with disease progression (p .001). Five GC-enriched bacterial taxa whose species identifications correspond to Peptostreptococcus stomatis , Streptococcus anginosus , Parvimonas micra , Slackia exigua and Dialister pneumosintes had significant centralities in the GC ecological network (p .05) and classified GC from SG with an area under the receiver-operating curve (AUC) of 0.82. Moreover, stronger interactions among gastric microbes were observed in Helicobacter pylori -negative s les compared with H. pylori -positive s les in SG and IM. The fold changes of selected bacteria, and strengths of their interactions were successfully validated in the Inner Mongolian cohort, in which the five bacterial markers distinguished GC from SG with an AUC of 0.81. In addition to microbial compositional changes, we identified differences in bacterial interactions across stages of gastric carcinogenesis. The significant enrichments and network centralities suggest potentially important roles of P. stomatis , D. pneumosintes , S. exigua , P. micra and S. anginosus in GC progression.
Publisher: Oxford University Press (OUP)
Date: 05-03-0001
DOI: 10.1111/J.1365-2249.2004.02415.X
Abstract: Severe acute respiratory syndrome (SARS) is a recently emerged infectious disease caused by a novel coronavirus, but its immunopathological mechanisms have not yet been fully elucidated. We investigated changes in plasma T helper (Th) cell cytokines, inflammatory cytokines and chemokines in 20 patients diagnosed with SARS. Cytokine profile of SARS patients showed marked elevation of Th1 cytokine interferon (IFN)-γ, inflammatory cytokines interleukin (IL)-1, IL-6 and IL-12 for at least 2 weeks after disease onset, but there was no significant elevation of inflammatory cytokine tumour necrosis factor (TNF)-α, anti-inflammatory cytokine IL-10, Th1 cytokine IL-2 and Th2 cytokine IL-4. The chemokine profile demonstrated significant elevation of neutrophil chemokine IL-8, monocyte chemoattractant protein-1 (MCP-1), and Th1 chemokine IFN-γ-inducible protein-10 (IP-10). Corticosteroid reduced significantly IL-8, MCP-1 and IP-10 concentrations from 5 to 8 days after treatment (all P & 0·001). Together, the elevation of Th1 cytokine IFN-γ, inflammatory cytokines IL-1, IL-6 and IL-12 and chemokines IL-8, MCP-1 and IP-10 confirmed the activation of Th1 cell-mediated immunity and hyperinnate inflammatory response in SARS through the accumulation of monocytes/macrophages and neutrophils.
Publisher: Springer Science and Business Media LLC
Date: 25-06-2002
Publisher: Wiley
Date: 02-12-2008
DOI: 10.1002/CNCR.23989
Abstract: Abnormal activation of the Wnt/beta-catenin signaling pathway is common and critical in the pathogenesis of digestive cancers. In this study, the authors investigated the promoter methylation of the dickkopf homolog 3 gene Dkk-3 in these cancers and its prognostic significance in gastric cancer. Dkk-3 methylation was assessed in 173 patients with gastric cancers (including 104 patients who were followed for up to 4090 days) and in 128 patients with colorectal cancer. Cell growth was evaluated by using a colony-formation assay. For survival analyses, the authors used Kaplan-Meier plots, the log-rank test, and Cox proportional regression. Dkk-3 was silenced or down-regulated in 12 of 17 gastric cancer cell lines (70.6%) and in 3 of 9 colon cancer cell lines (33.3%). The loss of gene expression was associated with promoter methylation, which could be restored by demethylating agents. Ectopic expression of Dkk-3 suppressed colony formation. Moreover, methylation of Dkk-3 was detected in 117 of 173 primary gastric tumors (67.6%) and in 67 of 128 colorectal tumors (52.3%). The clinical significance and the prognostic value of Dkk-3 methylation also were examined in 104 gastric cancers and in 84 colorectal cancers. Multivariate analysis indicated that Dkk-3 methylation was associated significantly and independently with poor disease survival (relative risk, 2.534 95% confidence interval, 1.54-4.17 P=.002) in gastric cancer, but not in colorectal cancer. Kaplan-Meier survival curves revealed that patients who had Dkk-3 methylated gastric cancers had a significantly shorter survival (median, 0.76 years) compared with patients who did not have Dkk-3 methylation (median, 2.68 years P<.0001 log-rank test). Epigenetic silencing of the Dkk-3 gene by promoter methylation was a common event in gastric cancer and was associated with a poor outcome in such patients.
Publisher: Springer Science and Business Media LLC
Date: 10-2004
DOI: 10.1023/B:DDAS.0000043384.26092.F4
Abstract: Inflammatory bowel disease is rare in the Chinese population, which may result in limited support, misinformation, and unalleviated fears and adversely affect quality of life (QOL). This study compared the inflammatory bowel disease (IBD)-related knowledge, QOL, and use of complementary and alternative medicines and therapies (CAMT) in two contrasting IBD populations. Chinese and Caucasian IBD patients completed a questionnaire on IBD knowledge and CAMT usage. QOL was evaluated using the validated Inflammatory Bowel Disease Questionnaire. One hundred sixty-two IBD patients were recruited, 81 Chinese and 81 Caucasian. The IBD knowledge score was higher in Caucasian than in Chinese IBD patients (median difference, 6.5 P = 0.001) and was independent of education and occupation. Twenty-one-percent of Chinese subjects incorrectly identified their IBD type (0% in the Caucasian group P < 0.001). QOL was higher in the Chinese than the Caucasian group, but not significantly different after adjusting for disease activity. QOL was unassociated with IBD knowledge. The overall use of CAMT was similar in both groups (33% of Chinese and 37% of Caucasian patients) and similar for Crohn's disease and ulcerative colitis. IBD-related knowledge was inferior in Chinese compared to Caucasian IBD patients. Health-related QOL is unlikely to be greatly influenced by disease-related knowledge or education. A high proportion of Chinese and Caucasian IBD patients uses CAMT.
Publisher: BMJ
Date: 11-2008
Abstract: Polymorphisms of CLEC4M have been associated with predisposition for infection by the severe acute respiratory syndrome coronavirus (SARS-CoV). DC-SIGNR, a C-type lectin encoded by CLEC4M, is a receptor for the virus. A variable number tandem repeat (VNTR) polymorphism in its neck region was recently associated with susceptibility to SARS infection. However, this association was controversial and was not supported by subsequent studies. Two explanations may account for this discrepancy: (1) there may be an unknown predisposition polymorphism located in the proximity which is linked to the VNTR or (2) it was a spurious association due to unrecognised population structure in the VNTR. We performed a comprehensively genetic association study on this C-type lectin gene cluster (FCER2, CLEC4G, CD209, and CLEC4M) at 19p13.3 by a tagging single nucleotide polymorphisms (SNPs) approach. 23 tagSNPs were genotyped in 181 SARS patients and 172 population controls. No significant association with disease predisposition was detected. Genetic variations in this cluster also did not predict disease prognosis. However, we detected a population stratification of the VNTR alleles in a s le of 1145 Han Chinese collected from different parts of China. The results indicated that the genetic predisposition allele was not found in this lectin gene cluster and population stratification might cause the previous positive association.
Publisher: Informa UK Limited
Date: 25-10-2013
DOI: 10.4161/AUTO.25573
Abstract: Eukaryotes have two major intracellular protein degradation pathways, namely the ubiquitin-proteasome system (UPS) and autophagy. Inhibition of proteasomal activities has been previously shown to induce autophagy, indicating a coordinated and complementary relationship between these two systems. However, little is known about the regulation of the UPS by autophagy. In this study, we showed for the first time that proteasomes were activated in response to pharmacological inhibition of autophagy as well as disruption of autophagy-related genes by RNA interference under nutrient-deficient conditions in cultured human colon cancer cells. The induction was evidenced by the increased proteasomal activities and the upregulation of proteasomal subunits, including the proteasome β5 subunit, PSMB5. Co-inhibition of the proteasome and autophagy also synergistically increased the accumulation of polyubiquitinated proteins. Collectively, our findings suggest that proteasomes are activated in a compensatory manner for protein degradation upon autophagy inhibition. Our studies unveiled a novel regulatory mechanism between the two protein degradation pathways.
Publisher: Springer Science and Business Media LLC
Date: 21-11-2011
DOI: 10.1038/ONC.2011.511
Abstract: Using genome-wide methylation screening, we identified that paired box gene 5 (PAX5) is involved in human cancer development. However, the function of PAX5 in gastric cancer (GC) development is largely unclear. We analyzed its epigenetic inactivation, biological functions and clinical application in GC. PAX5 was silenced in seven out of eight GC cell lines. A significant downregulation was also detected in paired gastric tumors compared with adjacent non-cancerous tissues. The downregulation of PAX5 was closely linked to the promoter hypermethylation status and could be restored with demethylation treatment. Ectopic expression of PAX5 in silenced GC cell lines (AGS and BGC823) inhibited colony formation and cell viability, arrested cell cycle, induced apoptosis, suppressed cell migration and invasion and repressed tumorigenicity in nude mice. Consistent with the induction of apoptosis by PAX5 in vitro, terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling (TUNEL) staining showed significantly enhanced apoptotic cells in PAX5-expressed tumors compared with the vector control tumors. On the other hand, knockdown of PAX5 by PAX5-short hairpin RNA increased the cell viability and proliferation. The anti-tumorigenic function of PAX5 was revealed to be mediated by upregulating downstream targets of tumor protein 53 (p53), p21, BCL2-associated X protein, metastasis suppressor 1 and tissue inhibitors of metalloproteinase 1, and downregulating BCL2, cyclin D1, mesenchymal-epithelial transition factor (MET) and matrix metalloproteinase 1. Immunoprecipitation assay demonstrated that PAX5 directly bound to the promoters of p53 and MET. Moreover, PAX5 hypermethylation was detected in 77% (144 of 187) of primary GCs compared with 10.5% (2/19) of normal gastric tissues (P<0.0001). GC patients with PAX5 methylation had a significant poor survival compared with the unmethylated cases as demonstrated by Cox regression model and log-rank test. In conclusion, PAX5 is a novel functional tumor suppressor in gastric carcinogenesis. Detection of methylated PAX5 can be utilized as an independent prognostic factor in GC.
Publisher: Elsevier BV
Date: 10-2002
Publisher: Oxford University Press (OUP)
Date: 22-01-2016
Abstract: Accumulating evidence supports epigenetic modifications in mediating intestinal immunity in inflammatory bowel disease [IBD] pathogenesis. This study aimed to identify key dysregulated epigenetic modulators and the molecular downstream pathways in IBD. Expression of 116 well-defined epigenetic modulators was profiled and validated in 96 intestinal tissues from patients with Crohn's disease [CD], ulcerative colitis [UC], and healthy controls using quantitative reverse transcriptase polymerase chain reaction [QRT-PCR], western blot, and immunohistochemistry. Dysregulation of histone modifications and IBD-related cytokines were examined by chromatin immunoprecipitation, luciferase activity, and gene expression analyses in normal colonic epithelial cell line, NCM460, upon small-molecule inhibition or RNA interference, followed by validation in primary colonic tissues. Targeted expression profiling uncovered seven differentially expressed epigenetic modulators, of which the down-regulation of lysine acetyltransferase 2B [KAT2B] mRNA and protein was the most significant and was consequently validated in inflamed CD and UC compared with healthy colonic tissues. KAT2B protein localised abundantly in nuclei of normal colonic epithelium but diminished in paired inflamed CD and UC tissues. Pharmacological inhibition of KAT2B by anacardic acid in NCM460 cells reduced the levels of histone H4 lysine 5 acetylation [H4K5ac] and interleukin-10 [IL-10] in a dose-dependent manner. Knockdown of KAT2B reduced the IL-10 promoter occupancy of KAT2B and H4K5ac, resulting in transcriptional silencing. IL-10 level was also diminished in inflamed IBD tissues. Our findings demonstrated a novel epigenetic mechanism of IL-10 dysregulation in IBD. Down-regulation of KAT2B may disrupt the innate and adaptive inflammatory responses due to the suppression of this crucial anti-inflammatory cytokine.
Publisher: Wiley
Date: 20-08-2010
DOI: 10.1002/IJC.25489
Publisher: Wiley
Date: 22-11-2002
DOI: 10.1002/IJC.10783
Abstract: Promoter hypermethylation is an alternative mechanism of gene silencing in human cancers including gastric cancer. While intestinal metaplasia (IM) is generally regarded as a precancerous lesion of the stomach, our study examines the presence of gene promoter hypermethylation in IM of patients with and without gastric cancer. We examined 31 s les of gastric cancer, 36 gastric IM (21 associated with gastric cancer and 15 from noncancer patients) and 10 normal gastric biopsies. Tissues containing foci of IM were carefully microdissected from paraffin-embedded section. Bisulfite-modified DNA was examined for gene promoter hypermethylation in DAP-kinase, E-cadherin, GSTP1, p14, p15, p16, RASSF1A and hMLH1 by methylation-specific-PCR. None of the control gastric tissues had hypermethylation detected, but gene promoter hypermethylation was frequently detected in gastric cancer and IM. The mean number of methylated genes in cancer and IM was 3.0 and 1.4, respectively (p < 0.0001). Methylation in IM from cancer patients was all associated with concurrent methylation in the corresponding tumor s les. The numbers of methylated genes were similar in IM obtained from cancer and noncancer patients. By examining the methylation patterns of these genes, 3 differential methylation patterns were recognized: hypermethylation was more frequent in cancer than in IM (DAP-kinase, p14, p15 and p16) comparable frequencies of methylation in cancer and IM (E-cadherin and hMLH1) and no methylation (GSTP1). Aberrant methylation in tumor-related genes is frequently detected in gastric IM of both cancer and noncancer patients, suggesting their early involvement in the multistep progression of gastric carcinogenesis.
Publisher: Springer Science and Business Media LLC
Date: 29-06-2023
DOI: 10.1038/S41564-023-01418-7
Abstract: Non-alcoholic steatohepatitis (NASH) is the severe form of non-alcoholic fatty liver disease, and is characterized by liver inflammation and fat accumulation. Dietary interventions, such as fibre, have been shown to alleviate this metabolic disorder in mice via the gut microbiota. Here, we investigated the mechanistic role of the gut microbiota in ameliorating NASH via dietary fibre in mice. Soluble fibre inulin was found to be more effective than insoluble fibre cellulose to suppress NASH progression in mice, as shown by reduced hepatic steatosis, necro-inflammation, ballooning and fibrosis. We employed stable isotope probing to trace the incorporation of 13 C-inulin into gut bacterial genomes and metabolites during NASH progression. Shotgun metagenome sequencing revealed that the commensal Parabacteroides distasonis was enriched by 13 C-inulin. Integration of 13 C-inulin metagenomes and metabolomes suggested that P. distasonis used inulin to produce pentadecanoic acid, an odd-chain fatty acid, which was confirmed in vitro and in germ-free mice. P. distasonis or pentadecanoic acid was protective against NASH in mice. Mechanistically, inulin, P. distasonis or pentadecanoic acid restored gut barrier function in NASH models, which reduced serum lipopolysaccharide and liver pro-inflammatory cytokine expression. Overall this shows that gut microbiota members can use dietary fibre to generate beneficial metabolites to suppress metabolic disease.
Publisher: Radiological Society of North America (RSNA)
Date: 08-2003
Publisher: Wiley
Date: 27-05-2002
DOI: 10.1046/J.1365-2036.2002.01282.X
Abstract: Helicobacter species, which may colonize the biliary tract, have been implicated as a possible cause of hepatobiliary diseases ranging from chronic cholecystitis and primary sclerosing cholangitis to gall-bladder carcinoma and primary hepatic carcinomas. Research in this area has been limited by the lack of a gold standard in the diagnosis of these organisms in bile. Most published data to date have been based on molecular techniques that detect the DNA of Helicobacter species in bile, rather than evidence of viable organisms in bile. Helicobacter species have not been shown to induce histological injury to the biliary epithelium or liver parenchyma. The strongest association of the presence of these organisms in bile is with cholestatic conditions. This article reviews the literature on this newly developing field as it has evolved historically, taking pertinent methodological issues into account.
Publisher: Oxford University Press (OUP)
Date: 04-2008
DOI: 10.1002/IBD.20335
Abstract: Phenotypic evolution of Crohn's disease occurs in whites but has never been described in other populations. The Montreal classification may describe phenotypes more precisely. The aim of this study was to validate the Montreal classification through a longitudinal sensitivity analysis in detecting phenotypic variation compared to the Vienna classification. This was a retrospective longitudinal study of consecutive Chinese Crohn's disease patients. All cases were classified by the Montreal classification and the Vienna classification for behavior and location. The evolution of these characteristics and the need for surgery were evaluated. A total of 109 patients were recruited (median follow-up: 4 years, range: 6 months-18 years). Crohn's disease behavior changed 3 years after diagnosis (P = 0.025), with an increase in stricturing and penetrating phenotypes, as determined by the Montreal classification, but was only detected by the Vienna classification after 5 years (P = 0.015). Disease location remained stable on follow-up in both classifications. Thirty-four patients (31%) underwent major surgery during the follow-up period with the stricturing [P = 0.002 hazard ratio (HR): 3.3 95% CI: 1.5-7.0] and penetrating (P = 0.03 HR: 5.8 95% CI: 1.2-28.2) phenotypes according to the Montreal classification associated with the need for major surgery. In contrast, colonic disease was protective against a major operation (P = 0.02 HR: 0.3 95% CI: 0.08-0.8). This is the first study demonstrating phenotypic evolution of Crohn's disease in a nonwhite population. The Montreal classification is more sensitive to behavior phenotypic changes than is the Vienna classification after excluding perianal disease from the penetrating disease category and was useful in predicting course and the need for surgery.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-02-2009
DOI: 10.1038/AJG.2008.74
Abstract: The incidence of ulcerative colitis (UC) in Asia is increasing but reports on its long-term course are few. We set out determine the incidence, prevalence, and survival rate of UC in the Chinese population and phenotypic stability by longitudinal follow-up. A cohort of Chinese UC patients were followed up in a tertiary referral center in Hong Kong between 1985 and 2006. Clinical data were prospectively collected since 2001. Population statistics were obtained from the Census and Statistics Department of Hong Kong for the calculation of age-specific incidence, prevalence, and survival. The disease phenotypes at diagnosis and upon follow-up were documented. A total of 172 patients (51.7% men) with a median age at diagnosis of 37.0 years (range: 12.0-85.0) were included. The cohort was observed for a total of 1,393 person-years with a median follow-up duration of 7.0 years (range: 0.5-22.0). The age-standardized incidence and prevalence rates of UC per 100,000 were 2.1 (95% confidence interval, CI: 1.1-3.7) and 26.5 (95% CI: 22.6-30.9), respectively, in 2006. The 10-year cumulative rate of proximal extension was 23.8%. Only one patient developed colorectal cancer during the observation period. The cumulative colectomy rates were 2.4% and 7.6% at 1 and 10 years of follow-up. Overall survival was similar to that expected (P=0.07). The incidence of UC has increased sixfold in the past two decades in Hong Kong. The complication, colorectal cancer, and colectomy rates are low in Chinese patients but increase with duration of illness.
Publisher: Springer Science and Business Media LLC
Date: 11-2006
Publisher: Elsevier BV
Date: 11-2009
DOI: 10.1016/J.PBB.2009.07.013
Abstract: Paeoniflorin (PF), a chief active ingredient in the root of Paeonia lactiflora Pall (family Ranunculaceae), is effective in relieving colorectal distention (CRD)-induced visceral pain in rats with visceral hyperalgesia induced by neonatal maternal separation (NMS). This study aimed at exploring the underlying mechanisms of PF's analgesic effect on CRD-evoked nociceptive signaling in the central nervous system (CNS) and investigating whether the adenosine A(1) receptor is involved in PF's anti-nociception. CRD-induced visceral pain as well as phosphorylated-extracellular signal-regulated protein kinase (p-ERK) and phospho-cAMP response element-binding protein (p-CREB) expression in the CNS structures of NMS rats were suppressed by NMDA receptor antagonist dizocilpine (MK-801) and ERK phosphorylation inhibitor U0126. PF could similarly inhibit CRD-evoked p-ERK and c-Fos expression in laminae I-II of the lumbosacral dorsal horn and anterior cingulate cortex (ACC). PF could also reverse the CRD-evoked increased glutamate concentration by CRD as shown by dynamic microdialysis monitoring in ACC, whereas, DPCPX, an antagonist of adenosine A(1) receptor, significantly blocked the analgesic effect of PF and PF's inhibition on CRD-induced p-ERK and p-CREB expression. These results suggest that PF's analgesic effect is possibly mediated by adenosine A(1) receptor by inhibiting CRD-evoked glutamate release and the NMDA receptor dependent ERK signaling.
Publisher: BMJ
Date: 25-09-2015
DOI: 10.1136/GUTJNL-2015-309800
Abstract: To evaluate the potential for diagnosing colorectal cancer (CRC) from faecal metagenomes. We performed metagenome-wide association studies on faecal s les from 74 patients with CRC and 54 controls from China, and validated the results in 16 patients and 24 controls from Denmark. We further validated the biomarkers in two published cohorts from France and Austria. Finally, we employed targeted quantitative PCR (qPCR) assays to evaluate diagnostic potential of selected biomarkers in an independent Chinese cohort of 47 patients and 109 controls. Besides confirming known associations of Fusobacterium nucleatum and Peptostreptococcus stomatis with CRC, we found significant associations with several species, including Parvimonas micra and Solobacterium moorei. We identified 20 microbial gene markers that differentiated CRC and control microbiomes, and validated 4 markers in the Danish cohort. In the French and Austrian cohorts, these four genes distinguished CRC metagenomes from controls with areas under the receiver-operating curve (AUC) of 0.72 and 0.77, respectively. qPCR measurements of two of these genes accurately classified patients with CRC in the independent Chinese cohort with AUC=0.84 and OR of 23. These genes were enriched in early-stage (I-II) patient microbiomes, highlighting the potential for using faecal metagenomic biomarkers for early diagnosis of CRC. We present the first metagenomic profiling study of CRC faecal microbiomes to discover and validate microbial biomarkers in ethnically different cohorts, and to independently validate selected biomarkers using an affordable clinically relevant technology. Our study thus takes a step further towards affordable non-invasive early diagnostic biomarkers for CRC from faecal s les.
Publisher: American Association for Cancer Research (AACR)
Date: 29
DOI: 10.1158/1078-0432.CCR-07-1644
Abstract: Purpose: Aberrant activation of the Wnt/β-catenin signaling pathway is associated with multiple tumors including colorectal cancer (CRC). WNT5A is a member of the nontransforming Wnt protein family, whose role in tumorigenesis is still ambiguous. We investigated its epigenetic alteration in CRCs. Experimental Design: We examined its expression and methylation in normal colon, CRC cell lines, and tumors. We also evaluated its tumor-suppressive function and its modulation to Wnt signaling in CRC cells. Results: WNT5A is silenced in most CRC cell lines due to promoter methylation, but is expressed in most normal tissues including the colon, and is unmethylated in normal colon epithelial cells. WNT5A expression could be reactivated by pharmacologic or genetic demethylation, indicating that methylation directly mediates its silencing. WNT5A methylation was frequently detected in CRC tumors (14 of 29, 48%), but only occasionally in paired normal colon tissues (2 of 15, 13% P = 0.025). Ectopic expression of WNT5A, but not its nonfunctional short-isoform with the WNT domain deleted, in silenced CRC cells resulted in substantial inhibition of tumor cell clonogenicity, which is associated with down-regulated intracellular β-catenin protein level and concomitant decrease in β-catenin activity. Conclusions: WNT5A is frequently inactivated in CRC by tumor-specific methylation, and thus, is a potential biomarker. WNT5A could act as a tumor suppressor for CRC by antagonizing the Wnt/β-catenin signaling.
Publisher: Elsevier BV
Date: 04-2003
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2011
Publisher: BMJ
Date: 24-08-2022
DOI: 10.1136/GUTJNL-2022-327377
Abstract: The Asia-Pacific region has the largest number of cases of colorectal cancer (CRC) and one of the highest levels of mortality due to this condition in the world. Since the publishing of two consensus recommendations in 2008 and 2015, significant advancements have been made in our knowledge of epidemiology, pathology and the natural history of the adenoma-carcinoma progression. Based on the most updated epidemiological and clinical studies in this region, considering literature from international studies, and adopting the modified Delphi process, the Asia-Pacific Working Group on Colorectal Cancer Screening has updated and revised their recommendations on (1) screening methods and preferred strategies (2) age for starting and terminating screening for CRC (3) screening for in iduals with a family history of CRC or advanced adenoma (4) surveillance for those with adenomas (5) screening and surveillance for sessile serrated lesions and (6) quality assurance of screening programmes. Thirteen countries/regions in the Asia-Pacific region were represented in this exercise. International advisors from North America and Europe were invited to participate.
Publisher: Springer Science and Business Media LLC
Date: 17-08-2015
DOI: 10.1038/ONC.2015.300
Abstract: The Ras association domain family (RASSF) encodes several members with tumor-suppressive potentials. We aimed to investigate the biological function and clinical implication of RASSF10 in gastric cancer (GC). We found that RASSF10 was silenced in six of seven GC cell lines and in primary GC tissues, but was highly expressed in normal gastric tissues. The silence of RASSAF10 was mediated by promoter methylation as evaluated by bisulfite genomic sequencing. RASSF10 expression could be restored by demethylation treatment. A negative correlation between methylation and mRNA expression of RASSF10 was observed in 223 gastric s les of The Cancer Genome Atlas study (P<0.0001). Re-expression of RASSF10 in GC cell lines (AGS and MKN45) significantly suppressed cell viability, colony formation, migration and invasion, reduced cells in S phase, accumulated cells in G2 phase and induced cell apoptosis in vitro, and inhibited tumorigenicity in nude mice. These were confirmed by decreased expression of proliferation markers (proliferating cell nuclear antigen, p-CDC2 and p-CDC25) and increased apoptotic cascades (cleaved caspases-9, -8, -3 and cleaved poly (ADP-ribose) polymerase). Conversely, RASSF10 knockdown in normal gastric cell line yielded an opposing effect. Co-immunoprecipitation combined with mass spectrometry analyses were performed to reveal the downstream effectors of RASSF10. The result revealed that glutathione S-transferase Pi 1 (GSTP1) was a direct cooperator of RASSF10. The tumor-suppressive effect of RASSF10 was partially mediated by cooperating with GSTP1 to deregulate Jun N-terminal kinase (JNK)/c-Jun/AP-1 pathway. Importantly, RASSF10 methylation was detected in 56.6% (98/173) of primary GCs and is an independent risk factor for poor survival of GC patients (P=0.001). In conclusions, RASSF10 functions as a tumor suppressor by cooperating with GSTP1 to deregulate JNK/c-Jun/AP-1 pathway in GC. Promoter methylation of RASSF10 is associated with poor survival of GC patients.
Publisher: Oxford University Press (OUP)
Date: 02-2006
Abstract: Severe acute respiratory syndrome (SARS) is a virulent viral infection that affects a number of organs and systems. This study examined if SARS may result in cardiovascular complications. 121 patients (37.5 (SD13.2) years, 36% male) diagnosed to have SARS were assessed continuously for blood pressure, pulse, and temperature during their stay in hopsital. Hypotension occurred in 61 (50.4%) patients in hospital, and was found in 28.1%, 21.5%, and 14.8% of patients during the first, second, and third week, respectively. Only one patient who had transient echocardiographic evidence of impaired left ventricular systolic function required temporary inotropic support. Tachycardia was present in 87 (71.9%) patients, and was found in 62.8%, 45.4%, and 35.5% of patients from the first to third week. It occurred independent of hypotension, and could not be explained by the presence of fever. Tachycardia was also present in 38.8% of patients at follow up. Bradycardia only occurred in 18 (14.9%) patients as a transient event. Reversible cardiomegaly was reported in 13 (10.7%) patients, but without clinical evidence of heart failure. Transient atrial fibrillation was present in one patient. Corticosteroid therapy was weakly associated with tachycardia during the second (χ2 = 3.99, p = 0.046) and third week (χ2 = 6.53, p = 0.01), although it could not explain tachycardia during follow up. In patients with SARS, cardiovascular complications including hypotension and tachycardia were common but usually self limiting. Bradycardia and cardiomegaly were less common, while cardiac arrhythmia was rare. However, only tachycardia persisted even when corticosteroid therapy was withdrawn.
Publisher: Springer Science and Business Media LLC
Date: 12-01-2007
Publisher: American Association for Cancer Research (AACR)
Date: 13-04-2017
DOI: 10.1158/1078-0432.CCR-16-1599
Abstract: Purpose: Gut microbiota have been implicated in the development of colorectal cancer. We evaluated the utility of fecal bacterial marker candidates identified by our metagenome sequencing analysis for colorectal cancer diagnosis. Experimental Design: Subjects (total 439 203 colorectal cancer and 236 healthy subjects) from two independent Asian cohorts were included. Probe-based duplex quantitative PCR (qPCR) assays were established for the quantification of bacterial marker candidates. Results: Candidates identified by metagenome sequencing, including Fusobacterium nucleatum (Fn), Bacteroides clarus (Bc), Roseburia intestinalis (Ri), Clostridium hathewayi (Ch), and one undefined species (labeled as m7), were examined in fecal s les of 203 colorectal cancer patients and 236 healthy controls by duplex-qPCR. Strong positive correlations were demonstrated between the quantification of each candidate by our qPCR assays and metagenomics approach (r = 0.801–0.934, all P & 0.0001). Fn was significantly more abundant in colorectal cancer than controls (P & 0.0001), with AUROC of 0.868 (P & 0.0001). At the best cut-off value maximizing sum of sensitivity and specificity, Fn discriminated colorectal cancer from controls with a sensitivity of 77.7%, and specificity of 79.5% in cohort I. A simple linear combination of four bacteria (Fn + Ch + m7-Bc) showed an improved diagnostic ability compared with Fn alone (AUROC = 0.886, P & 0.0001) in cohort I. These findings were further confirmed in an independent cohort II. In particular, improved diagnostic performances of Fn alone (sensitivity 92.8%, specificity 79.8%) and four bacteria (sensitivity 92.8%, specificity 81.5%) were achieved in combination with fecal immunochemical testing for the detection of colorectal cancer. Conclusions: Stool-based colorectal cancer–associated bacteria can serve as novel noninvasive diagnostic biomarkers for colorectal cancer. Clin Cancer Res 23(8) 2061–70. ©2016 AACR.
Publisher: Wiley
Date: 25-01-2011
Publisher: Wiley
Date: 28-02-2003
DOI: 10.1046/J.1365-2036.2003.01489.X
Abstract: Health-related quality of life is an important outcome measure in inflammatory bowel disease. The Inflammatory Bowel Disease Questionnaire is a quality of life questionnaire that has not been validated previously in Chinese patients with inflammatory bowel disease. To develop and validate a Chinese translation of the Inflammatory Bowel Disease Questionnaire, specifically determining its construct validity, discriminant ability, reliability and sensitivity to change. We developed a Chinese version of the Inflammatory Bowel Disease Questionnaire. Chinese patients with Crohn's disease and ulcerative colitis completed the Chinese Inflammatory Bowel Disease Questionnaire and visual analogue scales measuring systemic, social, bowel and emotional well-being. Patients also completed a validated Chinese SF-36 generic quality of life questionnaire, the Crohn's disease activity index or the clinical activity index for ulcerative colitis. One hundred and thirty-five patients (59 with Crohn's disease and 76 with ulcerative colitis) were enrolled, 99 of whom also completed the Chinese Inflammatory Bowel Disease Questionnaire for a second time. The Chinese Inflammatory Bowel Disease Questionnaire correlated well with the SF-36 for all four domains (Spearman: r = 0.55-0.80), the Crohn's disease activity index (r = -0.62-0.72) and the clinical activity index for ulcerative colitis (r = -0.44-0.68), as well as with the visual analogue scales. The Chinese Inflammatory Bowel Disease Questionnaire accurately distinguished between active and inactive disease. Test-re-test reliability showed excellent intra-class correlation (0.76-0.92 all P < 0.001). The Chinese Inflammatory Bowel Disease Questionnaire was also sensitive to changes in disease activity (P < 0.05). The Chinese Inflammatory Bowel Disease Questionnaire is a valid and reliable test that correlates well with the patients' subjective well-being and clinical disease activity.
Publisher: Public Library of Science (PLoS)
Date: 25-06-2015
Publisher: American Association for Cancer Research (AACR)
Date: 31-05-2011
DOI: 10.1158/0008-5472.CAN-10-3342
Abstract: Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of the Polycomb-repressive complex 2 (PRC2) that represses gene transcription through histone H3 lysine 27 trimethylation (H3K27me3). Although EZH2 is abundantly present in various cancers, the molecular consequences leading to oncogenesis remain unclear. Here, we show that EZH2 concordantly silences the Wnt pathway antagonists operating at several subcellular compartments, which in turn activate Wnt/β-catenin signaling in hepatocellular carcinomas (HCC). Chromatin immunoprecipitation promoter array and gene expression analyses in HCCs revealed EZH2 occupancy and reduced expression of Wnt antagonists, including the growth-suppressive AXIN2, NKD1, PPP2R2B, PRICKLE1, and SFRP5. Knockdown of EZH2 reduced the promoter occupancy of PRC2, histone deacetylase 1 (HDAC1), and H3K27me3, whereas the activating histone marks were increased, leading to the transcriptional upregulation of the Wnt antagonists. Combinatorial EZH2 and HDAC inhibition dramatically reduced the levels of nuclear β-catenin, T-cell factor–dependent transcriptional activity, and downstream pro-proliferative targets CCND1 and EGFR. Functional analysis revealed that downregulation of EZH2 reduced HCC cell growth, partially through the inhibition of β-catenin signaling. Conversely, ectopic overexpression of EZH2 in immortalized hepatocytes activated Wnt/β-catenin signaling to promote cellular proliferation. In human HCCs, concomitant overexpression of EZH2 and β-catenin was observed in one-third (61/179) of cases and significantly correlated with tumor progression. Our data indicate that EZH2-mediated epigenetic silencing contributes to constitutive activation of Wnt/β-catenin signaling and consequential proliferation of HCC cells, thus representing a novel therapeutic target for this highly malignant tumor. Cancer Res 71(11) 4028–39. ©2011 AACR.
Publisher: BMJ
Date: 12-02-2020
DOI: 10.1136/GUTJNL-2019-319635
Abstract: Fusobacteria are not common nor relatively abundant in non-colorectal cancer (CRC) populations, however, we identified multiple Fusobacterium taxa nearly absent in western and rural populations to be comparatively more prevalent and relatively abundant in southern Chinese populations. We investigated whether these represented known or novel lineages in the Fusobacterium genus, and assessed their genomes for features implicated in development of cancer. Prevalence and relative abundances of fusobacterial species were calculated from 3157 CRC and non-CRC gut metagenomes representing 16 populations from various biogeographies. Microbial genomes were assembled and compared with existing reference genomes to assess novel fusobacterial ersity. Phylogenetic distribution of virulence genes implicated in CRC was investigated. Irrespective of CRC disease status, southern Chinese populations harboured increased prevalence (maximum 39% vs 7%) and relative abundances (average 0.4% vs 0.04% of gut community) of multiple recognised and novel fusobacterial taxa phylogenetically distinct from Fusobacterium nucleatum . Genomes assembled from southern Chinese gut metagenomes increased existing fusobacterial ersity by 14.3%. Homologues of the FadA adhesin linked to CRC were consistently detected in several monophyletic lineages sister to and inclusive of F. varium and F. ulcerans , but not F. mortiferum . We also detected increased prevalence and relative abundances of F. varium in CRC compared with non-CRC cohorts, which together with distribution of FadA homologues supports a possible association with gut disease. The proportion of fusobacteria in guts of southern Chinese populations are higher compared with several western and rural populations in line with the notion of environment/biogeography driving human gut microbiome composition. Several non-nucleatum taxa possess FadA homologues and were enriched in CRC cohorts whether this imposes a risk in developing CRC and other gut diseases deserves further investigation.
Publisher: Springer Science and Business Media LLC
Date: 30-08-2010
DOI: 10.1038/ONC.2010.370
Abstract: T-box transcription factor 5 (TBX5) is a member of a phylogenetically conserved family of genes involved in the regulation of developmental processes. The function of TBX5 in cancer development is largely unclear. We identified that TBX5 was preferentially methylated in cancer using methylation-sensitive arbitrarily primed PCR. We aim to clarify the epigenetic inactivation, biological function and clinical significance of TBX5 in colon cancer. Promoter methylation was evaluated by combined bisulfite restriction analysis and bisulfite genomic sequencing. Cell proliferation was examined by cell viability assay and colony formation assay, apoptosis by flow cytometry and cell migration by wound-healing assay. TBX5 target genes were identified by cDNA microarray analysis. Cox regression model and log-rank test were used to identify independent predictors of prognosis. TBX5 was silenced or downregulated in 88% (7/8) colon cancer cell lines, but was expressed in normal colon tissues. Loss of gene expression was associated with promoter methylation. The biological function of TBX5 in human colon cancer cells was examined. Re-expression of TBX5 in silenced colon cancer cell lines suppressed colony formation (P<0.001), proliferation (P<0.001), migration and induced apoptosis (P<0.01). Induction of apoptosis was mediated through cross-talk of extrinsic apoptosis pathway, apoptotic BCL2-associated X protein and Granzyme A signaling cascades. TBX5 suppressed tumor cell proliferation and metastasis through the upregulation of cyclin-dependent kinase inhibitor 2A, metastasis suppressor 1 and downregulation of synuclein gamma and metastasis-associated protein 1 family member 2. TBX5 methylation was detected in 68% (71/105) of primary colon tumors. Multivariate analysis showed that patients with TBX5 methylation had a significantly poor overall survival (P=0.0007). In conclusion, we identified a novel functional tumor suppressor gene TBX5 inactivated by promoter methylation in colon cancer. Detection of methylated TBX5 may serve as a potential biomarker for the prognosis of this malignancy.
Publisher: Springer Science and Business Media LLC
Date: 11-04-2018
Publisher: Wiley
Date: 20-04-2012
DOI: 10.1111/J.1440-1746.2011.06984.X
Abstract: Inflammatory bowel disease (IBD), common in Melbourne, was rare but is now increasing in incidence in Hong Kong (HK). To investigate whether these are the same diseases in the West and East, potential causes of changing incidence, and to plan resource needs, an appreciation of clinical characteristics in contrasting populations is essential. Disease characteristics were collected from prospectively populated IBD databases in two specialist centers in Melbourne, Australia and HK. Of 795 patients (Crohn's disease [CD] : ulcerative colitis [UC] Melbourne 272:159 and HK 161:203), the age of diagnosis was higher, there were proportionally more male patients with CD but no UC sex difference, fewer patients were current or ex-smokers (CD 8% vs 50% UC 17% vs 35%) and a family history of IBD was less common (2% vs 11% P < 0.001) in HK compared to Melbourne. Stricturing and perianal CD were more common in HK (12% vs 6% P < 0.001 and 29% vs 16% P = 0.001, respectively). In HK for UC, more patients had extensive disease at diagnosis (42% vs 22%) but colectomy was less common (7% vs 20% P < 0.001). In Melbourne there was greater steroid use at diagnosis and patients were more likely to receive an immunomodulator or anti-tumor necrosis factor agent. IBD in HK was diagnosed at an older age, and had more complicated disease behavior than in Melbourne. Medical therapy, however, was less intense in HK. These differences may relate to real differences in disease or delayed diagnosis due to late presentation and less disease recognition in HK.
Publisher: Elsevier BV
Date: 04-2007
DOI: 10.1016/J.BBRC.2007.02.129
Abstract: Dietary model of steatohepatitis was established by feeding mice a methionine choline deficient (MCD) diet. Mice on MCD or control diet for 3 weeks were treated with or without NO-1886, a newly synthetic lipoprotein lipase (LPL) activator. In a separate experiment, NO-1886 was given after pre-treatment with 3 weeks of MCD diet. NO-1886 significantly reduced MCD-induced inflammation by repressing levels of hepatic lipid peroxides and pro-inflammatory tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and cyclooxygenase-2 (COX-2). In addition, NO-1886 d ened hepatic steatosis via accelerating fatty acid oxidation caused by enhanced expression of PPARalpha, cytochrome P450-10 (Cyp4a10), and Acyl-CoA oxidase (ACO). It failed to regulate genes of fatty acid uptake and synthesis pathways. In conclusion, NO-1886 ameliorated and induced regression of experimental steatohepatitis via increasing endogenous LPL activation resulting in suppression on pro-inflammatory factors and reduction of hepatic fatty acids. These findings indicate that NO-1886 is a potential therapeutic agent for steatohepatitis.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2016
DOI: 10.1158/0008-5472.CAN-15-2443
Abstract: Gastric cancer is not a single disease, and its subtype classification is still evolving. Next-generation sequencing studies have identified novel genetic drivers of gastric cancer, but their use as molecular classifiers or prognostic markers of disease outcome has yet to be established. In this study, we integrated somatic mutational profiles and clinicopathologic information from 544 gastric cancer patients from previous genomic studies to identify significantly mutated genes (SMG) with prognostic relevance. Gastric cancer patients were classified into regular (86.8%) and hypermutated (13.2%) subtypes based on mutation burden. Notably, TpCpW mutations occurred significantly more frequently in regular, but not hypermutated, gastric cancers, where they were associated with APOBEC expression. In the former group, six previously unreported (XIRP2, NBEA, COL14A1, CNBD1, ITGAV, and AKAP6) and 12 recurrent mutated genes exhibited high mutation prevalence (≥3.0%) and an unexpectedly higher incidence of nonsynonymous mutations. We also identified two molecular subtypes of regular-mutated gastric cancer that were associated with distinct prognostic outcomes, independently of disease staging, as confirmed in a distinct patient cohort by targeted capture sequencing. Finally, in diffuse-type gastric cancer, CDH1 mutation was found to be associated with shortened patient survival, independently of disease staging. Overall, our work identified previously unreported SMGs and a mutation signature predictive of patient survival in newly classified subtypes of gastric cancer, offering opportunities to stratify patients into optimal treatment plans based on molecular subtyping. Cancer Res 76(7) 1724–32. ©2016 AACR.
Publisher: Oxford University Press (OUP)
Date: 03-12-2014
Abstract: The carboxyl terminus of Hsc70-interacting protein (CHIP, also named Stub1), a U-box containing E3 ubiquitin ligase, is involved in degradation of certain oncogenic proteins. Recent studies indicated that CHIP suppresses tumor progression in human cancers by targeting Src-3, hypoxia inducible factor 1α, NF-κB, ErbB2 and c-Myc. Here, we report that CHIP was downregulated, predominantly, in the late stages of human colorectal cancer (CRC), and that the CHIP promoter was hypermethylated in CRC specimens. Overexpression of CHIP in HCT-116 cells resulted in impaired tumor growth in nude mice and decreased abilities of tumor cell migration and invasion. Conversely, depletion of CHIP in HCT-116 cells promoted tumor growth and increased tumor cell migration and invasion. CHIP was further found to negatively regulate NF-κB signaling in HCT-116 cells by promoting ubiquitination and degradation of p65, a subunit of the NF-κB complex. The suppressive effect of CHIP led to decreased expression of NF-κB-targeted oncogenes including Cyclin D1, c-Myc, MMP-2, VEGF and IL-8. We proposed that CHIP inhibits the malignancy of CRC cells, possibly through targeting NF-κB signaling. This study provides functional evidence for CHIP as a potential tumor suppressor in CRC, and CHIP expression may be a marker for stages of CRC.
Publisher: Public Library of Science (PLoS)
Date: 29-05-2012
Publisher: BMJ
Date: 20-05-2011
Abstract: Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and is associated with cardiovascular risk. The aim of this study was to determine the role of fatty liver in predicting coronary artery disease and clinical outcomes in patients undergoing coronary angiogram. This was a prospective cohort study carried out in a University hospital. Consecutive patients who underwent coronary angiogram had ultrasound screening for fatty liver. Significant cardiovascular disease was defined as ≥50% stenosis in at least one coronary artery. The primary outcome was a composite end point comprising cardiovascular deaths, non-fatal myocardial infarction and the need for further coronary intervention during prospective follow-up. Among 612 recruited patients, 356 (58.2%) had fatty liver by ultrasonography, 318 (52.0%) had elevated serum alanine aminotransferase and 465 (76.0%) had significant coronary artery disease. Coronary artery disease occurred in 84.6% of patients with fatty liver and 64.1% of those without fatty liver (p<0.001). After adjusting for demographic and metabolic factors, fatty liver (adjusted OR 2.31 95% CI 1.46 to 3.64) and alanine aminotransferase level (adjusted OR 1.01 95% CI 1.00 to 1.02) remained independently associated with coronary artery disease. At a mean follow-up of 87±22 weeks, 30 (10.0%) patients with fatty liver and 18 (11.0%) patients without fatty liver reached the composite clinical end point (p=0.79). In patients with clinical indications for coronary angiogram, fatty liver is associated with coronary artery disease independently of other metabolic factors. However, fatty liver cannot predict cardiovascular mortality and morbidity in patients with established coronary artery disease.
Publisher: Oxford University Press (OUP)
Date: 25-01-2019
Publisher: American Association for Cancer Research (AACR)
Date: 15-02-2015
DOI: 10.1158/0008-5472.CAN-14-1301
Abstract: 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 profiled by miRNA expression array. miR-490-3p exhibited progressive downregulation in gastritis, intestinal metaplasia, and adenocarcinoma during H. pylori and MNU-induced gastric carcinogenesis. Significant downregulation of miR-490-3p was confirmed 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 significantly 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, hypermethylation-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. ©2014 AACR.
Publisher: Informa UK Limited
Date: 06-11-2013
Publisher: BMJ
Date: 18-07-2023
DOI: 10.1136/GUTJNL-2023-329701
Abstract: New screening tests for colorectal cancer (CRC) are rapidly emerging. Conducting trials with mortality reduction as the end point supporting their adoption is challenging. We re-examined the principles underlying evaluation of new non-invasive tests in view of technological developments and identification of new biomarkers. A formal consensus approach involving a multidisciplinary expert panel revised eight previously established principles. Twelve newly stated principles emerged. Effectiveness of a new test can be evaluated by comparison with a proven comparator non-invasive test. The faecal immunochemical test is now considered the appropriate comparator, while colonoscopy remains the diagnostic standard. For a new test to be able to meet differing screening goals and regulatory requirements, flexibility to adjust its positivity threshold is desirable. A rigorous and efficient four-phased approach is proposed, commencing with small studies assessing the test’s ability to discriminate between CRC and non-cancer states ( phase I ), followed by prospective estimation of accuracy across the continuum of neoplastic lesions in neoplasia-enriched populations ( phase II ). If these show promise, a provisional test positivity threshold is set before evaluation in typical screening populations. Phase III prospective studies determine single round intention-to-screen programme outcomes and confirm the test positivity threshold. Phase IV studies involve evaluation over repeated screening rounds with monitoring for missed lesions. Phases III and IV findings will provide the real-world data required to model test impact on CRC mortality and incidence. New non-invasive tests can be efficiently evaluated by a rigorous phased comparative approach, generating data from unbiased populations that inform predictions of their health impact.
Publisher: Oxford University Press (OUP)
Date: 25-01-2019
Publisher: BMJ
Date: 23-07-2015
Publisher: Springer Science and Business Media LLC
Date: 18-07-2011
DOI: 10.1038/ONC.2011.295
Abstract: Autophagy, hallmarked by the formation of double-membrane bound organelles known as autophagosomes, is a lysosome-dependent pathway for protein degradation. The role of autophagy in carcinogenesis is context dependent. As a tumor-suppressing mechanism in early-stage carcinogenesis, autophagy inhibits inflammation and promotes genomic stability. Moreover, disruption of autophagy-related genes accelerates tumorigenesis in animals. However, autophagy may also act as a pro-survival mechanism to protect cancer cells from various forms of cellular stress. In cancer therapy, adaptive autophagy in cancer cells sustains tumor growth and survival in face of the toxicity of cancer therapy. To this end, inhibition of autophagy may sensitize cancer cells to chemotherapeutic agents and ionizing radiation. Nevertheless, in certain circumstances, autophagy mediates the therapeutic effects of some anticancer agents. Data from recent studies are beginning to unveil the apparently paradoxical nature of autophagy as a cell-fate decision machinery. Taken together, modulation of autophagy is a novel approach for enhancing the efficacy of existing cancer therapy, but its Janus-faced nature may complicate the clinical development of autophagy modulators as anticancer therapeutics.
Publisher: Wiley
Date: 05-2008
DOI: 10.1111/J.1440-1746.2007.05110.X
Abstract: As liver fibrosis is the result of persistent necroinflammation in the liver, pro-inflammatory cytokines secreted in response to cell injury have a central role in the pathogenesis of liver fibrosis. We aimed to investigate the association of cytokine gene polymorphism and liver fibrosis among Chinese patients with chronic hepatitis B. Polymorphisms at interleukin-10 (IL-10-627, -1117), interleukin-1-beta (IL-1beta-511, -31, -3964), interleukin-1 receptor antagonist (IL-1RN), and tumor necrosis factor-alpha (TNF-alpha-308, -238) among Chinese chronic hepatitis B patients were determined. Severe liver fibrosis was defined as Ishak fibrosis score = 4 (of 6). Fifty-nine of 273 (22%) patients had severe fibrosis. The distribution of genotypes for IL-10-627 was CC (11%), CA (41%), and AA (48%). The CC genotype at IL-10-627 was protective against severe fibrosis (odds ratio (OR) 0.11 95% CI 0.014-0.82 P = 0.032). After adjusted for baseline variables, the adjusted OR of CC genotypes at IL-10-627 for severe fibrosis was 0.063 (95% CI 0.06-0.64 P = 0.063). Other gene polymorphisms at IL-1beta, IL-1RN, TNF-alpha, and IL-10 had no significant association with severe fibrosis. Weak linkage disequilibrium was observed between IL-10-627 and IL-10-1117 with linkage disequilibrium coefficient of 0.12 (P < 0.001). The distribution of haplotypes of IL-10-1117 and IL-10-627 was A-A (69%), A-C (26%), and G-C (5%). High and intermediate IL-10 production (A-C and G-C) haplotypes were protective against severe fibrosis (OR 0.62 95% CI 0.39-0.99 P = 0.046). High production genotype and haplotypes of IL-10 were associated with less severe liver fibrosis in chronic hepatitis B in Chinese.
Publisher: Oxford University Press (OUP)
Date: 15-04-2007
DOI: 10.1086/512819
Publisher: Elsevier BV
Date: 06-2010
DOI: 10.1016/J.BIOCEL.2010.02.006
Abstract: Nonalcoholic steatohepatitis with fibrosis is a more severe form of nonalcoholic fatty liver disease, one of the most common liver diseases. We have previously shown that peroxisome proliferator-activated receptors gamma (PPARgamma) ligand, rosiglitazone, prevented the development of the methionine choline deficient (MCD) diet-induced fibrosing steatohepatitis. We have now tested whether overexpression of PPARgamma ameliorates established steatohepatitis and fibrosis. Male C57BL6 mice fed with MCD diet for 8 weeks developed hepatic fibrosis with increased hepatic expression of collagen1alpha(I), inhibitors of fibrosis reversal-1, regulator involved in matrix degradation-9 and connective tissue growth factor. After 2 weeks of transduction of PPARgamma through an adenovirus-expressing PPARgamma (Ad-PPARgamma), expression of these genes was reduced in a manner that paralleled the reduction in activated hepatic stellate cells (HSCs) and resolution of liver fibrosis. On the in vitro study, PPARgamma is expressed in primary quiescent HSC, but depleted in culture activated HSC. Conversely, ectopic expression of PPARgamma in activated HSC achieved the phenotypic reversal to the quiescent cell. Such induction markedly suppressed cell viability and cell proliferation, downregulated proliferating cell nuclear antigen, and caused cell cycle arrest at G0/G1 phase. Further, introduction of PPARgamma in HSC increased cell apoptosis, this was confirmed by enhanced expression of FasL, cleaved caspase-3, cleaved caspase-7 and poly ADP-ribose polymerase, indicating an extrinsic apoptosis pathway. In conclusion, the present study shows that MCD diet-induced fibrosing steatohepatitis can be reversed by overexpression of PPARgamma. It is likely that PPARgamma reverses fibrosis by reducing HSCs proliferation, inducing cell cycle arrest and apoptosis.
Publisher: BMJ
Date: 12-05-2012
DOI: 10.1136/GUTJNL-2011-301776
Abstract: Zinc-finger protein 545 (ZNF545) is a member of the family of Krüppel-associated box-containing zinc-finger proteins. The aim of this study was to clarify its biological function as a tumour suppressor in gastric cancer. The biological function of ZNF545 was determined by cell growth and apoptosis assays. The ZNF545 target signal pathway was identified by promoter luciferase assay, northern blot, run-on transcription assay, chromatin immunoprecipitation and coimmunoprecipitation assays. The clinical application of ZNF545 was assessed in primary gastric cancers. ZNF545 was silenced or reduced in 16 out of 18 gastric cancer cell lines by promoter hypermethylation. Restoration of ZNF545 expression in gastric cancer cell lines suppressed cell proliferation and induced apoptosis. These effects of ZNF545 were attributed to inhibition of ribosomal RNA (rRNA) transcription. Inhibition of rRNA transcription by ZNF545 was further revealed to be associated with direct ribosomal DNA (rDNA) promoter binding, recruitment of the corepressor, heterochromatin protein 1β, and reduction of trimethylated histone H3 at the Lys4 residue at the rDNA locus. ZNF545 methylation was detected in 51.9% (41/79) of gastric cancer tissues, 27.0% (20/74) of adjacent non-tumour gastric tissues (p=0.001), but none of 20 normal controls. Multivariate analysis revealed that patients with ZNF545 methylation had a significant decrease in overall survival. Kaplan-Meier survival curves showed that ZNF545 methylation was significantly associated with shortened survival in patients with stage I-II gastric cancer. ZNF545 acts as a functional tumour suppressor in gastric cancer by inhibiting rRNA transcription. Its methylation at early stages of gastric carcinogenesis is an independent prognostic factor.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2010
DOI: 10.1038/AJG.2009.560
Abstract: Chronic hepatitis B patients with diabetes and metabolic syndrome are at increased risk of cirrhosis and hepatocellular carcinoma, but the underlying mechanism is unclear. Our objective was to test whether dysregulation of adipokines contributes to liver injury. We also studied whether viral factors affected adipokines, insulin resistance, and hepatic steatosis. A prospective cohort of 266 chronic hepatitis B patients undergoing liver biopsy was studied. Fasting blood was taken for the analysis of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), adiponectin, leptin, and resistin. Insulin resistance was assessed by the homeostasis model assessment of insulin resistance (HOMA-IR). Factors associated with significant necroinflammation and cirrhosis were identified. Histological activity index was correlated with serum TNF-alpha (R=0.40, P<0.0001) and IL-6 (R=0.32, P<0.0001) but not with adiponectin, leptin, or resistin. By multivariate analysis, TNF-alpha was associated with significant necroinflammation after adjusting for age and viral factors (odds ratio (OR) 1.041, 95% confidence interval (CI) 1.002-1.082, P=0.04). Serum adiponectin had positive correlation with hepatitis B virus DNA (R=0.17, P=0.007) and was decreased in patients with insulin resistance and hepatic steatosis. On the other hand, viral load, hepatitis B e-antigen status, and genotypes had no association with insulin resistance, hepatic steatosis, and the levels of TNF-alpha and IL-6. A total of 68 (25.6%) patients had cirrhosis. HOMA-IR, but not adipokine dysregulation, was independently associated with cirrhosis (OR 1.09, 95% CI 1.02-1.15, P=0.006). TNF-alpha and/or IL-6 contribute to hepatic necroinflammation in chronic hepatitis B patients. Adiponectin protects against insulin resistance and hepatic steatosis but does not affect liver injury. Adipokines and viral factors contribute to liver injury independently.
Publisher: Springer Science and Business Media LLC
Date: 11-2001
Publisher: Radiological Society of North America (RSNA)
Date: 08-2003
Publisher: Elsevier BV
Date: 04-2011
DOI: 10.1016/J.CANEP.2010.08.006
Abstract: Today, the causal relationship between inflammation and gastric cancer is more widely accepted. Genetic variations in inflammation-related genes especially cytokines and their receptors, were thought to partly determine the outcome of Helicobacter pylori (H. pylori) infection and progression of gastric lesions. Interleukin 23 receptor (IL23R), as a key cytokine receptor gene in the important inflammatory IL-17/IL-23 axis, may contribute to gastric cancer predisposition. Up till now, the associations of IL23R gene polymorphisms with subtypes of gastric cancer are largely unknown. We investigated whether the association between IL23R +2199 rs10889677 and gastric cancer risk varies by clinical characteristics and the prognostic value of the polymorphism in a case-control study. A population-based case-control study was conducted in Guangdong. 1010 gastric cancer patients and 800 healthy controls were enrolled. Polymorphism in IL23R was analyzed by PCR-RFLP. Compared with AA, CC carriers of IL23R +2199 polymorphism were associated with protection against gastric cancer (OR=0.47, 95% CI=0.31-0.71). In stratified analyses, CC genotype was significantly associated with decreased risk of intestinal type (OR=0.44, 95% CI=0.27-0.70), but not with diffuse or mix type of gastric cancer. CC genotype was found to be associated with poorly differentiated (OR=0.43, 95% CI=0.26-0.70), but not with moderately or well differentiated gastric cancer. Multivariate analysis showed IL23R +2199A/C variant was not an independent prognostic factor for gastric cancer patients. IL23R polymorphism influences certain subtypes of gastric cancer according to clinical and pathological features. Understanding the etiologic heterogeneity of gastric cancer may result in improvements in controlling this disorder.
Publisher: Elsevier BV
Date: 08-2008
DOI: 10.1016/J.BBRC.2008.05.069
Abstract: Hepatic COX-2 overexpression is sufficient to induce hepatitis, but its role on liver fibrosis remains unknown. We aim to elucidate possible biological effects of COX-2 in liver fibrosis using both gain-of-function and loss-of-function mouse models. COX-2 transgenic (TG) mice that specifically overexpress the human COX-2 cDNA in the liver, knockout (KO), and wild type (WT) mice were studied in two different murine fibrosis models induced by carbon tetrachloride (CCl(4)) injection or methionine and choline-deficient (MCD) diet. Liver injury was assessed by serum ALT and bilirubin levels and histological examination. Hepatic collagen content was determined by picrosirius red stain morphometry assay and quantitation of hydroxyproline. Hepatic stellate cell (HSC) activation was determined by immunohistochemical analysis of alpha-smooth muscle actin (alpha-SMA). mRNA expression of fibrogenic genes was assayed by real-time quantitative PCR. COX-2 protein was overexpressed in the liver of TG mice compared with WT littermates. CCl(4) or MCD-induced liver fibrotic injury was equally severe in TG and WT mice, as demonstrated by similar elevated levels of hepatic collagen contents. Enhanced COX-2 expression in TG liver did not affect HSC activation and fibrogenic gene expression upon CCl(4) or MCD treatment. Importantly, CCl(4)-treated KO mice did not show significant difference in liver fibrotic damage and fibrogenic gene expression compared with the WT counterparts. This is the first report on the effect of COX-2 in liver fibrosis based on genetic mouse models. The results suggest that COX-2 does not appear to mediate the development of liver fibrosis.
Publisher: BMJ
Date: 14-03-2011
Abstract: To develop and validate a clinical risk score predictive of risk for colorectal advanced neoplasia for Asia. A prospective, cross-sectional and multicentre study was carried out in tertiary hospitals in 11 Asian cities. The subjects comprise 2752 asymptomatic patients undergoing screening colonoscopy. From a development set of 860 asymptomatic subjects undergoing screening colonoscopy, multiple logistic regression was applied to identify significant risk factors for advanced colorectal neoplasia defined as invasive carcinoma or advanced adenoma. The ORs for significant risk factors were utilised to develop a risk score ranging from 0 to 7 (Asia-Pacific Colorectal Screening (APCS) score). Three tiers of risk were arbitrarily defined: 0-1 'average risk' (AR) 2-3 'moderate risk' (MR) and 4-7 'high risk' (HR). Subjects undergoing screening colonoscopy between July 2006 and December 2007 were prospectively enrolled to form an independent validation group. Each subject had a personal APCS score calculated by summing the points attributed from the presence of risk factors in the in iduals. The performance of the APCS score in predicting risk of advanced neoplasia was evaluated. There were 860 subjects in the derivation set and 1892 subjects in the validation set, with a baseline prevalence of advanced neoplasia of 4.5% and 3%, respectively. Applying the APCS stratification in the validation set, 559 subjects (29.5%) were in the AR tier, 966 subjects (51.1%) in the MR tier and 367 (19.4%) subjects in the HR tier. The prevalence of advanced neoplasia in the AR, MR and HR groups was 1.3, 3.2 and 5.2%, respectively. The subjects in the MR and HR tiers had 2.6-fold (95% CI 1.1 to 6.0) and 4.3-fold (95% CI 1.8 to 10.3) increased prevalence of advanced neoplasia, respectively, than those in the AR tier. The APCS score based on age, gender, family history and smoking is useful in selecting asymptomatic Asian subjects for priority of colorectal screening.
Publisher: Oxford University Press (OUP)
Date: 12-2005
DOI: 10.1373/CLINCHEM.2005.054460
Abstract: Background: Exaggerated activation of cytokines/chemokines has been proposed as a factor in adverse outcome of severe acute respiratory syndrome (SARS). Previous studies on chemokines have included only small numbers of patients, and the utility of plasma chemokines as prognostic indicators is unclear. Methods: We studied 255 archival plasma s les collected during the first or second week after disease onset. The chemokines interferon-inducible protein-10 (IP-10), monokine induced by interferon-γ (MIG), interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), and regulated upon activation normal T cell expressed and secreted (RANTES) were measured by cytometric bead array with a 4-color FACSCalibur flow cytometer. Reverse transcription and real-time quantitative PCR and immunohistochemical staining were performed to analyze the production of IP-10 in lung tissue at autopsy. Conditional logistic regression was used to identify independent predictors for adverse disease outcome. Results: Increases in IP-10, MIG, and IL-8 during the first week after onset of fever were associated with adverse outcome (intensive care unit admission or death) in the univariate analysis. During the second week, only MIG concentration was associated with prognosis. After adjusting for other risk factors, plasma IP-10 concentration at the first week remained as an independent prognostic factor, with an odds ratio for adverse outcome of 1.52 (95% confidence interval, 1.05–2.55) per fold increase in plasma IP-10 concentration above the median. During the second week, chemokines provided little independent prognostic information. IP-10 was increased in lung tissue from patients who died of SARS. Conclusions: Increased plasma IP-10 during the first week of SARS symptoms is an independent predictor of outcome. Chemokine activation may be an early event in SARS, and an exaggerated host response may produce complications.
Publisher: Public Library of Science (PLoS)
Date: 25-04-2013
Publisher: Elsevier BV
Date: 07-2003
Publisher: Elsevier BV
Date: 11-2018
Abstract: Cancer-related genes are under intense evolutionary pressure. We conjectured that gene size is an important determinant of lification propensity for oncogenes and thus cancer susceptibility and therefore could be subject to natural selection. Gene information, including size and genomic locations, of all protein-coding genes were downloaded from Ensembl (release 87). Quantification of gene lification was based on Genomic Identification of Significant Targets in Cancer scores obtained from available The Cancer Genome Atlas studies. Oncogenes are larger in size as compared with non-cancer genes (mean size: 92.1 kb versus 61.4 kb P < 0.0001) in the human genome, which is contributed by both increased total exon size (mean size: 4.6 kb versus 3.4 kb P < 0.0001) and higher intronic content (mean %: 84.8 versus 78.0 P < 0.01). Such non-random size distribution and intronic composition are conserved in mouse and Drosophila (all P < 0.0001). Stratification by gene age indicated that young oncogenes have been subject to a stronger evolutionary pressure for gene expansion than their non-cancer counterparts. Pan-cancer analysis demonstrated that larger oncogenes were lified to a lesser extent. Tumor-suppressor genes also moved toward small oncogenes in the course of evolution. Oncogenes expand in size whereas tumor-suppressor genes move closer to small oncogenes in the course of evolution to withstand oncogenic somatic lification. Our findings have shed new light on the previously unappreciated influence of gene size on oncogene lification and elucidated how cancers have shaped our genome to its present configuration.
Publisher: Springer Science and Business Media LLC
Date: 27-02-2012
DOI: 10.1038/ONC.2012.54
Abstract: Zinc-finger protein 331 (ZNF331), a Kruppel-associated box zinc-finger protein gene, was identified as a putative tumor suppressor in our previous study. However, the role of ZNF331 in tumorigenesis remains elusive. We aimed to clarify its epigenetic regulation and biological functions in gastric cancer. ZNF331 was silenced or downregulated in 71% (12/17) gastric cancer cell lines. A significant downregulation was also detected in paired gastric tumors compared with adjacent non-cancer tissues. In contrast, ZNF331 was readily expressed in various normal adult tissues. The downregulation of ZNF331 was closely linked to the promoter hypermethylation as evidenced by methylation-specific PCR, bisulfite genomic sequencing and reexpression by demethylation agent treatment. DNA sequencing showed no genetic mutation/deletion of ZNF331 in gastric cancer cell lines. Ectopic expression of ZNF331 in the silenced cancer cell lines MKN28 and HCT116 significantly reduced colony formation and cell viability, induced cell cycle arrests and repressed cell migration and invasive ability. Concordantly, knockdown of ZNF331 increased cell viability and colony formation ability of gastric cancer cell line MKN45. Two-dimensional gel electrophoresis and mass spectrometry-based comparative proteomic approach were applied to analyze the molecular basis of the biological functions of ZNF331. In all, 10 downstream targets of ZNF331 were identified to be associated with regulation of cell growth and metastasis. The tumor-suppressive effect of ZNF331 is mediated at least by downregulation of genes involved in cell growth promotion (DSTN, EIF5A, GARS, DDX5, STAM, UQCRFS1 and SET) and migration/invasion (DSTN and ACTR3), and upregulation of genome-stability gene (SSBP1) and cellular senescence gene (PNPT1). A novel target of ZNF331 (DSTN) was functionally validated. Overexpression of DSTN in BGC-823 cells increased colony formation and migration ability. In conclusion, our results suggest that ZNF331 possesses important functions for the suppression of gastric carcinogenesis as a novel functional tumor-suppressor gene.
Publisher: BMJ
Date: 03-06-2015
DOI: 10.1136/GUTJNL-2014-309086
Abstract: Colorectal cancer (CRC) ranks third among the most commonly diagnosed cancers worldwide, with wide geographical variation in incidence and mortality across the world. Despite proof that screening can decrease CRC incidence and mortality, CRC screening is only offered to a small proportion of the target population worldwide. Throughout the world there are widespread differences in CRC screening implementation status and strategy. Differences can be attributed to geographical variation in CRC incidence, economic resources, healthcare structure and infrastructure to support screening such as the ability to identify the target population at risk and cancer registry availability. This review highlights issues to consider when implementing a CRC screening programme and gives a worldwide overview of CRC burden and the current status of screening programmes, with focus on international differences.
Publisher: Springer Science and Business Media LLC
Date: 11-09-2007
Publisher: Springer Science and Business Media LLC
Date: 03-2012
DOI: 10.1038/GT.2012.22
Abstract: Cathelicidin is a pleiotropic host defense peptide secreted by epithelial and immune cells. Whether endogenous cathelicidin is protective against ulcerative colitis, however, is unclear. Here we sought to delineate the role of endogenous murine cathelicidin (mCRAMP) and the therapeutic efficacy of intrarectal administration of mCRAMP-encoding plasmid in ulcerative colitis using dextran sulfate sodium (DSS)-challenged cathelicidin-knockout (Cnlp(-/-)) mice as a model. Cnlp(-/-) mice had more severe symptoms and mucosal disruption than the wild-type mice in response to DSS challenge. The tissue levels of interleukin-1β and tumor necrosis factor-α, myeloperoxidase activity and the number of apoptotic cells were increased in the colon of DSS-challenged Cnlp(-/-) mice. Moreover, mucus secretion and mucin gene expression were impaired in Cnlp(-/-) mice. All these abnormalities were reversed by the intrarectal administration of mCRAMP or mCRAMP-encoding plasmid. Taken together, endogenous cathelicidin may protect against ulcerative colitis through modulation of inflammation and mucus secretion.
Publisher: Springer Science and Business Media LLC
Date: 14-09-2015
DOI: 10.1038/ONC.2015.324
Publisher: Wiley
Date: 2009
DOI: 10.1111/J.1478-3231.2008.01760.X
Abstract: Celecoxib was used in the treatment of inflammation in patients with cirrhosis. However, data on the progression of liver fibrosis after treatment by celecoxib are not available. This study aims to elucidate the effects of celecoxib on cholestatic liver fibrosis in rats. Rats underwent bile duct ligation (BDL) for 1 or 2 weeks to induce hepatic fibrosis. Celecoxib was introduced on day 1 after operation. The effects of celecoxib were assessed by comparison of the severity of hepatic fibrosis. Infiltration of inflammatory cells and proliferation of bile ducts was seen after 1 week of BDL and fibrosis was induced after 2 weeks. Reduced alanine aminotransferase (ALT) levels and blunted expression of inflammatory factors [tumour necrosis factor-alpha, interleukin (IL)-1beta and IL-6] were seen in the liver of BDL-treated rats that received celecoxib at week 1. Although celecoxib was sufficient in suppressing the cyclo-oxygenase (COX)-2 expression in the control organ (kidney), it failed to suppress the enhanced hepatic COX-2 expression. At week 2, celecoxib did not alter the ALT level, the severity of fibrosis and hepatic collagen contents. This was associated with unchanged alpha-smooth muscle actin protein expression and tissue inhibitor of metalloproteinase-2 (TIMP-2), matrix metalloproteinase (MMP)-2 and MMP-9 mRNA expressions in the liver. Celecoxib had no effect on the BDL-dependent increase in bilirubin levels at any time point. The present study provides morphological and molecular biological evidences for the role of celecoxib in cholestatic liver fibrosis. Celecoxib protects against hepatic inflammation in the early stage of BDL rats, but does not have an effect on liver fibrosis.
Publisher: Elsevier BV
Date: 09-2008
DOI: 10.1016/J.BBRC.2008.06.098
Abstract: The oncogenic hepatitis B virus X protein (HBx) and cyclooxygenase (COX)-2 are highly co-expressed in chronic hepatitis, cirrhosis and well-differentiated hepatocellular carcinoma (HCC). Although HBx is shown to activate COX-2, the functional consequences of this interaction in hepatocarcinogenesis remain unknown. Using an engineered hepatoma cell system in which the expression of wild-type p53 can be chemically modulated, we show here that COX-2 mediates HBx actions in opposing p53. Enforced expression of HBx sequestrates p53 in the cytoplasm and significantly abolishes p53-induced apoptosis. The anti-apoptotic Mcl-1 protein is suppressed by p53 but reactivated by HBx. The abrogation of apoptosis is completely reversed by specific COX-2 inhibition, suggesting that HBx blocks p53-induced apoptosis via activation of COX-2/PGE(2) pathway. We further show that COX-2 inhibition blocks HBx reactivation of Mcl-1, linking this protein to the anti-apoptotic function of COX-2. These results demonstrate that COX-2 is an important survival factor mediating the oncogenic actions of HBx. Over-expression of HBx and COX-2 may provide a selective clonal advantage for preneoplastic or neoplastic hepatocytes and contribute to the initiation and progression of HCC.
Publisher: Wiley
Date: 2000
Publisher: Public Library of Science (PLoS)
Date: 08-11-2011
Publisher: Oxford University Press (OUP)
Date: 15-08-2009
DOI: 10.1086/600383
Publisher: Oxford University Press (OUP)
Date: 07-07-2008
Abstract: Cyclooxoygenase (COX)-2 overexpression is involved in gastric carcinogenesis. While high-salt intake is a known risk factor for gastric cancer development, we determined the effects of high salt on gastric chemical carcinogenesis in COX-2 transgenic (TG) mice. COX-2 TG mice were developed in C57/BL6 strain using the full-length human cox-2 complementary DNA construct. Six-week-old COX-2 TG and wild-type (WT) littermates were randomly allocated to receive alternate week of N-methyl-N-nitrosourea (MNU, 240 p.p.m.) in drinking water or control for 10 weeks. Two groups of mice were further treated with 10% NaCl during the initial 10 weeks. All mice were killed at the end of week 50. Both forced COX-2 overexpression and high-salt intake significantly increased the frequency of gastric cancer development in mice as compared with WT littermates treated with MNU alone. However, no additive effect was observed on the combination of high salt and COX-2 expression. We further showed that MNU and high-salt treatment increased chronic inflammatory infiltrates and induced prostaglandin E(2) (PGE(2)) production in the non-cancerous stomach. Whereas high-salt treatment markedly increased the expression of inflammatory cytokines (tumor necrosis factor-alpha, interferon-gamma, interleukin (IL)-1 beta and IL-6) in the gastric mucosa, COX-2 overexpression significantly altered the cell kinetics in the MNU-induced gastric cancer model. In conclusion, both high salt and COX-2 overexpression promote chemical-induced gastric carcinogenesis, possibly related to chronic inflammation, induction of PGE(2), disruption of cell kinetics and induction of inflammatory cytokines.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2008
DOI: 10.1002/HEP.22343
Abstract: The ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) is a carboxyl-terminal ubiquitin hydrolase regulating cellular ubiquitin levels, recently suggested as a tumor suppressor. However, the role of UCHL1 in hepatocellular carcinoma (HCC) is not clear. We investigated the expression and DNA methylation of the UCHL1 in primary HCC, liver metastases from digestive carcinomas, and primary digestive cancers. UCHL1 is expressed in all normal tissues and immortalized normal epithelial cell lines, but was low or silenced in 77% (10/13) of HCC cell lines, which is well correlated with its promoter methylation status. Methylation was further detected in 44% (12/27) of HCCs, but less in metastatic tumors generated from colorectal and stomach in the liver (19%, 3/16 P < 0.05). Methylation was also detected in primary digestive tumors, including 71% (22/31) of colon, 77% (53/69) of gastric, and 40% (18/45) of esophageal carcinomas, but none or occasionally in paired adjacent nontumor tissues. Detailed methylation analysis of 49 CpG sites at a 540-bp promoter region by bisulfite genomic sequencing confirmed the methylation. UCHL1 silencing could be reversed by chemical or genetic demethylation of the promoter, indicating direct epigenetic silencing. Restoring UCHL1 expression in silenced cell lines significantly inhibited their growth and colony formation ability by inhibiting cell proliferation, causing cell cycle arrest in G2/M phase and inducing apoptosis through the intrinsic caspase-dependent pathway. Moreover, UCHL1 directly interacts with p53 and stabilizes p53 through the ubiquitination pathway. Epigenetic inactivation of UCHL1 is common in primary HCCs and other digestive tumors. UCHL1 appears to be a functional tumor suppressor involved in the tumorigenesis of HCCs and other digestive cancers.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2004
DOI: 10.1097/00004728-200411000-00010
Abstract: To evaluate thin-section computed tomography findings of patients with severe acute respiratory syndrome (SARS) in the convalescent period and to correlate the results with clinical parameters and lung function tests. Ninety-nine severe acute respiratory syndrome patients with persistent changes on follow-up chest radiography were included. One hundred seventy computed tomography examinations at baseline (n=70), 3 months (n=56), and 6 months (n=44) were retrospectively evaluated to determine the extent of ground-glass opacification, reticulation, and total parenchymal involvement. Patients' demographic information, clinical information during treatment, and results of lung function tests at 3 and 6 months were correlated with computed tomography findings. A significant serial improvement in the extent of overall ground-glass opacification, overall reticulation, and total parenchymal involvement was observed (P <0.01). Advanced age, previous intensive care unit admission, mechanical ventilation, alternative treatment, higher peak lactate dehydrogenase, and peak radiographic involvement during treatment showed a positive correlation with overall reticulation and total parenchymal involvement at 6 months. There was a significant negative correlation between overall reticulation and total parenchymal involvement with diffusion capacity adjusted for hemoglobin at 3 and 6 months (P <0.01). Lung changes on thin-section computed tomography of severe acute respiratory syndrome patients improved with time during the convalescent period and showed a significant correlation with advanced age, parameters indicating severe illness, and diffusion capacity adjusted for hemoglobin on follow-up.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 28-01-2010
DOI: 10.1002/HEP.23550
Abstract: Although peroxisome proliferator-activated receptor gamma (PPARgamma) agonist have been shown to inhibit hepatocellular carcinoma (HCC) development, the role of PPARgamma in hepatocarcinogenesis remains unclear. We investigated the therapeutic efficacy of PPARgamma against HCC. PPARgamma-deficient (PPARgamma(+/-)) and wild-type (PPARgamma(+/+)) littermates were used in a diethylnitrosamine (DEN)-induced HCC model and treated with PPARgamma agonist (rosiglitazone) or the vehicle alone for 8 months. The effects of PPARgamma on HCC cell growth and apoptosis were examined using PPARgamma-expressing adenovirus (Ad-PPARgamma). PPARgamma(+/-) mice were more susceptible to DEN-induced HCC than PPARgamma(+/+) mice (94% versus 62%, P < 0.05), and rosiglitazone significantly reduced the incidence of HCC in PPARgamma(+/+) mice (vehicle 62% versus treatment 24%, P < 0.01), but not in PPARgamma(+/-) mice, indicating that PPARgamma suppresses hepatocellular carcinogenesis. A pronounced expression of PPARgamma was observed in a HCC cell line (Hep3B) infected with Ad-PPARgamma. Such induction markedly suppressed HCC cell viability (P < 0.01). Further, Hep3B infection with Ad-PPARgamma revealed a decreased proportion of cells in S-phase (12.92% versus 11.58%, P < 0.05), with arrest at G(2)/M phase (38.2% versus 55.68%, P < 0.001), and there was concomitant phosphorylation of the key G(2)/M phase inhibitors cdc25C and cdc2. PPARgamma overexpression increased cell apoptosis (21.47% versus 35.02%, P < 0.01), mediated by both extrinsic (Fas and tumor necrosis factor-alpha) and intrinsic (caspase-9, caspase-3, caspase-7, and poly[ADP-ribose] polymerase) pathways. Moreover, PPARgamma directly induced a putative tumor suppressor gene, growth differentiation factor-15. Loss of one PPARgamma allele is sufficient to enhance susceptibility to HCC. PPARgamma suppresses tumor cell growth through reducing cell proliferation and inducing G(2)/M phase arrest, apoptosis, and up-regulating growth differentiation factor-15. Thus, PPARgamma acts as a tumor-suppressor gene in the liver.
Publisher: BMJ
Date: 24-05-2017
Publisher: American Association for Cancer Research (AACR)
Date: 12-04-2018
DOI: 10.1158/0008-5472.CAN-17-2683
Abstract: Gene lification is a hallmark of cancer and is frequently observed in colorectal cancer. Previous whole-genome sequencing of colorectal cancer clinical specimens identified lification 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 lification. Furthermore, RNF6 expression and its gene lification 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 β-catenin/TCF4 complex. RNF6-mediated degradation of TLE3 significantly suppressed the association of TLE3 with TCF4/LEF, which in turn led to recruitment of β-catenin to TCF4/LEF, triggering Wnt/β-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/β-catenin pathway in colorectal carcinogenesis. Cancer Res 78(8) 1958–71. ©2018 AACR.
Publisher: Wiley
Date: 10-2000
DOI: 10.1046/J.1440-1746.2000.02267.X
Abstract: Non-steroidal anti-inflammatory drug (NSAID) toxicity in the upper gastrointestinal tract is the most common serious drug-induced toxicity reported to drug regulatory authorities. In the last two decades, the rediscovery of H. pylori, development of potent ulcer-healing drugs and specific Cox-II inhibitors have opened new horizons in the management of NSAID toxicity. A Working Party composed of gastroenterologists and rheumatologists in the Asia-Pacific region met in Cairns, Australia, in 1999 to review the literature and develop appropriate guidelines. Recommendations were made based on the latest existing evidence. The importance of clinical events as study endpoints was emphasized. While differences exist between NSAIDs and aspirin, most studies have shown that advanced age, history of peptic ulcer disease, serious concomitant illnesses and coprescription of NSAID/aspirin with anticoagulants and steroids are high risk factors. These patients should be considered for prophylactic anti-ulcer therapy. Helicobacter pylori infection may aggravate the toxicity of NSAIDs and, in selected cases, should be treated before NSAID/aspirin is prescribed. Proton pump inhibitors and misoprostol are the most promising agents in preventing gastric and duodenal ulcers. When NSAID/aspirin needs to be continued in patients who develop an NSAID-related ulcer, proton pump inhibitors offer the best healing effect. With the discovery of cyclo-oxygenase isoforms (Cox-I and Cox-II), preferential and specific Cox-II inhibitors have been developed. While early clinical data have suggested promising antiinflammatory effects and improved safety profile in the gastrointestinal tract, several key issues on long-term safety remain unresolved. The use of potent anti-ulcer therapy, treatment of H. pylori infection and the development of Cox-II inhibitor will change the scenario of NSAID/aspirin-related gastrointestinal toxicity in the next millennium.
Publisher: Springer Science and Business Media LLC
Date: 30-08-2010
DOI: 10.1038/ONC.2010.352
Abstract: Gastric carcinogenesis is a multistep process involving genetic and epigenetic alteration of protein-coding proto-oncogenes and tumor-suppressor genes. Recent discoveries have shed new light on the involvement of a class of noncoding RNA known as microRNA (miRNA) in gastric cancer. A substantial number of miRNAs show differential expression in gastric cancer tissues. Genes coding for these miRNAs have been characterized as novel proto-oncogenes and tumor-suppressor genes based on findings that these miRNAs control malignant phenotypes of gastric cancer cells. In this connection, miRNA dysregulation promotes cell-cycle progression, confers resistance to apoptosis, and enhances invasiveness and metastasis. Moreover, certain polymorphisms in miRNA genes are associated with increased risks for atrophic gastritis and gastric cancer, whereas circulating levels of miRNAs may serve as biomarkers for early diagnosis. Several miRNAs have also been shown to correlate with gastric cancer progression, and thus may be used as prognostic markers. Elucidating the biological aspects of miRNA dysregulation may help us better understand the pathogenesis of gastric cancer and promote the development of miRNA-directed therapeutics against this deadly disease.
Publisher: American Association for Cancer Research (AACR)
Date: 29-05-2014
DOI: 10.1158/1078-0432.CCR-13-1750
Abstract: Purpose: Detecting microRNA (miRNA) in stool is a novel approach for colorectal cancer (CRC) screening. This study aimed to identify stool-based miRNA as noninvasive biomarkers for detection of CRC and adenoma. Experimental Design: A miRNA expression array covering 667 human miRNAs was performed on five pairs of CRC and two pairs of advanced adenoma tissues. The most upregulated miRNAs were validated in 40 pairs of CRC tissues, 16 pairs of advanced adenoma tissues, and 424 stool s les, including 104 CRCs, 169 adenomas, 42 inflammatory bowel diseases (IBD), and 109 healthy controls. miRNA levels were followed-up after removal of lesions. Results: In an array analysis, miR-31 and miR-135b were the most upregulated miRNAs in CRC and advanced adenoma as compared with their adjacent normal tissues (& -fold increase). In stool s les, level of miR-135b was significantly higher in subjects with CRC (P & 0.0001) or adenomas (P & 0.0001), but not in patients with IBD compared with controls. miR-135b showed a significant increasing trend across the adenoma to cancer sequence (P & 0.0001). Levels of miR-31 were not significantly different among groups. The sensitivity of stool mR-135b was 78% for CRC, 73% for advanced adenoma, and 65% for any adenoma, respectively, with a specificity of 68%. No significant difference in the miR-135b level was found between proximal and distal colorectal lesions. Stool miR-135b dropped significantly upon removal of CRC or advanced adenoma (P & 0.0001). Conclusion: Stool-based miR-135b can be used as a noninvasive biomarker for the detection of CRC and advanced adenoma. Clin Cancer Res 20(11) 2994–3002. ©2014 AACR.
Publisher: Elsevier BV
Date: 2016
DOI: 10.1053/J.GASTRO.2015.09.005
Abstract: The incidence of inflammatory bowel disease (IBD) is increasing in Asia, but little is known about disease progression in this region. The Asia-Pacific Crohn's and Colitis Epidemiology Study was initiated in 2011, enrolling subjects from 8 countries in Asia (China, Hong Kong, Indonesia, Sri Lanka, Macau, Malaysia, Singapore, and Thailand) and Australia. We present data from this ongoing study. We collected data on 413 patients diagnosed with IBD (222 with ulcerative colitis [UC], 181 with Crohn's disease [CD], 10 with IBD unclassified median age, 37 y) from 2011 through 2013. We analyzed the disease course and severity and mortality. Risks for medical and surgical therapies were assessed using Kaplan-Meier analysis. The cumulative probability that CD would change from inflammatory to stricturing or penetrating disease was 19.6%. The cumulative probabilities for use of immunosuppressants or anti-tumor necrosis factor agents were 58.9% and 12.0% for patients with CD, and 12.7% and 0.9% for patients with UC, respectively. Perianal CD was associated with an increased risk of anti-tumor necrosis factor therapy within 1 year of its diagnosis (hazard ratio, 2.97 95% confidence interval, 1.09-8.09). The cumulative probabilities for surgery 1 year after diagnosis were 9.1% for patients with CD and 0.9% for patients with UC. Patients with CD and penetrating disease had a 7-fold increase for risk of surgery, compared with patients with inflammatory disease (hazard ratio, 7.67 95% confidence interval, 3.93-14.96). The overall mortality for patients with IBD was 0.7%. In a prospective population-based study, we found that the early course of disease in patients with IBD in Asia was comparable with that of the West. Patients with CD frequently progress to complicated disease and have accelerated use of immunosuppressants. Few patients with early stage UC undergo surgery in Asia. Increasing our understanding of IBD progression in different populations can help optimize therapy and improve outcomes.
Publisher: Springer Science and Business Media LLC
Date: 20-12-2012
DOI: 10.1038/GT.2012.92
Abstract: Cathelicidin, an antimicrobial peptide of the innate immune system, has been shown to modulate microbial growth, wound healing and inflammation. However, whether cathelicidin controls Helicobacter pylori infection in vivo remains unexplored. This study sought to elucidate the role of endogenous and exogenous mouse cathelicidin (CRAMP) in the protection against H. pylori infection and the associated gastritis in mice. Results showed that genetic ablation of CRAMP in mice significantly increased the susceptibility of H. pylori colonization and the associated gastritis as compared with the wild-type control. Furthermore, replenishment with exogenous CRAMP, delivered via a bioengineered CRAMP-secreting strain of Lactococcus lactis, reduced H. pylori density in the stomach as well as the associated inflammatory cell infiltration and cytokine production. Collectively, these findings indicate that cathelicidin protects against H. pylori infection and its associated gastritis in vivo. Our study also demonstrates the feasibility of using the transformed food-grade bacteria to deliver cathelicidin, which may have potential clinical applications in the treatment of H. pylori infection in humans.
Publisher: Wiley
Date: 17-02-2010
DOI: 10.1002/JMV.21725
Abstract: Human infection with the novel pandemic influenza A (H1N1) virus was first identified in April 2009. Two months later, the World Health Organization (WHO) had raised the pandemic level to phase 6. Rapid case identification is essential for prompt patient management and public health actions. This study developed real-time and conventional reverse transcription-polymerase chain reaction (rRT-PCR and cRT-PCR) assays for pandemic H1N1 detection, and compared their sensitivities with protocols developed by WHO reference centres. Altogether, three rRT-PCR and one cRT-PCR targeting the matrix gene for universal detection of influenza A three rRT-PCR, one cRT-PCR targeting the hemagglutinin (HA) gene for specific detection of pandemic H1N1 and one multiplex cRT-PCR for differentiating co-circulating seasonal H1N1, H3N2, and pandemic H1N1 were examined. The lower detection limit ranged from 1.252 to 125.2 copy equivalents. In general, rRT-PCR assays were more sensitive than cRT-PCR assays. All assays showed 100% sensitivity for "optimal" specimens (nasopharyngeal s les collected within 4 days after illness onset). For the other 36 s les, cRT-PCR assays were less sensitive except that the new Protocol I-cRT-pdmH1 still retained 100% sensitivity. The new Protocol F-rRT-PCR-pdmH1 was the only pandemic virus-specific rRT-PCR assay with 100% sensitivity across all specimen categories. In conclusion, rRT-PCR assays are 10-fold more sensitive than cRT-PCR assays. The newly developed cRT-PCR assay targeting the HA gene allows rapid, specific, and sensitive screening of this novel agent, which can serve as an alternative for laboratories where a real-time PCR machine is not available.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2016
DOI: 10.1038/AJG.2016.52
Abstract: We tested the hypothesis that the risk of colorectal cancer (CRC), advanced colorectal neoplasia (ACN), and colorectal adenoma among screening participants with different first-degree relatives (FDRs) affected by CRC was similar. A multi-center, prospective colonoscopy study involving 16 Asia-Pacific regions was performed from 2008 to 2015. Consecutive self-referred CRC screening participants aged 40-70 years were recruited, and each subject received one direct optical colonoscopy. The prevalence of CRC, ACN, and colorectal adenoma was compared among subjects with different FDRs affected using Pearson's χ Among 11,797 asymptomatic subjects, the prevalence of CRC was 0.6% (none: 0.6% siblings: 1.1% mother: 0.5% father: 1.2% ≥2 members: 3.1%, P<0.001), that of ACN was 6.5% (none: 6.1% siblings: 8.3% mother: 7.7% father: 8.7% ≥2 members: 9.3%, P<0.001), and that of colorectal adenoma was 29.3% (none: 28.6% siblings: 33.5% mother: 31.8% father: 31.1% ≥2 members: 38.1%, P<0.001). In multivariate regression analyses, subjects with at least one FDR affected were significantly more likely to have CRC (adjusted odds ratio (AOR)=2.02-7.89), ACN (AOR=1.55-2.06), and colorectal adenoma (AOR=1.31-1.92) than those without a family history. The risk of CRC (AOR=0.90, 95% confidence interval (CI) 0.34-2.35, P=0.830), ACN (AOR=1.07, 95% CI 0.75-1.52, P=0.714), and colorectal adenoma (AOR=0.96, 95% CI 0.78-1.19, P=0.718) in subjects with either parent affected was similar to that of subjects with their siblings affected. The risk of colorectal neoplasia was similar among subjects with different FDRs affected. These findings do not support the need to discriminate proband identity in screening participants with affected FDRs when their risks of colorectal neoplasia were estimated.
Publisher: Oxford University Press (OUP)
Date: 25-01-2019
Publisher: Oxford University Press (OUP)
Date: 2002
Abstract: Beta-catenin is critical for intercellular adhesion and also plays a role as a transcription activating protein in the Wnt signalling pathway. Increased protein levels and mutation of the beta-catenin gene have been demonstrated in various cancers however, the role of beta-catenin in gastric cancer remains largely unknown. Using gastric cancer tissues and normal adjacent gastric mucosa obtained from 20 patients with gastric cancer (eight diffuse-type, 12 intestinal-type) undergoing gastric resection or endoscopy, we assessed the expression of beta-catenin by immunohistochemistry and quantitative PCR analysis. Furthermore, the tumour suppressor gene APC, which down-regulates the beta-catenin levels was analysed for mutations. Overall mRNA levels of beta-catenin were significantly increased in the tumour s les compared with the matched normal gastric mucosa (P < 0.05). Increased beta-catenin mRNA levels were significantly more frequent in intestinal-type gastric cancers as compared to diffuse-type gastric cancers (P 6-fold increased beta-catenin mRNA levels as compared with normal mucosa. APC gene mutations were found in four cases. A beta-catenin gene mutation was identified only in one intestinal-type gastric cancer exhibiting a massive overexpression of beta-catenin mRNA in the tumour. In intestinal-type gastric cancers beta-catenin mRNA levels are greatly enhanced. APC and beta-catenin gene mutations are also present primarily in intestinal-type gastric cancers. These findings support the hypothesis that in intestinal-type gastric cancers the accumulation of beta-catenin protein may result from impaired degradation of the beta-catenin protein due to alterations of the beta-catenin and APC genes, as well as from enhanced beta-catenin transcription which is present in the great majority of intestinal-type gastric cancers.
Publisher: Wiley
Date: 22-04-2020
DOI: 10.1111/JGH.15053
Publisher: Elsevier BV
Date: 08-2018
DOI: 10.1053/J.GASTRO.2018.04.028
Abstract: 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. 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. 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 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.
Publisher: Wiley
Date: 05-2009
DOI: 10.1111/J.1440-1746.2008.05720.X
Abstract: There is currently no safe and effective treatment for liver fibrosis. We have previously shown that Stephania tetrandra (ST) and Salvia miltiorrhiza (SM) suppress cell proliferation and enhance apoptosis of hepatic stellate cell (HSC) in vitro. In this study, we aimed to investigate the anti-fibrotic effect of these two herbs in vivo. Liver fibrosis was induced by carbon tetrachloride (CCl(4)) injection in rats for 5 weeks. SM, ST or SM + ST was gavaged on day 1 of CCl(4) administration to study the preventive effects of herbs on hepatic fibrosis. In a separate study designed to assess possible fibrosis regression, rats were randomly allocated to be treated with SM, ST or SM + ST when fibrosis was established. Liver injury and collagen content were assessed. HSC activation and apoptosis were determined. As compared with the CCL(4)-only rats, serum ALT was significantly lower in CCl(4)-treated rats that received either SM (P < 0.01) or ST (P < 0.01). Administration of ST significantly prevented (P < 0.01) or reversed the hepatic fibrosis (P < 0.01) induced by CCL(4). Moreover, rats treated with ST had reduced protein expression of alpha-SMA both in prevention (P < 0.05) and in regression (P < 0.01) experiments. The double-color staining of alpha-SMA and TUNEL showed that ST increased HSC apoptosis. However, co-treatment of SM + ST did not increase the antifibrotic effect of ST. Stephania tetrandra safely and effectively prevents and reverses hepatic fibrosis through activating HSC apoptosis in rats.
Publisher: American Association for Cancer Research (AACR)
Date: 13-04-2017
DOI: 10.1158/0008-5472.CAN-16-1595
Abstract: There remains a paucity of functional biomarkers in gastric cancer. Here, we report the identification of the sodium channel subunit SCNN1B as a candidate biomarker in gastric cancer. SCNN1B mRNA expression was silenced commonly by promoter hypermethylation in gastric cancer cell lines and primary tumor tissues. Tissue microarray analysis revealed that high expression of SCNN1B was an independent prognostic factor for longer survival in gastric cancer patients, especially those with late-stage disease. Functional studies demonstrated that SCNN1B overexpression was sufficient to suppress multiple features of cancer cell pathophysiology in vitro and in vivo. Mechanistic investigations revealed that SCNN1B interacted with the endoplasmic reticulum chaperone, GRP78, and induced its degradation via polyubiquitination, triggering the unfolded protein response (UPR) via activation of PERK, ATF4, XBP1s, and C/EBP homologous protein and leading in turn to caspase-dependent apoptosis. Accordingly, SCNN1B sensitized gastric cancer cells to the UPR-inducing drug tunicamycin. GRP78 overexpression abolished the inhibitory effect of SCNN1B on cell growth and migration, whereas GRP78 silencing aggravated growth inhibition by SCNN1B. In summary, our results identify SCNN1B as a tumor-suppressive function that triggers UPR in gastric cancer cells, with implications for its potential clinical applications as a survival biomarker in gastric cancer patients. Cancer Res 77(8) 1968–82. ©2017 AACR.
Publisher: Elsevier BV
Date: 12-2014
DOI: 10.1016/J.CANLET.2014.08.025
Abstract: B cell CLL/lymphoma 6 member B (BCL6B) is a novel tumor suppressor silenced in human cancer. In this study, we investigated the functional role and underlying mechanisms of BCL6B in hepatocellular carcinoma (HCC). BCL6B was expressed in normal HCC tissues, but its expression was suppressed in 6 out of 9 HCC cell lines. Loss of BCL6B expression was associated with promoter hypermethylation. Ectopic expression of BCL6B in HepG2 and Huh7 cell lines inhibited colony formation (P <0.05), cell viability (P <0.01), and tumorigenicity in nude mice (P <0.05). BCL6B expression also induced apoptosis (P <0.05), an effect associated with activation of the caspase cascade and cleavage of PARP. Stable expression of BCL6B in MHCC97L cells suppressed cell migration (P <0.05) and invasion (P <0.05), and significantly reduced the incidence and severity of lung metastasis in an orthotopic HCC mouse model. The anti-metastatic effect of BCL6B was mediated by up-regulation of cell adhesion gene E-cadherin, OB-cadherin, HIV-1 Tat interactive protein 2, and transient receptor potential cation channel, subfamily M, member 1 and down-regulation of angiogenesis gene VEGFA. BCL6B functions as a tumor suppressor that inhibits HCC metastases in vitro and in vivo.
Publisher: BMJ
Date: 03-2004
Abstract: Severe acute respiratory syndrome (SARS) became a worldwide outbreak with a mortality of 9.2%. This new human emergent infectious disease is dominated by severe lower respiratory illness and is aetiologically linked to a new coronavirus (SARS-CoV). Pulmonary pathology and clinical correlates were investigated in seven patients who died of SARS in whom there was a strong epidemiological link. Investigations include a review of clinical features, morphological assessment, histochemical and immunohistochemical stainings, ultrastructural study, and virological investigations in postmortem tissue. Positive viral culture for coronavirus was detected in most premortem nasopharyngeal aspirate specimens (five of six) and postmortem lung tissues (two of seven). Viral particles, consistent with coronavirus, could be detected in lung pneumocytes in most of the patients. These features suggested that pneumocytes are probably the primary target of infection. The pathological features were dominated by diffuse alveolar damage, with the presence of multinucleated pneumocytes. Fibrogranulation tissue proliferation in small airways and airspaces (bronchiolitis obliterans organising pneumonia-like lesions) in subpleural locations was also seen in some patients. Viable SARS-CoV could be isolated from postmortem tissues. Postmortem examination allows tissue to be s led for virological investigations and ultrastructural examination, and when coupled with the appropriate lung morphological changes, is valuable to confirm the diagnosis of SARS-CoV, particularly in clinically unapparent or suspicious but unconfirmed cases.
Publisher: Springer Science and Business Media LLC
Date: 22-03-2018
Publisher: Elsevier BV
Date: 12-2014
DOI: 10.1053/J.GASTRO.2014.08.036
Abstract: The mechanisms by which Epstein-Barr virus (EBV) contributes to the development of gastric cancer are unclear. We investigated EBV-associated genomic and epigenomic variations in gastric cancer cells and tumors. We performed whole-genome, transcriptome, and epigenome sequence analyses of a gastric adenocarcinoma cell line (AGS cells), before and after EBV infection. We then looked for alterations in gastric tumor s les, with (n = 34) or without (n = 100) EBV infection, collected from patients at the Prince of Wales Hospital, Chinese University of Hong Kong (from 1998 through 2004), or the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China (from 1999 through 2006). Transcriptome analysis showed that infected cells expressed 9 EBV genes previously detected in EBV-associated gastric tumors and 71 EBV genes not previously reported in gastric tumors. Ten viral genes that had not been reported previously in gastric cancer but were expressed most highly in EBV-infected cells also were expressed in primary EBV-positive gastric tumors. Whole-genome sequence analysis identified 45 EBV-associated nonsynonymous mutations. These mutations, in genes such as AKT2, CCNA1, MAP3K4, and TGFBR1, were associated significantly with EBV-positive gastric tumors, compared with EBV-negative tumors. An activating mutation in AKT2 was associated with reduced survival times of patients with EBV-positive gastric cancer (P = .006) this mutation was found to dysregulate mitogen-activated protein kinase signaling. Integrated epigenome and transcriptome analyses identified 216 genes transcriptionally down-regulated by EBV-associated hypermethylation methylation of ACSS1, FAM3B, IHH, and TRABD increased significantly in EBV-positive tumors. Overexpression of Indian hedgehog (IHH) and TraB domain containing (TRABD) increased proliferation and colony formation of gastric cancer cells, whereas knockdown of these genes reduced these activities. We found 5 signaling pathways (axon guidance, focal adhesion formation, interactions among cytokines and receptors, mitogen-activated protein kinase signaling, and actin cytoskeleton regulation) to be affected commonly by EBV-associated genomic and epigenomic alterations. By using genomic, transcriptome, and epigenomic comparisons of EBV infected vs noninfected gastric cancer cells and tumor s les, we identified alterations in genes, gene expression, and methylation that affect different signaling networks. These might be involved in EBV-associated gastric carcinogenesis.
Publisher: Elsevier BV
Date: 07-2004
Publisher: Wiley
Date: 2007
DOI: 10.1002/JMV.20873
Publisher: BMJ
Date: 24-04-2018
DOI: 10.1136/GUTJNL-2018-316276
Abstract: 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.
Publisher: Massachusetts Medical Society
Date: 15-05-2003
DOI: 10.1056/NEJMOA030685
Publisher: Elsevier BV
Date: 2013
DOI: 10.1053/J.GASTRO.2012.10.002
Abstract: 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. We used integrative genome-wide scans to identify concomitant hypermethylated genes in mice infected with H pylori and human gastric cancer s les. 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. 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 s les, compared with control tissues. 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.
Publisher: Elsevier BV
Date: 06-2013
DOI: 10.1016/J.CRITREVONC.2012.11.009
Abstract: Multiple intracellular signaling pathways, such as Wnt/β-catenin signaling, epidermal growth factor receptor/Ras signaling, and p53 signaling are frequently dysregulated in colorectal cancer. Recent evidence also points to the involvement of signaling pathways in the developmental process, including Notch signaling, Hedgehog signaling, and Hippo signaling. Dysregulation of these signaling pathways contribute to the acquisition of malignant phenotypes, including unchecked cell cycle progression, evasion of apoptosis, induction of genetic instability, and enhanced invasiveness and metastasis. Understanding their relative importance and crosstalk will provide a rational basis for anticancer drug development.
Publisher: BMJ
Date: 25-06-2010
Abstract: Patients with non-alcoholic steatohepatitis (NASH) have increased mortality and liver-related complications. In contrast, simple steatosis is considered benign and non-progressive. To investigate disease progression in patients with different degrees of non-alcoholic fatty liver disease (NAFLD) activity. Prospective longitudinal hospital-based cohort study. Fifty-two patients (age 44+/-9 years) with biopsy-proven NAFLD had liver biopsies repeated at month 36. Among 13 patients with simple steatosis at baseline, 2 (15%) had a normal liver at month 36, 3 (23%) continued to have simple steatosis, 5 (39%) developed borderline NASH and 3 (23%) developed NASH. Among 22 patients with borderline NASH at baseline, 4 (18%) had simple steatosis and 13 (59%) had borderline NASH at month 36, while 5 (23%) developed NASH. Among 17 patients with NASH at baseline, 10 (59%) continued to have NASH and 6 (35%) had borderline NASH at month 36. Only 1 (6%) patient regressed to simple steatosis. Overall, 14 (27%) patients had fibrosis progression, 25 (48%) had static disease, and 13 (25%) had fibrosis regression. Reduction in body mass index and waist circumference was independently associated with non-progressive disease activity and fibrosis. The baseline serum levels and month 36 changes in adiponectin, tumour necrosis factor alpha, interleukin 6 and leptin were not associated with disease progression. Serum cytokeratin-18 fragment level reflected disease activity and its change correlated with the change in NAFLD activity score (R=0.51, p<0.001). Patients with simple steatosis may still develop NASH and fibrosis progression. Weight reduction is associated with non-progressive disease. All patients with NAFLD should undergo periodic assessment and lifestyle modification.
Publisher: American Chemical Society (ACS)
Date: 03-08-2004
DOI: 10.1021/PR049916L
Abstract: A well-described animal model was used to understand the molecular mechanisms of carcinogenesis and metastasis of gastric cancer at the protein level. Gastric cancer was induced in 12 Wistar rats by oral administration of N-methyl-N'-Nitro-N-Nitrosoguanidine (MNNG). The protein expression patterns of normal gastric tissue, gastric cancer, and corresponding metastases were analyzed by proteomics in matched tissues of 3 rats. Proteins in the region of molecular masses of 15-75 kDa and an isoelectric point of 3-7 were separated by two-dimensional electrophoresis (2-DE) and identified by peptide fingerprinting with matrix-assisted laser desorption/ionization-time-of-flight-mass spectrometry (MALDI-TOF-MS). Twenty-seven spots corresponding to 25 different proteins served as landmarks for comparison between tissues. The identified proteins included cytoskeletal proteins, stress associated proteins, proteins involved in signal transduction, cell proliferation and differentiation, and metabolism. Eleven proteins were up-regulated and 2 proteins were down-regulated in tumor tissue when compared with normal tissue. Twelve proteins were up-regulated and 8 proteins were down-regulated in the metastases when compared with the primary tumor. The overexpression of HSP27 in gastric cancer was confirmed by immunohistochemical analysis of human gastric cancer specimens. Combining well-defined animal models with proteome analysis will improve our understanding of the fundamental changes that contribute to the process of carcinogenesis and the formation of metastases in gastric cancer.
Publisher: Wiley
Date: 04-2021
DOI: 10.1111/JGH.15501
Abstract: Gut microbiota has been shown to associate with the development of gastrointestinal diseases. In the last decade, development in whole metagenome sequencing and 16S rRNA sequencing technology has dramatically accelerated the gut microbiome's research and revealed its association with gastrointestinal disorders. Because of high dimensionality and complexity's intrinsic data characteristics, traditional bioinformatical methods could only explain the most significant changes with limited prediction accuracy. In contrast, machine learning is the application of artificial intelligence that provides the computational systems to automatically learn and improve from experience (training cohort) without being explicitly programmed. It is thus capable of unwiring high dimensionality and complicated correlational hitches. With modern computation power, machine learning is widely utilized to analyze microorganisms related to disease onset and other clinical features. It could help explore and identify novel biomarkers or improve the accuracy rate of disease diagnostic. This review summarized the most recent research that utilized machine learning to reveal the role of gut microbiota in intestinal disorders.
Publisher: Mary Ann Liebert Inc
Date: 09-2008
Publisher: Wiley
Date: 04-12-2012
DOI: 10.1002/CNCR.27865
Abstract: Previous reports from these authors found that activation of peroxisome proliferator-activated receptor gamma (PPARγ) suppressed hepatocellular carcinoma (HCC). This study sought to identify the molecular target of PPARγ and characterize its antitumor effect in HCC. Optimal PPARγ binding activity was obtained using the PPARγ agonist rosiglitazone (100 μM) as determined by enzyme-linked immunosorbent assay. Under PPARγ activation, 114 PPARγ downstream targets associated with cancer development were identified by oligonucleotide microarray and Gene Ontology analysis. Among them, Cbp 300-interacting transactivator, with Glu/Asp-rich carboxy-terminal domain, 2 (CITED2) was the most prominent PPARγ-bound target, as determined by chromatin immunoprecipitation-polymerase chain reaction. CITED2 messenger RNA and protein was significantly down-regulated in primary HCCs compared with their adjacent nontumor tissues. PPARγ induced expression of CITED2 in HCC cell lines after adenovirus-PPARγ transduction. The biological function of CITED2 was evaluated by loss- and gain-of-function assays. CITED2 knockdown in the hepatocyte cell line LO2 and HCC cell line Hep3B significantly increased cell viability and clonogenicity, and promoted G1 -S phase transition in both cell lines. In contrast, ectopic expression of CITED2 in HepG2 and BEL7404 HCC cell lines significantly suppressed cell growth. The tumor suppressive effect of CITED2 was associated with up-regulation of cyclin-dependent kinase inhibitors p15(INK4B) , p21(Wat1/Cip1) , p27(Kip1) , antiproliferative regulator interferon alpha 1, proapoptotic mediators including tumor necrosis factor receptor superfamily member 1A (TNFRSF1A), TNFRSF25, caspase-8, granzyme A, and the tumor suppressor gene maspin. CITED2 was also associated with the down-regulation of cell cycle regulator cyclin D1, oncogene telomerase reverse transcriptase, and proinvasion/metastasis gene matrix metallopeptidase 2. CITED2 is a direct effector of PPARγ for tumor suppression. Cancer 2013. © 2012 American Cancer Society.
Publisher: Spandidos Publications
Date: 23-07-2009
DOI: 10.3892/OR_00000456
Publisher: Elsevier BV
Date: 08-2018
DOI: 10.1053/J.GASTRO.2018.04.018
Abstract: Patients with colorectal cancer (CRC) have a different gut microbiome signature than in iduals 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. We performed shotgun metagenomic analyses of viromes of fecal s les from 74 patients with CRC (cases) and 92 in iduals 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 s les 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. The ersity 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 In a metagenomic analysis of fecal s les from patients and controls, we identified virome signatures associated with CRC. These data might be used to develop tools to identify in iduals with CRC or predict outcomes.
Publisher: BMJ
Date: 06-05-2015
Publisher: Elsevier BV
Date: 08-2007
Publisher: Elsevier BV
Date: 02-2022
DOI: 10.1016/J.CGH.2020.10.014
Abstract: Second forward view (SFV) examination of the right colon (RC) in colonoscopy was suggested to improve the adenoma detection rate (ADR), but multicenter data to inform its routine use remain limited. We performed an international multicenter randomized trial comparing SFV vs a standard single forward view examination of the RC on adenoma detection. Asymptomatic in iduals undergoing screening or surveillance colonoscopies from 6 Asia Pacific regions were invited for study. A forward view examination of the RC was first performed in all patients, followed by randomization at the hepatic flexure to either SFV examination of the RC and standard withdrawal examination from the hepatic flexure to rectum, or a standard withdrawal colonoscopy (SWC) examination from the hepatic flexure to rectum. The primary outcome was RC ADR. Between 2016 and 2019, there were 1011 patients randomized (SFV group, 502 patients SWC group, 509 patients). Forty-five endoscopists performed the colonoscopies. The RC ADR was significantly higher in the SFV group than in the SWC group (27.1% vs 21.6% P = .042). The whole-colon ADR was high in both groups (49.0% vs 45.0% P =.201). The SFV examination identified 58 additional adenomas in 49 patients (9.8%), leading to a change in surveillance recommendations in 15 patients (3.0%). The median overall withdrawal time was 1.5 minutes longer in the SFV group (12.0 vs 10.5 min P < .001). Older age, male sex, ever smoking, and longer RC withdrawal time were independent predictors of right-sided adenoma detection. In this multicenter trial, SFV examination significantly increased the RC ADR in screening and surveillance colonoscopies. Routine RC SFV examination should be considered. ClinicalTrials.gov ID: NCT03121495.
Publisher: BMJ
Date: 23-09-2205
DOI: 10.1136/GUTJNL-2011-300411
Abstract: Using genome-wide promoter methylation assay, B cell CLL/lymphoma 6 member B (BCL6B) was found to be preferentially methylated in cancer. A study was undertaken to examine the epigenetic regulation, biological function and clinical significance of BCL6B in gastric cancer (GC). BCL6B promoter methylation was evaluated by combined bisulfite restriction analysis and sequencing. The biological functions of BCL6B were determined by cell viability, colony formation, flow cytometry and in vivo tumorigenicity assays. The molecular targets of BCL6B were identified by cDNA expression array. BCL6B was silenced or downregulated in all nine GC cell lines and readily expressed in normal gastric tissues. Loss of BCL6B expression was regulated by promoter hypermethylation. Re-expression of BCL6B in GC cell lines inhibited colony formation, suppressed cell viability, induced apoptosis and restrained the tumorigenecity in nude mice. These effects were associated with upregulation of the pro-apoptosis genes tumour necrosis factor receptor superfamily member 1A, caspase-8, caspase-9, caspase-3 and caspase-7 and nuclear enzyme poly (ADP-ribose) polymerase, downregulation of the pro-proliferation genes S100 calcium binding protein A4 and vascular endothelial growth factor A, and induction of the tumour suppressor genes ataxia telangiectasia mutated homologue and p53. BCL6B hypermethylation was detected in 49.0% (102/208) and 66.3% (67/101) of two independent cohorts of patients with GC, respectively. BCL6B methylation was an independent factor for the survival of patients with GC (p=0.001 for cohort I, p=0.02 for cohort II). BCL6B plays a pivotal role as a potential tumour suppressor in GC. Detection of methylated BCL6B may serve as an independent biomarker for the prognosis of GC.
Publisher: Informa UK Limited
Date: 15-08-2011
DOI: 10.3109/07357907.2011.605411
Abstract: We investigated the association of Interleukin (IL)-6-6331 polymorphisms with susceptibility to gastric cancer in 375 patients with gastric cancer and 386 age- and gender-matched healthy controls. After adjustment for the potential confounding effects of gender and age, IL-6-6331TC genotype was associated with a decreased risk of gastric cancer compared with the CC genotype. Further stratification analyses indicated that the protective effect of TC genotype was also observed in poorly differentiated gastric cancer, noncardia gastric cancer, and intestinal-type gastric cancer, respectively. These results suggest that the IL-6-6331 polymorphism is involved in susceptibility to developing gastric cancer.
Publisher: BMJ
Date: 03-2202
DOI: 10.1136/GUTJNL-2021-325851
Abstract: Aberrant lipid metabolism is a hallmark of colorectal cancer (CRC). Squalene epoxidase (SQLE), a rate-limiting enzyme in cholesterol biosynthesis, is upregulated in CRC. Here, we aim to determine oncogenic function of SQLE and its interplay with gut microbiota in promoting colorectal tumourigenesis. Paired adjacent normal tissues and CRC from two cohorts were analysed (n=202). Colon-specific Sqle transgenic (Sqle tg) mice were generated by crossing Rosa26-lsl-Sqle mice to Cdx2-Cre mice. Stools were collected for metagenomic and metabolomic analyses. SQLE messenger RNA and protein expression was upregulated in CRC (p .01) and predict poor survival of patients with CRC. SQLE promoted CRC cell proliferation by inducing cell cycle progression and suppressing apoptosis. In azoxymethane-induced CRC model, Sqle tg mice showed increased tumourigenesis compared with wild-type mice (p .01). Integrative metagenomic and metabolomic analyses unveiled gut dysbiosis in Sqle tg mice with enriched pathogenic bacteria, which was correlated to increased secondary bile acids. Consistent with detrimental effect of secondary bile acids, gut barrier function was impaired in Sqle tg mice, with reduced tight junction proteins Jam-c and occludin. Transplantation of Sqle tg mice stool to germ-free mice impaired gut barrier function and stimulated cell proliferation compared with control mice stool. Finally, we demonstrated that terbinafine, a SQLE inhibitor, could be repurposed for CRC by synergising with oxaliplatin and 5-fluorouracil to inhibit CRC growth. This study demonstrates that SQLE mediates oncogenesis via cell intrinsic effects and modulation of gut microbiota-metabolite axis. SQLE represents a therapeutic target and prognostic marker in CRC.
Publisher: Elsevier BV
Date: 06-2012
DOI: 10.1038/MT.2012.36
Publisher: BMJ
Date: 24-10-2016
Publisher: Wiley
Date: 09-2007
Abstract: Enhancer of zeste homolog 2 (EZH2) is suggested to be a potential therapeutic target and a diagnostic marker for cancer. Our previous study also showed the critical role of EZH2 in hepatocellular carcinoma (HCC) tumorigenesis. The present study is aimed at revealing the comprehensive downstream pathways of EZH2 by functional proteomic profiling. Lentivirus mediated RNA interference (RNAi) was employed to knockdown EZH2 in HCC cells. The 2-DE was employed to compare the expression profile difference between parental and EZH2-knockdown HCC cells. In total, 28 spots were differentially expressed during EZH2 inhibition. Among all, 18 proteins were identified by PMF with MALDI-TOF MS. Western blotting further validated upregulation of 60S acidic ribosomal protein P0 (L10E), and downregulation of two proteins with EZH2 inhibition: stathmin1 and probable protein disulfide isomerase (PDI) ER-60 precursor (ERp57). Moreover, L10E was downregulated with overexpression of EZH2 in hepatocytes, and L10E reversed the effect of EZH2 on cell proliferation, suggesting it a downstream target of EZH2. The comprehensive and comparative analyses of proteins associated with EZH2 could further our understanding on the downstream signal cascade of EZH2 leading to tumorigenesis.
Publisher: Elsevier BV
Date: 12-2007
Publisher: Elsevier BV
Date: 11-2020
Publisher: Elsevier BV
Date: 04-2014
Publisher: Elsevier BV
Date: 12-2017
DOI: 10.1053/J.GASTRO.2017.08.022
Abstract: Altered gut microbiota is implicated in development of colorectal cancer (CRC). Some intestinal bacteria have been reported to potentiate intestinal carcinogenesis by producing genotoxins, altering the immune response and intestinal microenvironment, and activating oncogenic signaling pathways. We investigated whether stool from patients with CRC could directly induce colorectal carcinogenesis in mice. We obtained stored stool s les from participants in a metagenome study performed in Hong Kong. Conventional (male C57BL/6) mice were given azoxymethane to induce colon neoplasia after receiving a course of antibiotics in drinking water. Mice were gavaged twice weekly with stool from 5 patients with CRC or 5 healthy in iduals (controls) for 5 weeks. Germ-free C57BL/6 mice were gavaged once with stool from 5 patients with CRC or 5 controls. We collected intestinal tissues from mice and performed histology, immunohistochemistry, expression microarray, quantitative polymerase chain reaction, immunoblot, and flow cytometry analyses. We performed 16S ribosomal RNA gene sequencing analysis of feces from mice. Significantly higher proportions of conventional mice fed with stool from in iduals with CRC than control stool developed high-grade dysplasia (P < .05) and macroscopic polyps (P < .01). We observed a higher proportion of proliferating (Ki-67-positive) cells in colons of germ-free mice fed with stool from patients with CRC vs those fed with stool from controls (P < .05). Feces from germ-free and conventional mice fed with stool from patients with CRC vs controls contained different microbial compositions, with lower richness in mice fed with stool from patients with CRC. Intestines collected from conventional and germ-free mice fed with stool from patients with CRC had increased expression of cytokines that modulate inflammation, including C-X-C motif chemokine receptor 1, C-X-C motif chemokine receptor 2, interleukin 17A (IL17A), IL22, and IL23A. Intestines from conventional and germ-free mice fed with stool from patients with CRC contained higher proportions of T-helper 1 (Th1) cells (2.25% vs 0.44%) and Th17 cells (2.08% vs 0.31%) (P < .05 for each) than mice fed with stool from controls. Real-time polymerase chain reaction arrays revealed up-regulation of genes involved in cell proliferation, stemness, apoptosis, angiogenesis, invasiveness, and metastasis in mice fed with stool from patients with CRC. We fed stool s les from patients with CRC and heathy in iduals to germ-free mice and conventional mice with azoxymethane. We found stool from patients with CRC to increase the numbers of polyps, levels of intestinal dysplasia and proliferation, markers of inflammation, and proportions of Th1 and Th17 cells in colon, compared with stool from in iduals without CRC. This study provides evidence that the fecal microbiota from patients with CRC can promote tumorigenesis in germ-free mice and mice given a carcinogen.
Publisher: Informa UK Limited
Date: 21-06-2020
Publisher: BMJ
Date: 05-2004
Abstract: The outcome is reported of a prospective uncontrolled study based on a stepwise treatment protocol during an outbreak of severe acute respiratory syndrome (SARS) in Hong Kong. One hundred and thirty eight patients were treated with broad spectrum antibiotics, a combination of ribavirin and low dose corticosteroid, and then intravenous high dose methylprednisolone according to responses. Sustained response to treatment was defined as (1) defervescence for > or =4 consecutive days, (2) resolution of lung consolidation by >25%, and (3) oxygen independence by the fourth day without fever. Patients with defervescence who achieved either criterion 2 or 3 were classified as partial responders. Patients who fell short of criteria 2 and 3 were non-responders. Laboratory confirmation of SARS coronavirus infection was established in 132 (95.7%). None responded to antibiotics but 25 (18.1%) responded to ribavirin + low dose corticosteroid. Methylprednisolone was used in 107 patients, of whom 95 (88.8%) responded favourably. Evidence of haemolytic anaemia was observed in 49 (36%). A high level of C-reactive protein at presentation was the only independent predictor for use of methylprednisolone (odds ratio 2.18 per 10 mg/dl increase, 95% confidence interval 1.12 to 4.25, p = 0.02). Thirty seven patients (26.8%) required admission to the intensive care unit and 21 (15.2%) required invasive mechanical ventilation. There were 15 deaths (mortality rate 10.9%), most with significant co-morbidities, whereas 122 (88.4%) had been discharged home 4 months after the outbreak onset. The use of high dose pulse methylprednisolone during the clinical course of a SARS outbreak was associated with clinical improvement, but randomised controlled trials are needed to ascertain its efficacy in this condition.
Publisher: Springer Science and Business Media LLC
Date: 26-10-2018
DOI: 10.1038/S41467-018-06931-6
Abstract: The underlining mechanisms of dietary cholesterol and nonalcoholic steatohepatitis (NASH) in contributing to hepatocellular carcinoma (HCC) remain undefined. Here we demonstrated that high-fat-non-cholesterol-fed mice developed simple steatosis, whilst high-fat-high-cholesterol-fed mice developed NASH. Moreover, dietary cholesterol induced larger and more numerous NASH-HCCs than non-cholesterol-induced steatosis-HCCs in diethylnitrosamine-treated mice. NASH-HCCs displayed significantly more aberrant gene expression-enriched signaling pathways and more non-synonymous somatic mutations than steatosis-HCCs (335 ± 84/s le vs 43 ± 13/s le). Integrated genetic and expressional alterations in NASH-HCCs affected distinct genes pertinent to five pathways: calcium, insulin, cell adhesion, axon guidance and metabolism. Some of the novel aberrant gene expression, mutations and core oncogenic pathways identified in cholesterol-associated NASH-HCCs in mice were confirmed in human NASH-HCCs, which included metabolism-related genes ( ALDH18A1, CAD , CHKA , POLD4 , PSPH and SQLE ) and recurrently mutated genes ( RYR1 , MTOR , SDK1 , CACNA1H and RYR2) . These findings add insights into the link of cholesterol to NASH and NASH-HCC and provide potential therapeutic targets.
Publisher: Elsevier BV
Date: 10-2010
DOI: 10.1016/J.CANEP.2010.05.013
Abstract: Colorectal cancer (CRC) screening improves survival and its success depends on the participation of the at-risk population. Few studies have adequately assessed screening knowledge, perception and participation according to birthplace. This study assesses the knowledge and perception of CRC in an ethnically erse population, and evaluates the association with screening participation and intention. Identification of specific predictors of screening may aid the development of interventions to improve overall CRC screening. An interview-based survey, conducted on subjects aged 30-70 years, assessed knowledge and perception towards CRC and screening tests. Primary endpoints were screening participation and intent. Statistical methods used were Chi-square, Mann-Whitney U and logistic regression. A total of 543 subjects (43% males, 53% Australian-born (AB), 63% aged 50 years and above) were recruited. Compared with AB, non-Australian-born (NAB) respondents had poorer knowledge, and NAB background predicted for poorer knowledge independent of sex, education, media and familiarity with CRC patient. Compared with AB respondents aged 50 years and above, NAB respondents had lower screening participation (17.4% vs. 31.8% P=0.01), lesser intention (75.8% vs. 90.5% P<0.001), and had received fewer doctors' screening recommendations (16.5% vs. 27.1% P=0.04). In multivariate analysis, doctors' recommendation, media and improved perception independently predicted screening participation knowledge and media exposure predicted intent. The knowledge of CRC and screening is significantly poorer in the immigrant population. Knowledge predicts for greater screening intent. Therefore, implementing language- and culture-specific educational programs involving medical practitioners and media are necessary to improve CRC screening participation rates.
Publisher: Springer Science and Business Media LLC
Date: 20-07-2015
DOI: 10.1038/NG.3359
Publisher: Wiley
Date: 28-08-2014
DOI: 10.1002/PATH.4391
Publisher: BMJ
Date: 19-09-2011
Abstract: The detection of molecular markers in stool s les is a potential strategy for colorectal cancer (CRC) screening. This study evaluated the feasibility of detecting miR-21 and miR-92a in stool s les of patients with CRC or polyps. The reproducibility of detection and stability of stool-based microRNA were evaluated. Stool s les were collected from 88 patients with CRC, 57 patients with colorectal polyps and 101 healthy controls. MiRNA levels in CRC tissues and stool s les were detected by real-time quantitative reverse transcription PCR. Stool miR-21 and miR-92a levels were compared before and after the removal of tumour or advanced adenoma. The study demonstrated that stool-based miRNA were stable with highly reproducible detection. The expression of miR-21 and miR-92a was significantly higher in CRC tissues compared with their adjacent normal tissues (p<0.0001). Patients with CRC had a significantly higher stool miR-21 level (p<0.01) and miR-92a level (p<0.0001) compared with normal controls. Stool miR-92a, but not miR-21, was significantly higher in patients with polyps than in controls (p<0.0001). At a cut-off value of 435 copies/ng of stool RNA, miR-92a had a sensitivity of 71.6% and 56.1% for CRC and polyp, respectively, and a specificity of 73.3%. In addition, the stool miR-92a level demonstrated a higher sensitivity for distal CRC than proximal CRC (p<0.05), and a higher sensitivity for advanced adenoma than minor polyps (p<0.05). Removal of tumour resulted in reduced stool miR-21 and miR-92a levels (p<0.01), and the removal of advanced adenoma resulted in a reduction of the stool miR-92a level (p<0.05). Stool miRNA are useful for screening CRC and polyps.
Publisher: Springer Science and Business Media LLC
Date: 30-03-2015
DOI: 10.1038/ONC.2015.72
Publisher: Public Library of Science (PLoS)
Date: 20-08-2008
Publisher: Springer Science and Business Media LLC
Date: 10-09-2018
DOI: 10.1038/S41467-018-06103-6
Abstract: Fecal microbiota transplantation (FMT) is effective in treating recurrent Clostridium difficile infection (CDI). Bacterial colonization in recipients after FMT has been studied, but little is known about the role of the gut fungal community, or mycobiota. Here, we show evidence of gut fungal dysbiosis in CDI, and that donor-derived fungal colonization in recipients is associated with FMT response. CDI is accompanied by over-representation of Candida albicans and decreased fungal ersity, richness, and evenness. Cure after FMT is associated with increased colonization of donor-derived fungal taxa in recipients. Recipients of successful FMT (“responders”) display, after FMT, a high relative abundance of Saccharomyces and Aspergillus , whereas “nonresponders” and in iduals treated with antibiotics display a dominant presence of Candida . High abundance of C. albicans in donor stool also correlates with reduced FMT efficacy. Furthermore, C. albicans reduces FMT efficacy in a mouse model of CDI, while antifungal treatment reestablishes its efficacy, supporting a potential causal relationship between gut fungal dysbiosis and FMT outcome.
Publisher: Springer Science and Business Media LLC
Date: 14-03-2018
Publisher: Informa UK Limited
Date: 04-2012
DOI: 10.4161/AUTO.19496
Publisher: American Association for the Advancement of Science (AAAS)
Date: 18-04-2018
DOI: 10.1126/SCITRANSLMED.AAP9840
Abstract: Squalene epoxidase is a therapeutic target in hepatocellular carcinoma arising from nonalcoholic fatty liver disease.
Publisher: Spandidos Publications
Date: 21-01-2011
DOI: 10.3892/OL.2011.249
Publisher: Elsevier BV
Date: 08-2008
DOI: 10.1016/J.DLD.2008.02.030
Abstract: Atrophic gastritis (resulting mainly from long-standing Helicobacter pylori infection) is a major risk factor for (intestinal-type) gastric cancer development and the extent/topography of the atrophic changes significantly correlates with the degree of cancer risk. The current format for histology reporting in cases of gastritis fails to establish an immediate link between gastritis phenotype and risk of malignancy. The histology report consequently does not give clinical practitioners and gastroenterologists an explicit message of use in orienting an in idual patient's clinical management. Building on current knowledge of the biology of gastritis and incorporating experience gained worldwide by applying the Sydney System for more than 15 years, an international group of pathologists (Operative Link for Gastritis Assessment) has proposed a system for reporting gastritis in terms of stage (the OLGA staging system). Gastritis staging arranges the histological phenotypes of gastritis along a scale of progressively increasing gastric cancer risk, from the lowest (stage 0) to the highest (stage IV). This tutorial aims to provide unequivocal information on how to consistently apply the OLGA staging system in routine diagnostic histology practice.
Publisher: Springer Science and Business Media LLC
Date: 14-07-2014
DOI: 10.1038/ONC.2014.201
Publisher: Wiley
Date: 25-07-2012
DOI: 10.1002/CNCR.27724
Abstract: Aberrant methylation of tumor-related genes has been reported in Epstein-Barr virus (EBV)-associated gastric cancers. This study sought to profile EBV-driven hypermethylation in EBV-infected cells. The EBV-positive AGS gastric cancer cell line (AGS-EBV) and EBV-negative AGS cells were used in this study. DNA methyltransferase-3b (DNMT3b) activity was assessed by EpiQuick activity assay, and genome-wide DNA methylation profiles were assessed by methyl-DNA immunoprecipitation microarray assay. EBV infection was confirmed in AGS-EBV cells by EBV-encoded RNA in situ hybridization. Expression and activity of DNA methyltransferase-3b (DNMT3b) was significantly increased in AGS-EBV compared to AGS. Ectopic expression of LMP2A (latent membrane protein 2A) in AGS increased activity of DNMT3b. A total of 1065 genes were differentially methylated by EBV infection (fold-changes ≥ 2, P < .05) in AGS-EBV compared to AGS cells. The majority of the differentially methylated genes (83.2%, 886 of 1065 genes) had cytosine-guanine dinucleotide (CpG) hypermethylation in AGS-EBV (fold-changes 2.43∼65.2) versus that found in AGS cells. Gene ontology analysis revealed that hypermethylated genes were enriched in the important cancer pathways (≥ 10 genes each, P ≤ .05) including mitogen-activated protein kinase signaling, cell adhesion molecules, wnt signaling pathway, and so forth. Six novel hypermethylated candidates (IL15RA, REC8, SSTR1, EPHB6, MDGA2, and SCARF2) were further validated. Higher levels of DNA methylation were confirmed for all these genes in AGS-EBV cells by bisulfite genomic sequencing. Furthermore, these candidates were silenced or down-regulated in AGS-EBV cells, but can be restored by demethylation treatment. EBV infection in AGS cells induced aberrant CpG hypermethylation of 886 genes involving in important cancer-related pathways. Induction of promoter methylation by EBV is regulated by up-regulation of DNMT3b through LMP2A.
Publisher: Springer Science and Business Media LLC
Date: 02-05-2016
DOI: 10.1038/ONC.2016.162
Publisher: Elsevier BV
Date: 10-2002
Publisher: Elsevier BV
Date: 06-2011
DOI: 10.1016/J.YEXCR.2011.03.005
Abstract: Mammalian target of rapamycin complex 1 (mTORC1) is dysregulated in gastric cancer. The biologic function of mTORC1 in gastric carcinogenesis is unclear. Here, we demonstrate that disruption of mTORC1 function by RNA interference-mediated downregulation of raptor substantially inhibited gastric cancer cell proliferation through induction of G(0)/G(1)-phase cell cycle arrest. The anti-proliferative effect was accompanied by concomitant downregulation of activator protein-1 and upregulation of Smad2/3 transcriptional activities. In addition, the expression of cyclin D(3) and p21(Waf1), which stabilizes cyclin D/cdk4 complex for G(1)-S transition, was reduced by raptor knockdown. In conclusion, disruption of mTORC1 inhibits gastric cancer cell proliferation through multiple pathways. This discovery may have an implication in the application of mTORC1-directed therapy for the treatment of gastric cancer.
Publisher: Springer Science and Business Media LLC
Date: 18-09-2014
DOI: 10.1038/BJC.2014.484
Publisher: Spandidos Publications
Date: 1994
DOI: 10.3892/OR_00000114
Publisher: Impact Journals, LLC
Date: 22-10-2014
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2004
DOI: 10.1111/J.1572-0241.2004.40486.X
Abstract: Inflammatory bowel disease manifests throughout all ethnic groups. Antisaccharomyces cerevisiae (ASCA) and antineutrophil cytoplasmic antibodies (pANCA) can aid in the differentiation between Crohn's disease (CD) and ulcerative colitis (UC), but their sensitivity may vary between races. This study compared the sensitivity, specificity, and positive and negative predictive values (PPV, NPV) of pANCA and ASCA between Chinese and Caucasian IBD populations and identified disease subtype associations. Three hundred patients were prospectively recruited from Caucasian and Chinese populations (CD, n = 50, UC, n = 50, controls, n = 50 each). pANCA detection was greater in Caucasian than Chinese UC patients (p= 0.046). ASCA IgG detection was similar, but IgA was lower in Chinese CD patients (p < 0.001). Differentiation between UC and CD (+ve pANCA/-ve ASCA) demonstrated a PPV of 92% in isolated colonic disease. Logistic regression in CD identified positive pANCA had a lower association with ileal (OR = 6.8, p= 0.0067) and complicated disease (OR = 5.5, p= 0.015). Caucasian CD patients with positive ASCA IgA/IgG had a greater association with ileal (OR = 6.7, p= 0.022) or complicated disease (OR = 9.4, p= 0.0073) and in Chinese CD patients positive ASCA IgA/IgG was associated with isolated ileal disease (OR = 16.8, p= 0.032). Linear regression demonstrated that higher ASCA titers predicted complicated CD and isolated ileal disease. This study identified that pANCA is more sensitive in Caucasian than Chinese UC and that ASCA IgA has a low yield in Chinese CD. pANCA and ASCA are useful for differentiating between UC and CD in both populations, and ASCA IgG and IgA titers have potential use in determining the risk of developing complicated CD.
Publisher: Wiley
Date: 2010
DOI: 10.1002/JCP.22026
Abstract: The human cathelicidin LL-37, a pleiotropic host defense peptide, is down-regulated in gastric adenocarcinomas. We therefore investigated whether this peptide suppresses gastric cancer growth. LL-37 lowered gastric cancer cell proliferation and delayed G(1)-S transition in vitro and inhibits the growth of gastric cancer xenograft in vivo. In this connection, LL-37 increased the tumor-suppressing bone morphogenetic protein (BMP) signaling, manifested as an increase in BMP4 expression and the subsequent Smad1/5 phosphorylation and the induction of p21(Waf1/Cip1). The anti-mitogenic effect, Smad1/5 phosphorylation, and p21(Waf1/Cip1) up-regulation induced by LL-37 were reversed by the knockdown of BMP receptor II. The activation of BMP signaling was paralleled by the inhibition of chymotrypsin-like and caspase-like activity of proteasome. In this regard, proteasome inhibitor MG-132 mimicked the effect of LL-37 by up-regulating BMP4 expression and Smad1/5 phosphorylation. Further analysis of clinical s les revealed that LL-37 and p21(Waf1/Cip1) mRNA expressions were both down-regulated in gastric cancer tissues and their expressions were positively correlated. Collectively, we describe for the first time that LL-37 inhibits gastric cancer cell proliferation through activation of BMP signaling via a proteasome-dependent mechanism. This unique biological activity may open up novel therapeutic avenue for the treatment of gastric cancer.
Publisher: Elsevier BV
Date: 02-2010
DOI: 10.1053/J.GASTRO.2009.09.058
Abstract: Heme oxygenase-1 (HO-1), an antioxidant defense enzyme, has been shown to protect against oxidant-induced tissue injury. We investigated the role of HO-1 in nutritional steatohepatitis in vitro and in vivo. AML-12 hepatocytes were cultured in methionine- and choline-deficient (MCD) medium. Cells were transfected with an adenovirus vector that expressed HO-1 (Ad-HO-1) or incubated with the HO-1 inducer hemin or the HO-1 inhibitor stannic mesoporphyrin for 24 hours. C57BL6 mice and db/db mice were fed MCD or control diets, with or without hemin, for up to 4 weeks. AML-12 cells exposed to MCD medium developed significant steatosis, increased release of alanine aminotransferase, and showed signs of oxidative injury. Incubation with hemin induced HO-1 protein, suppressed steatosis, and reduced levels of alanine aminotransferase and lipid peroxidation. A comparable effect was observed in cells transfected with Ad-HO-1, whereas incubation of these cells with stannic mesoporphyrin completely abolished the Ad-HO-1- or hemin-mediated protection of hepatocytes. Mice injected with hemin significantly attenuated MCD-induced steatohepatitis and increased HO-1 protein and activity. This effect was associated with up-regulation of antioxidant chaperones and enzymes, down-regulation of proinflammatory cytokines, and up-regulation of the anti-inflammatory interleukin-22. Moreover, the reduction in steatosis caused by hemin was affected by up-regulation of peroxisome proliferator-activated receptor-alpha and by down-regulation of sterol regulatory element binding protein-1c. HO-1 can interrupt progression of nutritional steatohepatitis by inducing an antioxidant pathway, suppressing production of cytokines, and modifying fatty acid turnover. Induction of HO-1 might provide a new approach for treatment of steatohepatitis.
Publisher: Elsevier BV
Date: 03-2016
DOI: 10.1053/J.GASTRO.2015.11.042
Abstract: Age, sex, smoking, and family history are risk factors for colorectal cancer in Asia. The Asia-Pacific Colorectal Screening (APCS) scoring system was developed to identify subjects with a high risk for advanced neoplasm (AN). We tested an algorithm that combined APCS scores with fecal immunochemical test (FIT) in colorectal cancer screening. We performed a multicenter prospective study, enrolling asymptomatic in iduals older than 40 years old in 12 Asia-Pacific regions from December 2011 to December 2013. APCS scores were calculated for each in idual (0-1 = low risk [LR], 2-3 = medium risk [MR], and 4-7 = high risk [HR] for AN). LR and MR subjects were offered FIT and referred for early colonoscopies if FIT results were positive. HR subjects were offered colonoscopies. The proportions of subjects with ANs were determined for each group based on colonoscopy findings odd ratios for LR and MR subjects were calculated compared to LR in iduals. We calculated the sensitivity of the APCS-FIT algorithm in identifying subjects with AN. A total of 5657 subjects were recruited: 646 subjects (11.4%) were considered LR, 3243 subjects (57.3%) were considered MR, and 1768 subjects (31.3%) were considered HR for AN. The proportions of in iduals with an AN in these groups were 1.5%, 5.1%, and 10.9%, respectively. Compared with LR group, MR and HR subjects had a 3.4-fold increase and a 7.8-fold increase in risk for AN, respectively. A total of 70.6% subjects with AN (95% confidence interval: 65.6%-75.1%) and 95.1% subjects with invasive cancers (95% confidence interval: 82.2%-99.2%) were correctly instructed to undergo early colonoscopy examination. The APCS scoring system, which is based on age, sex, family history, and smoking, is a useful tool for determining risk for colorectal cancer and advanced adenoma in asymptomatic subjects. Use of the APCS score-based algorithm in triaging subjects for FIT or colonoscopy can substantially reduce colonoscopy workload.
Publisher: BMJ
Date: 17-01-2014
DOI: 10.1136/GUTJNL-2013-305584
Abstract: Androgen receptor (AR) signalling contributes to male predominance in hepatocellular carcinoma (HCC), which is more pronounced in HBV-endemic areas. Cell cycle-related kinase (CCRK) is essential for AR-induced hepatocarcinogenesis but its molecular function in HBV-associated HCC remains obscure. To determine the molecular function of CCRK in HBV-associated HCC. Transcriptional regulation was assessed by chromatin immunoprecipitation, promoter mutation and luciferase reporter assays. Hepatocellular proliferation and tumourigenesis were examined by colony formation, soft agar assays and using HBV X protein (HBx) transgenic mice with low-dose exposure to diethylnitrosamine. Protein expressions were examined in clinical s les and correlated with patient survival by log-rank Mantel-Cox test. Overexpression of CCRK, but not its kinase-defective mutant, activated β-catenin/T cell factor signalling through phosphorylation of glycogen synthase kinase-3β (GSK-3β) at Ser9, led to upregulation of AR transcriptional activity and, subsequently, expression of HBx. The viral transactivator in turn induced CCRK expression through enhanced AR signalling, thus forming a positive regulatory loop. RNA interference silencing of CCRK, which suppressed the CCRK/GSK-3β/β-catenin/AR regulatory loop, significantly suppressed HBx-induced hepatocellular proliferation (p=0.001) and transformation (p 80% diethylnitrosamine-mediated hepatocarcinogenesis in HBx transgenic mice. Finally, patients with HBV-associated HCC with concordant overexpression of CCRK, GSK-3β phosphorylation at Ser9, active dephosphorylated β-catenin and AR phosphorylation at Ser81 had poorer overall (HR=31.26, p<0.0001) and disease-free (HR=3.60, p<0.01) survival rates. Our findings highlight the critical role of CCRK in a self-reinforcing circuitry that regulates HBV-associated hepatocarcinogenesis. Further characterisation of this intricate viral-host signalling may provide new prognostic biomarkers and therapeutic targets for HCC treatment.
Publisher: Wiley
Date: 27-09-2001
DOI: 10.1046/J.1365-2036.2001.01038.X
Abstract: Cyclins and cyclin-dependent kinase inhibitors play a crucial role in the control of cell cycle transitions. Enhanced expression of cyclin D2 and reduced expression of p27kip1 (p27) have been implicated in the pathogenesis of cancer. Because intestinal metaplasia has been regarded as a pre-malignant lesion, we investigated the expression of cyclin D2 and p27 in Helicobacter pylori-associated chronic gastritis with and without intestinal metaplasia, and followed the changes after H. pylori eradication. Expression of cyclin D2 and p27 was studied by immunohistochemistry in 59 patients (including 35 patients with intestinal metaplasia) and in 10 gastric cancer patients. Among them, 29 H. pylori-infected patients had serial gastric biopsies taken before and at 1-year after eradication of H. pylori. Expression of cyclin D2 was significantly higher in gastric cancers when compared to their adjacent non-tumour tissues (median score 3 vs. 1, P=0.015). Over-expression of cyclin D2 was detected in H. pylori-associated chronic gastritis and intestinal metaplasia, which was reduced after eradication of the organism (median score 2 vs. 1, P=0.037 in chronic gastritis median score 2 vs. 0, P=0.008 in intestinal metaplasia). While the normal gastric mucosa showed strong p27 expression, five of the 10 gastric cancer tissues exhibited reduced p27 expression (P=0.039). Diminished p27 expression was also seen in intestinal metaplasia, which was restored 1-year after H. pylori eradication (eight out of 16 vs. one out of 16, P=0.018). Reduced expression of p27 was frequently associated with increased cyclin D2 expression in H. pylori-associated intestinal metaplasia (P=0.02). Over-expression of cyclin D2 and reduced expression of p27 are closely linked to H. pylori-associated intestinal metaplasia. Eradication of H. pylori infection reverses the aberrant expression of cyclin D2 and p27 in intestinal metaplasia.
Publisher: American Association for Cancer Research (AACR)
Date: 14-04-2011
DOI: 10.1158/1078-0432.CCR-10-2467
Abstract: Purpose: Yes-associated protein 1 (YAP1) is a multifunctional protein that can interact with different transcription factors to activate gene expression. The role of YAP1 in tumorigenesis is unclear. We aimed to investigate the functional role of YAP1 in tumorigenesis of gastric cancer. Experimental Design: YAP1 expresson in gastric adenocarcinoma was evaluated. The biological function was determined by proliferation assay, colony formation, cell invasion, and flow cytometric analysis through knocking down or ectopic expressing YAP1 in gastric cancer cell lines coupled with in vivo study. The possible downstream effectors of YAP1 were investigated by expression microarray. Results: YAP1 protein expression was upregulated in gastric cancer. Nuclear accumulation of YAP1 was associated with poor disease-specific survival (P = 0.021), especially in patients with early-stage diseases (P & 0.001). Knockdown YAP1 resulted in a significant reduction in proliferation, anchorage-dependent colony formation, cell invasion, and cell motility. Ectopic YAP1 expression promoted anchorage-independent colony formation, induced a more invasive phenotype, and accelerated cell growth both in vitro and in vivo. Microarray analysis highlighted the alteration of MAPK (mitogen-activated protein kinase) pathway by YAP1. We confirmed a constitutive activation of RAF/MEK/ERK (extracellular signal-regulated kinase) in YAP1-expressing MKN45 cells and further showed that YAP1 enhanced serum/epidermal growth factor–induced c-Fos expression in gastric cancer cells. Conclusions: Our findings supported that YAP1 exhibits oncogenic property in gastric cancer. We provided the first evidence that YAP1 exerted the oncogenic function by enhancing the capacity to activate the early-response gene pathway. YAP1 could be a prognostic biomarker and potential therapeutic target for gastric cancer. Clin Cancer Res 17(8) 2130–9. ©2011 AACR.
Publisher: Oxford University Press (OUP)
Date: 15-09-2007
DOI: 10.1086/520981
Abstract: We postulate that hypercytokinemia plays a role in immunopathogenesis of severe human influenza. We prospectively studied 39 consecutive patients who were hospitalized with severe influenza A virus infection. On laboratory confirmation of the diagnosis, paired acute-phase (obtained at hospital admission) and convalescent-phase (obtained >10 days after hospital admission) plasma s les were collected for assay of 11 cytokines and chemokines (interleukin [IL] 1 beta IL-6 IL-10 IL-12p70 tumor necrosis factor alpha IL-8 monokine induced by interferon [IFN]-gamma IFN-inducible protein 10 monocyte chemoattractant protein 1 regulated upon activation, normal T cell-expressed and secreted and IFN-gamma) using cytometric bead-array analysis and enzyme-linked immunosorbent assay. Simultaneously, virus concentration in the acute-phase nasopharyngeal aspirate was determined using real-time quantitative reverse-transcriptase polymerase chain reaction. Intracellular signaling molecules regulating lymphocyte activation, phospho-p38 mitogen-activated protein kinase and phospho-extracellular signal-regulated protein kinase in CD4+ and CD8+ T lymphocytes were studied in the acute-phase s les using flow cytometric analysis and were compared with results for s les from healthy control subjects. Statistically significant increases in plasma IL-6 (3.7-fold increase), IL-8 (2.6-fold increase), IFN-induced protein 10 (4.9-fold increase), and monokine induced by IFN-gamma (2.3-fold increase) concentrations were detected during acute illness (P < .01 for all, by Wilcoxon signed-rank test) the highest concentrations were observed on symptom days 3 and 4. Corresponding plasma cytokine and chemokine concentrations and nasopharyngeal viral loads showed statistically significant correlations (rho = 0.41, 0.49, 0.54, and 0.46, respectively P < or = .01). Phospho-p38 mitogen-activated protein kinase expression in CD4+ lymphocytes was increased, correlating with cytokine concentrations (e.g., for IFN-induced protein 10, rho = 0.78 P < .01) phospho-extracellular signal-regulated protein kinase was suppressed. Advanced age and comorbidity were associated with aberrant IL-6, IL-8, and monokine induced by IFN-gamma responses (P 5 days P = .02), adjusted for age, comorbidity, and virus load. Hypercytokinemia (of proinflammatory and T helper 1 cytokines) is detected in severe influenza, correlating with clinical illness and virus concentration. Hyperactivation of phospho-p38 mitogen-activated protein kinase (in T helper cells) is possibly involved. Early viral suppression may attenuate these potentially deleterious cytokine responses.
Publisher: Oxford University Press (OUP)
Date: 09-2004
DOI: 10.1097/00054725-200409000-00022
Abstract: Inflammatory bowel disease is uncommon in Southeast Asia but is increasing in incidence. The epidemiology and phenotype of Crohn disease (CD) in the Chinese population is not well-known. The purpose of this study was to determine the incidence, temporal trend, clinical features, risk factors, extraintestinal manifestations, and the treatment of CD in the Chinese population of Hong Kong. We performed a single-center study of consecutive definite CD cases based on internationally accepted criteria, with strict exclusion of infective enterocolitis. Eighty Chinese CD patients were recruited, characterized by male gender predominance (male:female ratio 2.5:1), no association with ever smoking (OR 1.02, 95% CI: 0.54-1.92), absence of familial clustering (0%), high proportion of upper gastrointestinal tract disease proximal to the terminal ileum (19%), and a low proportion of isolated terminal ileal disease (4%). The mean age at diagnosis was 33 years. Forty-five percent of patients had penetrating disease, 18% stricturing disease, and 37% had nonstricturing, nonpenetrating disease. Twenty-five percent of patients had at least 1 extraintestinal manifestation, and there was a high rate of ankylosing spondylitis (9%). The incidence of CD was 1.0 per 100,000 and has increased by 3 fold during the past decade. The age-adjusted incidence was 3.0 per 100,000 (95% CI: 2.3-3.7 per 100,000). The incidence of CD in the Chinese is increasing. There are some notable epidemiological and phenotypic differences between Chinese CD with Caucasian CD including the lack of familial clustering, male predominance, and higher proportion of upper GIT involvement and lower frequency of isolated terminal ileal disease.
Publisher: Elsevier BV
Date: 2016
DOI: 10.1016/J.JHEP.2015.09.005
Abstract: CXC chemokine receptor 3 (CXCR3) is involved in virus-related chronic liver inflammation. However, the role of CXCR3 in non-alcoholic steatohepatitis (NASH) remains unclear. We aimed to investigate the role of CXCR3 in NASH. Human liver tissues were obtained from 24 non-alcoholic fatty liver disease (NAFLD) patients and 20 control subjects. CXCR3 knockout (CXCR3(-/-)), obese db/db mice and their wild-type (WT) littermates were used in both methionine-and-choline-deficient (MCD) diet and high-fat high-carbohydrate high-cholesterol (HFHC) diet-induced NASH models. In addition, MCD-fed WT mice were administrated with CXCR3 specific antagonists. CXCR3 was significantly upregulated in liver tissues of patients with NAFLD and in dietary-induced NASH animal models. Compared with WT littermates, CXCR3(-/-) mice were more resistant to both MCD and HFHC diet-induced steatohepatitis. Induction of CXCR3 in dietary-induced steatohepatitis was associated with the increased expression of hepatic pro-inflammatory cytokines, activation of NF-κB, macrophage infiltration and T lymphocytes accumulation (Th1 and Th17 immune response). CXCR3 was also linked to steatosis through inducing hepatic lipogenic genes. Moreover, CXCR3 is associated with autophagosome-lysosome impairment and endoplasmic reticulum (ER) stress in steatohepatitis as evidenced by LC3-II and p62/SQSTM1 accumulation and the induction of GRP78, phospho-PERK and phospho-eIF2α. Inhibition of CXCR3 using CXCR3 antagonist significantly suppressed MCD-induced steatosis and hepatocytes injury in AML-12 hepatocytes. Blockade of CXCR3 using CXCR3 antagonists in mice reversed the established steatohepatitis. CXCR3 plays a pivotal role in NASH development by inducing production of cytokines, macrophage infiltration, fatty acid synthesis and causing autophagy deficiency and ER stress.
Publisher: Wiley
Date: 05-2004
Publisher: Springer Science and Business Media LLC
Date: 05-2003
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2000
DOI: 10.1097/00042737-200012070-00013
Abstract: Helicobacter pylori has been classified as a human carcinogen contributing to the pathogenesis of gastric cancer. Extensive sero-epidemiological studies and recently animal experiments have established a close link between H. pylori infection and the development of gastric cancer. However, the molecular changes induced by H. pylori directly or the concomitant chronic inflammation of the gastric mucosa, and the impact of these changes on the subsequent development of gastric cancer, remain largely unknown. This review will highlight the present knowledge on the molecular pathogenesis of gastric cancer with an emphasis on molecular and genetic alterations which develop due to chronic infection of the gastric mucosa by H. pylori.
Publisher: SAGE Publications
Date: 02-2010
DOI: 10.3851/IMP1722
Abstract: Little is known about the virological and inflammatory responses of severe pandemic 2009 influenza A(H1N1) virus pneumonia during antiviral treatment. In a prospective observational study, we recruited consecutive adults hospitalized with confirmed pandemic 2009 H1N1 infection during a 16-week period. Nasopharyngeal aspirate and non-respiratory s les (blood, stool and urine) were collected at presentation, and serial nasopharyngeal flocked swabs (NPFS) and tracheal aspirates (TA) were collected after initiating oseltamivir treatment for quantitative viral RNA assay, using real-time reverse transcriptase-PCR. Serial plasma s les were collected for cytokine/chemokine assay using cytometric bead array. Patients with severe pneumonia (lung infiltrates and hypoxaemia) were compared to those with milder illnesses. A total of 66 patients were studied (mean age 43 ±20 years) 28 (42%) developed severe pneumonia, of whom 10 (15%) required intubation. Severe pneumonia was associated with older age, dyspnoea, delayed presentation days from onset, extrapulmonary virus detection (13–28%) and higher viral concentration despite late-presentation (multiple linear regression, β=0.94, 95% confidence interval 0.15–1.74 P=0.02). Patients with severe pneumonia exhibited slow viral clearance with oseltamivir treatment, particularly in the lower respiratory tract (median [interquartile range] durations of RNA positivity after antiviral initiation were NPFS 6.0 days [3.0–8.0], TA 11.0 days [7.8–14.3] versus milder illness group NPFS of 2.0 days [1.0–3.0] days P .01). High viral load in lower respiratory tract despite upper-tract RNA negativity and viral rebound after stopping treatment were noted in some patients. H275Y mutation was absent. High plasma levels of interleukin (IL)-6, CXCL-8 (IL-8), CCL2 (monocyte chemoattractant protein-1) and soluble tumour necrosis factor receptor-1 were observed, which correlated with the extent and progression of pneumonia in hospital. In severe 2009 H1N1 pneumonia, viral clearance is slow with treatment, particularly in the lower respiratory tract. A more sustained antiviral regime appears warranted.
Publisher: Elsevier BV
Date: 09-2006
Publisher: Springer Science and Business Media LLC
Date: 30-05-2013
DOI: 10.1038/BJC.2013.263
Publisher: American Association for Cancer Research (AACR)
Date: 15-05-2006
DOI: 10.1158/1078-0432.CCR-05-2442
Abstract: Purpose: Promoter hypermethylation of E-cadherin plays an important role on gastric cancer development. Whereas E-cadherin methylation was frequently detected in the stomach of Helicobacter pylori–infected in iduals, we tested whether eradication of H. pylori alters the methylation status of the noncancerous gastric epithelium. Experimental Design: Endoscopic biopsies were taken from the antrum and corpus of H. pylori–infected subjects without gastric cancer. Presence of methylated E-cadherin sequences in the gastric specimens was detected by methylation-specific PCR. Bisulfite DNA sequencing was done to determine the topographical distribution and changes in methylation profiles with H. pylori eradication. Results: Among the 28 H. pylori–infected subjects (median age, 44.5 years), 15 (53.6%) had E-cadherin methylation detected in stomach at baseline. Discordant methylation patterns between the antrum and corpus were noted in six patients. One year after successful H. pylori eradication, there was a significant reduction in the methylation density of the promoter region and exon 1 of the E-cadherin gene as detected by bisulfite DNA sequencing (P & 0.001). Conclusion: Promoter methylation in E-cadherin was frequently detected in the stomach of H. pylori–infected in iduals. Eradication of H. pylori might possibly reduce the methylation density in E-cadherin gene and the chance of subsequent neoplastic transformation.
Publisher: Elsevier BV
Date: 06-2010
DOI: 10.1016/J.DRUP.2010.04.003
Abstract: Macroautophagy and the ubiquitin-proteasome system are two complementary pathways for protein degradation. The former degrades long-lived proteins and damaged organelles while the later degrades short-lived proteins. Recent findings indicate that suppression of the ubiquitin-proteasome system by proteasome inhibitors induces macroautophagy through multiple pathways, including (1) accumulation of ubiquitinated proteins and activation of HDAC6 (2) activation of the IRE1-JNK pathway (3) proteasomal stabilization of ATF4 (4) inhibition of mTOR complex 1 signaling (5) reduced proteasomal degradation of LC3. Induction of macroautophagy attenuates the antitumor effect of proteasome inhibitors in various types of cancer. These findings suggest that inhibition of macroautophagy may represent a novel strategy to enhance cellular sensitivity to proteasome inhibition.
Publisher: Wiley
Date: 2002
DOI: 10.1002/PATH.1147
Abstract: Trefoil factor family (TFF) domain peptides consist of three members that play a role in intestinal mucosal defence and repair, and in tumourigenesis. The role of the three TFF members in the gastric carcinogenesis cascade remains poorly defined. This study examined seven gastric cell lines, 50 gastric cancers and their adjacent non-cancer tissues, and tissues from 40 non-cancer patients, in order to elucidate the chronology of TFF expression in various stages of gastric carcinogenesis. TFF expression was determined by RT-PCR, immunohistochemistry, and western blot. Aberrant expression of TFF1, TFF2, and TFF3 was frequently detected in gastric cell lines. Specifically, TFF1 was detected in all non-cancer patients, but was detected in only 50% of gastric cancer and 66% of adjacent normal tissues. TFF2 expression was demonstrated in 87.5% of non-cancer patients, 34% of gastric carcinomas, and 58% of adjacent non-cancer tissues. There was a significant correlation between TFF1 and TFF2 expression in gastric cancer and adjacent non-cancer tissues (p<0.001). By contrast, TFF3 was detected in 25% of non-cancer patients and showed a predilection for areas with intestinal metaplasia (p=0.005). Sixty-two per cent of gastric cancers and 24% of neighbouring non-cancer tissues showed TFF3 expression. Immunoreactivity against TFF3 was demonstrated in goblet cells of intestinal metaplasia and within the cytoplasm and nuclei of tumour cells. Progressive loss of TFF1 and TFF2, together with the induction of TFF3, is likely to be involved in the early stage of the multi-step gastric carcinogenesis pathway.
Publisher: Wiley
Date: 28-03-2023
DOI: 10.1111/JGH.16182
Publisher: Wiley
Date: 29-06-2011
DOI: 10.1002/CNCR.26184
Abstract: The role of Epstein-Barr virus (EBV) infection in gastric carcinogenesis remains largely unknown. The authors studied the effects of zinc finger E-box binding factor 1 (ZEB1) on latent-lytic switch of EBV infection in gastric cancer and explored the importance of EBV in gastric carcinogenesis. Loss or gain of ZEB1 function was obtained by ZEB1 small-interfering RNA (siRNA) knock-down or forced ZEB1 re-expression. Cell growth was evaluated by cell viability and colony formation assays, and the cell cycle was assessed by flow cytometry. EBV was detected using quantitative polymerase chain reaction (PCR) and in situ hybridization analyses. ZEB1 knock-down in a latent EBV-infected gastric cancer cell line (YCC10) increased lytic gene BamHI W leftward reading frame 1 (BZLF1) expression and decreased the expression of latent gene EB nuclear antigen 1 (EBNA1) concomitant with the inhibition of cell viability (P < .05) and S-phase DNA synthesis (P < .01). ZEB1 depletion combined with ganciclovir revealed a further reduction in cell viability (P < .001). ZEB1 knock-down induced cell apoptosis and the up-regulation of caspase 3 and poly(adenosine diphosphate-ribose) polymerase cleavage. Conversely, ectopic overexpression of ZEB1 in a lytic EBV-infected gastric cancer cell line (AGS-EBV) inhibited BZLF1 promoter (Zp) activity, BZLF1 expression, and apoptosis and promoted cell growth. EBV infection was detected in 11.3% (80 of 711) of gastric cancers. The presence of EBV was associated with age, men, and intestinal type cancer. ZEB1 was confirmed as a key mediator of the latent-lytic switch of EBV-associated gastric cancer, a distinct subtype with different clinicopathologic features. The current results indicated that inhibition of ZEB1 may be a potential target for EBV-associated gastric cancer therapy.
Publisher: Wiley
Date: 30-12-2016
DOI: 10.1111/JGH.12958
Abstract: The Asia Pacific Working Group on Inflammatory Bowel Disease was established in Cebu, Philippines, at the Asia Pacific Digestive Week conference in 2006 under the auspices of the Asian Pacific Association of Gastroenterology (APAGE) with the goal of developing best management practices, coordinating research and raising awareness of IBD in the region. The consensus group previously published recommendations for the diagnosis and management of ulcerative colitis (UC) with specific relevance to the Asia-Pacific region. The present consensus statements were developed following a similar process to address the epidemiology, diagnosis and management of Crohn's disease (CD). The goals of these statements are to pool the pertinent literature specifically highlighting relevant data and conditions in the Asia-Pacific region relating to the economy, health systems, background infectious diseases, differential diagnoses and treatment availability. It does not intend to be all-comprehensive and future revisions are likely to be required in this ever-changing field.
Publisher: Elsevier BV
Date: 12-2014
Publisher: BMJ
Date: 22-04-2202
Publisher: Wiley
Date: 19-03-2009
DOI: 10.1111/J.1365-2036.2009.03944.X
Abstract: Patients with inflammatory bowel disease (IBD) who are corticosteroid-dependent or -refractory are at higher risk of developing disease- and treatment-related complications. To identify retrospectively clinical factors present at diagnosis that predict the occurrence of corticosteroid dependency and refractoriness in Crohn's disease (CD) and ulcerative colitis (UC) patients. A total of 310 IBD patients (134 CD, 176 UC) were observed for 2140 person years and their use of systemic corticosteroids was determined. Outcomes of corticosteroid dependency and refractoriness were recorded. Univariate and multivariate analyses were performed to determine the clinical factors associated with outcomes. Seventy-seven (57.5%) CD and 95 (54.0%) UC patients had received corticosteroids during study period. In CD, thrombocytosis [Hazard ratio (HR):3.0] predicted, whereas colonic CD (HR:0.3) negatively predicted corticosteroid dependency. Stricturing phenotype (HR:4.5) predicted corticosteroid-refractory CD. For UC, thrombocytosis (HR:3.9) and extensive colitis (HR:1.7) predicted corticosteroid dependency. Presence of anaemia (HR:10.8) at diagnosis and initial requirement of total parenteral nutrition (TPN) (HR:18.8) predicted corticosteroid-refractory UC. The cumulative risks of surgery were 17.8% and 5.4% for CD and UC patients respectively at 1 year after starting corticosteroids. Thrombocytosis at diagnosis predicted corticosteroid-dependency in IBD. Stricturing phenotype of CD and the presence of anaemia in UC predicted subsequent course of corticosteroid refractoriness.
Publisher: BMJ
Date: 24-01-2007
Publisher: Massachusetts Medical Society
Date: 30-07-1998
Publisher: Elsevier BV
Date: 05-2017
DOI: 10.1053/J.GASTRO.2017.01.009
Abstract: Stool s les from patients with colorectal cancer (CRC) have a higher abundance of Peptostreptococcus anaerobius than stool from in iduals without CRC, based on metagenome sequencing. We investigated whether P anaerobius contributes to colon tumor formation in mice and its possible mechanisms of carcinogenesis. We performed quantitative polymerase chain reaction analyses to measure P anaerobius in 112 stool s les and 255 colon biopsies from patients with CRC or advanced adenoma and from healthy in iduals (controls) undergoing colonoscopy examination at hospitals in Hong Kong and Beijing. C57BL/6 mice were given broad-spectrum antibiotics, followed by a single dose of azoxymethane, to induce colon tumor formation. Three days later, mice were given P anaerobius or Esherichia coli MG1655 (control bacteria), via gavage, for 6 weeks. Some mice were also given the nicotinamide adenine dinucleotide phosphate oxidase inhibitor apocynin. Intestine tissues were collected and analyzed histologically. The colon epithelial cell line NCM460 and colon cancer cell lines HT-29 and Caco-2 were exposed to P anaerobius or control bacteria cells were analyzed by immunoblot, proliferation, and bacterial attachment analyses and compared in gene expression profiling studies. Gene expression was knocked down in these cell lines with small interfering RNAs. P anaerobius was significantly enriched in stool s les from patients with CRC and in biopsies from patients with colorectal adenoma or CRC compared with controls. Mice depleted of bacteria and exposed to azoxymethane and P anaerobius had a higher incidence of intestinal dysplasia (63%) compared with mice not given the bacteria (8.3% P < .01). P anaerobius mainly colonized the colon compared with the rest of the intestine. Colon cells exposed to P anaerobius had significantly higher levels of proliferation than control cells. We found genes that regulate cholesterol biosynthesis, Toll-like receptor (TLR) signaling, and AMP-activated protein kinase signaling to be significantly up-regulated in cells exposed to P anaerobius. Total cholesterol levels were significantly increased in colon cell lines exposed to P anaerobius via activation of sterol regulatory element-binding protein 2. P anaerobius interacted with TLR2 and TLR4 to increase intracellular levels of reactive oxidative species, which promoted cholesterol synthesis and cell proliferation. Depletion of reactive oxidative species by knockdown of TLR2 or TLR4, or incubation of cells with an antioxidant, prevented P anaerobius from inducing cholesterol biosynthesis and proliferation. Levels of P anaerobius are increased in human colon tumor tissues and adenomas compared with non-tumor tissues this bacteria increases colon dysplasia in a mouse model of CRC. P anaerobius interacts with TLR2 and TLR4 on colon cells to increase levels of reactive oxidative species, which promotes cholesterol synthesis and cell proliferation.
Publisher: Massachusetts Medical Society
Date: 03-06-2010
Publisher: Wiley
Date: 30-12-2016
DOI: 10.1111/JGH.12956
Abstract: Inflammatory bowel disease (IBD) was previously thought to be rare in Asia, but emerging data indicate rising incidence and prevalence of IBD in the region. The Asia Pacific Working Group on Inflammatory Bowel Disease was established in Cebu, Philippines, at the Asia Pacific Digestive Week conference in 2006 under the auspices of the Asian Pacific Association of Gastroenterology with the goal of developing best management practices, coordinating research, and raising awareness of IBD in the region. The consensus group previously published recommendations for the diagnosis and management of ulcerative colitis with specific relevance to the Asia-Pacific region. The present consensus statements were developed following a similar process to address the epidemiology, diagnosis, and management of Crohn's disease. The goals of these statements are to pool the pertinent literature specifically highlighting relevant data and conditions in the Asia-Pacific region relating to the economy, health systems, background infectious diseases, differential diagnoses, and treatment availability. It does not intend to be all comprehensive and future revisions are likely to be required in this ever-changing field.
Publisher: American Association for Cancer Research (AACR)
Date: 09-2013
DOI: 10.1158/1541-7786.MCR-13-0061
Abstract: Dysregulated microRNA (miRNA) expression was profiled through a miRNA array comparison between human colorectal cancer tumors and their adjacent normal tissues. Specifically, using laser capture micro-dissection, miR-133a was shown to be significantly downregulated in primary colorectal cancer specimens compared with matched adjacent normal tissue. Ectopic expression of miR-133a significantly suppressed colorectal cancer cell growth in vitro and in vivo. Cell-cycle analysis revealed that miR-133a induced a G0/G1-phase arrest, concomitant with the upregulation of the key G1-phase regulator p21Cip1. We further revealed that miR-133a markedly increased p53 protein and induced p21Cip1 transcription. Studies in silico revealed that the 3′UTR of the ring finger and FYVE-like domain containing E3-ubiquitin protein ligase (RFFL), which regulates p53 protein, contains an evolutionarily conserved miR-133a binding site. miR-133a repressed RFFL-3′UTR reporter activity and reduced RFFL protein levels, indicating that miR-133a directly bound to RFFL mRNA and inhibited RFFL translation. Moreover, miR-133a sensitized colon cancer cells to doxorubicin and oxaliplatin by enhancing apoptosis and inhibiting cell proliferation. These data add weight to the significance of miR-133a in the development of CRC. Implications: miR-133a serves as a potential tumor suppressor upstream of p53 in colorectal cancer and may sensitize cells to therapeutics. Mol Cancer Res 11(9) 1051–60. ©2013 AACR.
Publisher: Springer Science and Business Media LLC
Date: 03-11-2014
DOI: 10.1038/ONC.2014.348
Abstract: 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.
Publisher: Springer Science and Business Media LLC
Date: 23-05-2016
DOI: 10.1038/ONC.2016.187
Publisher: BMJ
Date: 12-06-2015
Publisher: American Association for Cancer Research (AACR)
Date: 12-05-2016
DOI: 10.1158/0008-5472.CAN-15-2083
Abstract: Bacterial infection is linked to colorectal carcinogenesis, but the species that contribute to a protumorigenic ecology are ill-defined. Here we report evidence that α-hemolysin–positive (hly+) type I Escherichia coli (E. coli) drives adenomagenesis and colorectal cancer in human females but not males. We classified E. coli into four types using a novel typing method to monitor fimH mutation patterns of fecal isolates from adenoma patients (n= 59), colorectal cancer patients (n= 83), and healthy subjects (n= 85). hly+ type I E. coli was found to be relatively more prevalent in stools from females with adenoma and colorectal cancer, correlating with poor survival in colorectal cancer patients. In mechanistic studies in female mice, we found that hly+ type 1 E. coli activated expression of the glucose transporter GLUT1 and repressed expression of the tumor suppressor BIM. hly-encoded alpha hemolysin partially accounted for these effects by elevating the levels of HIF1α. Notably, colon tumorigenesis in mice could be promoted by feeding hly+ type I E. coli to female but not male subjects. Collectively, our findings point to hemolytic type I E. coli as a candidate causative factor of colorectal cancer in human females, with additional potential as a biomarker of disease susceptibility. Cancer Res 76(10) 2891–900. ©2016 AACR.
Publisher: Springer Science and Business Media LLC
Date: 26-02-2014
DOI: 10.1007/S13277-014-1697-3
Abstract: Inflammatory cytokines modulate immune responses in the tumor microenvironment during progression. The role of interleukin (IL) 17A in cancer is currently under debate. We aim to investigate the expression of IL17A in situ tumors as well as in nontumor gastric mucosa tissues and further explore the functional significance of IL17A on gastric cancer cells in vitro. We found that compared with nontumor regions, the expression of IL17A were increased significantly in tumors of gastric cancer patients (P=0.007). The immunoreactivity for IL17A was found only in cytoplasm of inflammatory cells as well as vascular endothelial cells but not in tumor cells. Consistently, IL17A transcription was silenced in a variety of gastric cancer cell lines. In vitro, recombinant human IL17A protein promotes cell proliferation and monolayer wound healing of both AGS and SGC7901cells, in a dose-dependent manner. Besides, IL17A inhibits H2O2-induced cell apoptosis. Expression of IL6 and MMP13 mRNA was increased significantly after IL17A stimulation. These data suggest that accumulation of intratumoral IL17A-producing cells may promote gastric cancer progression directly or by inducing key signal transduction pathways implicated in gastric carcinogenesis.
Publisher: Elsevier BV
Date: 11-2013
DOI: 10.1016/J.JHEP.2013.06.029
Abstract: The World Health Organisation (WHO) Prevention & Control of Viral Hepatitis Infection: Framework for Global Action offers a global vision for the prevention and control of viral hepatitis. In October 2012, the Coalition to Eradicate Viral Hepatitis in Asia Pacific (CEVHAP) organised the North Asia Workshop on Viral Hepatitis in Taipei to discuss how to implement the WHO Framework in the North Asia region. This paper presents outcomes from this workshop. Twenty-eight representatives from local liver associations, patient organisations, and centres of excellence in Hong Kong, Japan, Korea, and Taiwan participated in the workshop. Priority areas for action were described along the four axes of the WHO Framework: (1) awareness, advocacy and resources (2) evidence and data (3) prevention of transmission and (4) screening and treatment. Priorities included: axis 1: greater public and professional awareness, particularly among primary care physicians and local advocacy networks. Axis 2: better economic data and identifying barriers to screening and treatment uptake. Axis 3: monitoring of vaccination outcomes and targeted harm reduction strategies. Axis 4: strengthening links between hospitals and primary care providers, and secure funding of screening and treatment, including for hepatocellular carcinoma. The WHO Framework provides an opportunity to develop comprehensive and cohesive policies in North Asia and the broader region. A partnership between clinical specialists, primary care physicians, policy makers, and people with or at risk of viral hepatitis is essential in shaping future policies.
Publisher: Elsevier BV
Date: 12-2020
Publisher: Elsevier BV
Date: 06-2005
DOI: 10.1053/J.GASTRO.2005.03.026
Abstract: Helicobacter pylori-negative idiopathic ulcers are increasingly recognized. The secular trend and long-term outcome of this condition are unknown. We prospectively studied consecutive patients with bleeding gastroduodenal ulcers from January to December 2000. The incidence and etiology of ulcers during this period were compared with that between September 1997 and August 1998. H. pylori-negative idiopathic ulcers were defined as negative tests for H. pylori, no exposure to analgesics within 4 weeks, and absence of other risk factors for ulcers. After the ulcers had healed, patients with H. pylori-negative idiopathic ulcers and patients with H. pylori ulcers who received eradication therapy were followed up for 12 months without anti-ulcer drugs. Six hundred thirty-eight patients had bleeding ulcers: 213 (33.4%) were H. pylori ulcers, and 120 (18.8%) were H. pylori-negative idiopathic ulcers (vs 480 [50.3%] H. pylori ulcers and 40 [4.2%] H. pylori-negative idiopathic ulcers in 1997-1998 P < .001). H. pylori-negative idiopathic ulcers accounted for 16.1% of patients who were admitted for bleeding and 42.4% of patients who bled while in the hospital (P < .0001) 28.3% of patients with H. pylori-negative idiopathic ulcers had histologic evidence of past H. pylori infection. The probability of recurrent ulcer complications in 12 months was 13.4% (95% CI: 7.3%-19.5%) in patients with H. pylori-negative idiopathic ulcers and 2.5% (95% CI: 0.4%-4.6%) in patients with H. pylori ulcers who received eradication therapy (P = .0002). The incidence of H. pylori-negative idiopathic bleeding ulcers is rising. These ulcers are prone to recurrent complications.
Publisher: Elsevier BV
Date: 07-2010
DOI: 10.1016/J.CANLET.2009.12.002
Abstract: The ubiquitin-proteasome system is a major pathway for protein degradation. Targeting this pathway using proteasome inhibitors represents a novel approach for the treatment of cancer. Proteasome inhibitors lower cell proliferation and induce apoptosis in solid and hematologic malignancies through multiple mechanisms, including stabilization of cell cycle regulators and pro-apoptotic factors, stimulation of bone morphogenetic protein signaling, inhibition of protein translation, and sensitization to ligand-induced apoptosis. In this connection, proteasome inhibition activates macroautophagy, a compensatory protein degradation system, as well as other pro-survival signaling pathways. Inhibition of these auto-protective responses sensitizes cancer cells to the anti-proliferative effects of proteasome inhibitors.
Publisher: Elsevier BV
Date: 06-2005
DOI: 10.1016/J.CANLET.2004.11.038
Abstract: We characterized the effects of selective Cox-2 inhibition on the angiogenesis gastric cancer cell line SGC7901 by stable transfection of antisense Cox-2 cDNA (Cox-2-AS) or pharmacological inhibition by selective cox-2 inhibitor (NS398). The conditioned media obtained from SGC7901 treated with Cox-2-AS or NS398 suppressed the proliferation, migration and tube formation of human umbilical vein endothelial cells. Moreover, both treatments inhibited in vivo angiogenesis. These inhibitions could be partially reversed by the addition of PGE2. Our findings support that selective inhibition of Cox-2 alone plays an instrumental role on gastric cancer associated angiogenesis.
Publisher: Oxford University Press (OUP)
Date: 05-2006
DOI: 10.1086/502975
Publisher: Springer Science and Business Media LLC
Date: 12-2012
Publisher: Elsevier BV
Date: 09-2004
Publisher: Wiley
Date: 12-2003
DOI: 10.1111/J.1523-5378.2003.00182.X
Abstract: To evaluate the protective effect of live attenuated Salmonella typhimurium expressing catalase against gastric Helicobacter pylori infection in mice, and to explore the underlying mechanisms of the protective immune reaction. The H. pylori catalase gene was introduced into attenuated S. typhimurium strain SL3261. C57BL/6 mice were orally immunized with the SL3261 vaccine strain expressing catalase or with SL3261 alone or phosphate-buffered saline (PBS). Mice were sacrificed 4 weeks after immunization and 5 weeks after H. pylori challenge, respectively. All PBS control mice were infected. Eight of 13 (61.5%) mice immunized with the SL3261 vaccine strain and three of 14 (21%) mice immunized with SL3261 alone showed protection against H. pylori infection. Serum anti-H. pylori IgG2a levels of S. typhimurium-immunized mice were higher than those of PBS controls, both before and after H. pylori challenge, while there were no differences for IgG1 and IgA. Similarly, mRNA expression of interleukin (IL)-2, IL-12 and interferon-gamma in the gastric mucosa of S. typhimurium-immunized mice was significantly higher than that of PBS controls both before and after challenge. Moreover, S. typhimurium-immunized mice were characterized by marked infiltration of lymphocyte and mononuclear cells in the gastric mucosa after challenge. IL-4 and IL-10 were not detected in any of the three groups. IL-6 expression was increased in the PBS group compared with the S. typhimurium-immunized groups after challenge. This study demonstrates that oral immunization of mice with catalase delivered by an attenuated S. typhimurium strain offers protection against H. pylori infection. This protective immunity was mediated through a predominantly Th1-type response and was associated with post-immunization gastritis.
Publisher: American Association for Cancer Research (AACR)
Date: 02-2014
DOI: 10.1158/1541-7786.MCR-13-0195
Abstract: A disintegrins and metalloproteinases with thrombospondin motifs (ADAMTS) family members have been reported dysregulated in various cancers. Through refining a loss of heterozygosity locus at 11q25 by array-CGH, we identified ADAMTS8 as a novel candidate tumor suppressor gene. Although ADAMTS8 downregulation has been reported in several tumors, its biologic function and underlying mechanism remain largely unknown. Here, we found that ADAMTS8 is broadly expressed in normal tissues but frequently downregulated or silenced by promoter methylation in common carcinoma cell lines, including nasopharyngeal, esophageal squamous cell, gastric, and colorectal carcinomas. Pharmacologic or genetic demethylation restored ADAMTS8 expression, indicating that promoter methylation mediates its silencing. Aberrant methylation of ADAMTS8 was also detected in several types of primary tumors but rarely in normal tissues. Further functional studies showed that restoring ADAMTS8 expression suppressed tumor cell clonogenicity through inducing apoptosis. ADAMTS8 as a secreted protease inhibited epidermal growth factor receptor (EGFR) signaling along with decreased levels of phosphorylated MEK and ERK. We further found that ADAMTS8 disrupted actin stress fiber organization and inhibited tumor cell motility. Thus, our data demonstrate that ADAMTS8 metalloprotease acts as a functional tumor suppressor through antagonizing EGFR–MEK–ERK signaling, in addition to its previously reported anti-angiogenesis function, and is frequently methylated in common tumors. Implications: This study uncovers the tumor suppressive function of ADAMTS8, one of the ADAMTS family members, and its frequent methylation in certain tumors could be developed as a potential biomarker. Mol Cancer Res 12(2) 228–38. ©2013 AACR.
Publisher: BMJ
Date: 28-09-2023
Publisher: Massachusetts Medical Society
Date: 07-10-2004
DOI: 10.1056/NEJMOA033364
Publisher: Springer Science and Business Media LLC
Date: 19-01-2023
Publisher: Wiley
Date: 22-10-2009
DOI: 10.1111/J.1440-1843.2009.01637.X
Abstract: Agents such as Mycoplasma pneumoniae, Chlamydophila pneumoniae and Legionella pneumophila are recognized as important causes of community-acquired pneumonia (CAP) worldwide. This study examined the role of these 'atypical pathogens' (AP) among adult hospitalized patients with CAP. A prospective, observational study of consecutive adult CAP (clinico-radiological diagnosis) patients hospitalized during 2004-2005 was conducted. Causal organisms were determined using cultures, antigen testing and paired serology. Clinical/laboratory/radiological variables and outcomes were compared between different aetiologies, and a clinical prediction rule for AP was constructed. There were 1193 patients studied (mean age 70.8 +/- 18.0 years, men 59.3%). Causal organisms were identified in 468 (39.2%) patients: 'bacterial' (48.7%), 'viral' (26.9%), 'AP' (28.6%). The AP infections comprised Mycoplasma or Chlamydophila pneumoniae (97.8%) and co-infection with bacteria/virus (30.6%). The majority of AP infections involved elderly patients (63.4%) with comorbidities (41.8%), and more than one-third of patients were classified as 'intermediate' or 'high' risk CAP on presentation (pneumonia severity index IV-V (35.1%) CURB-65 2-5 (42.5%)). Patients with AP infections had disease severities and outcomes similar to patients with CAP due to other organisms (oxygen therapy 29.1% vs 29.8% non-invasive ventilation 3.7% vs 3.3% admission to the intensive care unit 4.5% vs 2.7% length of hospitalization 6 day vs 7 day 30-day mortality: 2.2% vs 6.0% overall P > 0.05). Age or =38.0 degrees C, respiratory rate <25/min, pulse rate 130 mmol/L, leucocyte count <11 x 10(9)/L and Hb < 11 g/dL were features associated with AP infection, but the derived prediction rule failed to reliably discriminate CAP caused by AP from bacterial CAP (area under the curve 0.75). M. pneumoniae and C. pneumoniae as single/co-pathogens are important causes of severe pneumonia among older adults. No reliable clinical indicators exist, so empirical antibiotic coverage for hospitalized CAP patients may need to be considered.
Publisher: Springer Science and Business Media LLC
Date: 20-01-2009
Publisher: Elsevier BV
Date: 07-2013
DOI: 10.1053/J.GASTRO.2013.04.007
Abstract: Inflammatory bowel diseases (IBD) are becoming more common in Asia, but epidemiologic data are lacking. The Asia-Pacific Crohn's and Colitis Epidemiology Study aimed to determine the incidence and phenotype of IBD in 8 countries across Asia and in Australia. We performed a prospective, population-based study of IBD incidence in predefined catchment areas, collecting data for 1 year, starting on April 1, 2011. New cases were ascertained from multiple overlapping sources and entered into a Web-based database. Cases were confirmed using standard criteria. Local endoscopy, pathology, and pharmacy records were searched to ensure completeness of case capture. We identified 419 new cases of IBD (232 of ulcerative colitis [UC], 166 of Crohn's disease [CD], and 21 IBD-undetermined). The crude annual overall incidence values per 100,000 in iduals were 1.37 for IBD in Asia (95% confidence interval: 1.25-1.51 0.76 for UC, 0.54 for CD, and 0.07 for IBD-undetermined) and 23.67 in Australia (95% confidence interval: 18.46-29.85 7.33 for UC, 14.00 for CD, and 2.33 for IBD-undetermined). China had the highest incidence of IBD in Asia (3.44 per 100,000 in iduals). The ratios of UC to CD were 2.0 in Asia and 0.5 in Australia. Median time from symptom onset to diagnosis was 5.5 months (interquartile range, 1.4-15 months). Complicated CD (stricturing, penetrating, or perianal disease) was more common in Asia than Australia (52% vs 24% P = .001), and a family history of IBD was less common in Asia (3% vs 17% P < .001). We performed a large-scale population-based study and found that although the incidence of IBD varies throughout Asia, it is still lower than in the West. IBD can be as severe or more severe in Asia than in the West. The emergence of IBD in Asia will result in the need for specific health care resources, and offers a unique opportunity to study etiologic factors in developing nations.
Publisher: American College of Physicians
Date: 20-04-2004
DOI: 10.7326/0003-4819-140-8-200404200-00008
Abstract: Whether subclinical or atypical presentations of severe acute respiratory syndrome (SARS) occur and whether clinical judgment is accurate in detecting SARS are unknown. To describe the spectrum of SARS coronavirus infection in a large outbreak and to compare diagnoses based on clinical judgment with the SARS coronavirus test. Secondary analysis of prospectively collected clinical data and archived serum. A SARS screening clinic of a university hospital in the New Territories of Hong Kong. 1221 patients attending the clinic between 12 March 2003 and 12 May 2003. SARS coronavirus serology. 145 of 553 (26%) patients had serologic evidence of SARS coronavirus infection. Of 910 patients who were managed without hospitalization, only 6 had serologic evidence of SARS. Five of the six patients had normal chest radiographs, and four had symptoms such as myalgia, chills, coughing, and feeling feverish. With the SARS coronavirus serologic test as the gold standard, the clinical diagnosis of probable SARS at hospitalization had a sensitivity of 0.96 (95% CI, 0.91 to 0.98) and a specificity of 0.96 (CI, 0.92 to 0.97). Follow-up serologic s les were not obtained from almost half of the patients because they declined further testing. Some people living in the community who were infected but who had minor or no symptoms might not have visited the clinic. There is little evidence of widespread subclinical or mild forms of SARS coronavirus infection. Clinical diagnoses during the outbreak were reasonable and resulted in appropriate triaging.
Publisher: American Society for Microbiology
Date: 12-2007
DOI: 10.1128/CVI.00100-07
Abstract: To investigate whether genetic factors of innate immunity might influence susceptibility and/or progression in in iduals infected with SARS, we evaluated the CD14 gene polymorphism in 198 Hong Kong blood donors and 152 Hong Kong severe acute respiratory syndrome (SARS) patients who were previously genotyped for FcγRIIA polymorphisms. The prevalence of the CD14-159CC polymorphism was significantly higher in the patients with severe SARS than in the those with mild SARS or controls (31% versus 15% [mild SARS] or 20% [controls] mild SARS: P = 0.029 odds ratio, 2.74 95% confidence interval, 1.15 to 6.57 controls, P = 0.04 odds ratio, 2.41 95% confidence interval, 1.05 to 5.54), and both CD14-159CC and FcγRIIA-RR131 are risk genotypes for severe SARS-CoV infection.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2007
DOI: 10.1002/HEP.21668
Abstract: Enhancer of zeste homolog 2 (EZH2) has been shown to be overexpressed in hepatocellular (HCC). We investigated the potential role of EZH2 in HCC tumorigenesis and examined the usefulness of RNA interference (RNAi) targeting EZH2 as a form of HCC treatment. Lentivirus-mediated RNAi was employed to knock-down EZH2 expression in human hepatoma cells to study the function of EZH2 in tumorigenesis and evaluate the treatment efficacy. Lentivirus-mediated RNAi effectively reduced EZH2 expression. Suppression of EZH2 in HCC cells significantly reduced their growth rate in vitro and markedly diminished their tumorigenicity in vivo. Moreover, in a mice model of established large-sized HCC, we showed that intratumor injection of lentiviral (Lenti)-shRNA (short hairpin RNA) or siRNA (small interfering RNA) targeting EZH2 produced significant tumor regression. To understand its molecular mechanism of action, we employed proteomic profiling technique and found that stathmin 1 is the downstream target of EZH2, as Lenti-shEZH2 treatment decreased stathmin protein expression, and ectopic overexpression of stathmin prevented Lenti-shEZH2 mediated tumor growth inhibition. Results from our study suggested for the first time that EZH2 plays a key role in HCC tumorigenesis, and is a novel therapeutic target for HCC.
Publisher: Springer Science and Business Media LLC
Date: 16-07-2020
DOI: 10.1186/S40168-020-00847-4
Abstract: Altered microbiome composition and aberrant promoter hypermethylation of tumor suppressor genes (TSGs) are two important hallmarks of colorectal cancer (CRC). Here we performed concurrent 16S rRNA gene sequencing and methyl-CpG binding domain-based capture sequencing in 33 tissue biopsies (5 normal colonic mucosa tissues, 4 pairs of adenoma and adenoma-adjacent tissues, and 10 pairs of CRC and CRC-adjacent tissues) to identify significant associations between TSG promoter hypermethylation and CRC-associated bacteria, followed by functional validation of the methylation-associated bacteria. Fusobacterium nucleatum and Hungatella hathewayi were identified as the top two methylation-regulating bacteria. Targeted analysis on bona fide TSGs revealed that H. hathewayi and Streptococcus spp . significantly correlated with CDX2 and MLH1 promoter hypermethylation, respectively. Mechanistic validation with cell-line and animal models revealed that F. nucleatum and H. hathewayi upregulated DNA methyltransferase. H. hathewayi inoculation also promoted colonic epithelial cell proliferation in germ-free and conventional mice. Our integrative analysis revealed previously unknown epigenetic regulation of TSGs in host cells through inducing DNA methyltransferase by F. nucleatum and H. hathewayi , and established the latter as CRC-promoting bacteria.
Publisher: Springer Science and Business Media LLC
Date: 30-10-2015
DOI: 10.1038/NCOMMS9727
Abstract: Gut microbial dysbiosis contributes to the development of colorectal cancer (CRC). Here we catalogue the microbial communities in human gut mucosae at different stages of colorectal tumorigenesis. We analyse the gut mucosal microbiome of 47 paired s les of adenoma and adenoma-adjacent mucosae, 52 paired s les of carcinoma and carcinoma-adjacent mucosae and 61 healthy controls. Probabilistic partitioning of relative abundance profiles reveals that a metacommunity predominated by members of the oral microbiome is primarily associated with CRC. Analysis of paired s les shows differences in community configurations between lesions and the adjacent mucosae. Correlations of bacterial taxa indicate early signs of dysbiosis in adenoma, and co-exclusive relationships are subsequently more common in cancer. We validate these alterations in CRC-associated microbiome by comparison with two previously published data sets. Our results suggest that a taxonomically defined microbial consortium is implicated in the development of CRC.
Publisher: Wiley
Date: 08-2007
Publisher: Elsevier BV
Date: 02-2009
DOI: 10.1053/J.GASTRO.2008.10.050
Abstract: By using methylation-sensitive representational difference analysis, we identified protocadherin 10 (PCDH10), a gene that encodes a protocadherin and is silenced in a tumor-specific manner. We analyzed its epigenetic inactivation, biological effects, and prognostic significance in gastric cancer. Methylation status was evaluated by combined bisulfite restriction analysis and bisulfite sequencing. The effects of PCDH10 re-expression were determined in growth, apoptosis, proliferation, and invasion assays. PCDH10 target genes were identified by complementary DNA microarray analysis. PCDH10 was silenced or down-regulated in 94% (16 of 17) of gastric cancer cell lines expression levels were restored by exposure to demethylating agents. Re-expression of PCDH10 in MKN45 gastric cancer cells reduced colony formation in vitro and tumor growth in mice it also inhibited cell proliferation (P < .01), induced cell apoptosis (P < .001), and repressed cell invasion (P < .05), up-regulating the pro-apoptosis genes Fas, Caspase 8, Jun, and CDKN1A the antiproliferation gene FGFR and the anti-invasion gene HTATIP2. PCDH10 methylation was detected in 82% (85 of 104) of gastric tumors compared with 37% (38 of 104) of paired nontumor tissues (P < .0001). In the latter, PCDH10 methylation was higher in precancerous lesions (27 of 45 60%) than in chronic gastritis s les (11 of 59 19%) (P < .0001). After a median follow-up period of 16.8 months, multivariate analysis revealed that patients with PCDH10 methylation in adjacent nontumor areas had a significant decrease in overall survival. Kaplan-Meier survival curves showed that PCDH10 methylation was associated significantly with shortened survival in stage I-III gastric cancer patients. PCDH10 is a gastric tumor suppressor its methylation at early stages of gastric carcinogenesis is an independent prognostic factor.
Publisher: Elsevier BV
Date: 11-2016
DOI: 10.1053/J.GASTRO.2016.07.011
Abstract: Many colorectal cancer (CRC) cells contain mutations in KRAS. Analyses of CRC cells with mutations in APC or CTNNB1 and KRAS identified SLC25A22, which encodes mitochondrial glutamate transporter, as a synthetic lethal gene. We investigated the functions of SLC25A22 in CRC cells with mutations in KRAS. We measured levels of SLC25A22 messenger RNA and protein in paired tumor and nontumor colon tissues collected from 130 patients in Hong Kong and 17 patients in China and compared protein levels with patient survival times. Expression of SLC25A22 was knocked down in KRAS mutant CRC cell lines (DLD1, HCT116, LOVO, SW480, SW620, and SW1116) and CRC cell lines without mutations in KRAS (CACO-2, COLO205, HT29, and SW48) cells were analyzed for colony formation, proliferation, glutaminolysis and aspartate synthesis, and apoptosis in Matrigel and polymerase chain reaction array analyses. DLD1 and HCT116 cells with SLC25A22 knockdown were grown as xenograft tumors in nude mice tumor growth and metastasis were measured. SLC25A22 was expressed ectopically in HCT116 cells, which were analyzed in vitro and grown as xenograft tumors in nude mice. Levels of SLC25A22 messenger RNA and protein were increased in colorectal tumor tissues compared with matched nontumor colon tissues increased protein levels were associated with shorter survival times of patients (P = .01). Knockdown of SLC25A22 in KRAS mutant CRC cells reduced their proliferation, migration, and invasion in vitro, and tumor formation and metastasis in mice, compared with cells without SLC25A22 knockdown. Knockdown of SLC25A22 reduced aspartate biosynthesis, leading to apoptosis, decreased cell proliferation in KRAS mutant CRC cells. Incubation of KRAS mutant CRC cells with knockdown of SLC25A22 with aspartate increased proliferation and reduced apoptosis, which required GOT1, indicating that oxaloacetate is required for cell survival. Decreased levels of oxaloacetate in cells with knockdown of SLC25A22 reduced regeneration of oxidized nicotinamide adenine dinucleotide and reduced nicotinamide adenine dinucleotide phosphate. Reduced oxidized nicotinamide adenine dinucleotide inhibited glycolysis and decreased levels of adenosine triphosphate, which inactivated mitogen-activated protein kinase kinase and extracellular signal-regulated kinase signaling via activation of AMP-activated protein kinase. An increased ratio of oxidized nicotinamide adenine dinucleotide phosphate to reduced nicotinamide adenine dinucleotide phosphate induced oxidative stress and glutathione oxidation, which suppressed cell proliferation. Asparagine synthetase mediated synthesis of asparagine from aspartate to promote cell migration. SLC25A22 promotes proliferation and migration of CRC cells with mutations KRAS, and formation and metastasis of CRC xenograft tumors in mice. Patients with colorectal tumors that express increased levels of SLC25A22 have shorter survival times than patients whose tumors have lower levels. SLC25A22 induces intracellular synthesis of aspartate, activation of mitogen-activated protein kinase kinase and extracellular signal-regulated kinase signaling and reduces oxidative stress.
Publisher: Radiological Society of North America (RSNA)
Date: 09-2003
Publisher: Wiley
Date: 2004
DOI: 10.1002/JMV.20138
Publisher: Elsevier BV
Date: 2021
Publisher: Elsevier BV
Date: 07-2012
DOI: 10.1016/J.GIE.2012.03.168
Abstract: The rapid increase in the incidence of colorectal cancer (CRC) in the Asia-Pacific region in the past decade has resulted in recommendations to implement mass CRC screening programs. However, the knowledge of screening and population screening behaviors between countries is largely lacking. This multicenter, international study investigated the association of screening test participation with knowledge of, attitudes toward, and barriers to CRC and screening tests in different cultural and sociopolitical contexts. Person-to-person interviews by using a standardized survey instrument were conducted with subjects from 14 Asia-Pacific countries/regions to assess the prevailing screening participation rates, knowledge of and attitudes toward and barriers to CRC and screening tests, intent to participate, and cues to action. Independent predictors of the primary endpoint, screening participation was determined from subanalyses performed for high-, medium-, and low-participation countries. A total of 7915 subjects (49% male, 37.8% aged 50 years and older) were recruited. Of the respondents aged 50 years and older, 809 (27%) had undergone previous CRC testing the Philippines (69%), Australia (48%), and Japan (38%) had the highest participation rates, whereas India (1.5%), Malaysia (3%), Indonesia (3%), Pakistan (7.5%), and Brunei (13.7%) had the lowest rates. Physician recommendation and knowledge of screening tests were significant predictors of CRC test uptake. In countries with low-test participation, lower perceived access barriers and higher perceived severity were independent predictors of participation. Respondents from low-participation countries had the least knowledge of symptoms, risk factors, and tests and reported the lowest physician recommendation rates. "Intent to undergo screening" and "perceived need for screening" was positively correlated in most countries however, this was offset by financial and access barriers. Ethnic heterogeneity may exist in each country that was not addressed. In addition, the participation tests and physician recommendation recalls were self-reported. In the Asia-Pacific region, considerable differences were evident in the participation of CRC tests, physician recommendations, and knowledge of, attitudes toward, and barriers to CRC screening. Physician recommendation was the uniform predictor of screening behavior in all countries. Before implementing mass screening programs, improving awareness of CRC and promoting the physicians' role are necessary to increase the screening participation rates.
Publisher: Elsevier BV
Date: 03-2014
DOI: 10.1016/J.MOLCEL.2014.01.020
Abstract: Impaired phosphatase activity contributes to the persistent activation of STAT3 in tumors. Given that STAT family members with various or even opposite functions are often phosphorylated or dephosphorylated by the same enzymes, the mechanism for STAT3-specific dephosphorylation in cells remains largely unknown. Here, we report that GdX (UBL4A) promotes STAT3 dephosphorylation via mediating the interaction between TC45 (the nuclear isoform of TC-PTP) and STAT3 specifically. GdX stabilizes the TC45-STAT3 complex to bestow upon STAT3 an efficient dephosphorylation by TC45. Inasmuch, GdX suppresses tumorigenesis and tumor development by reducing the level of phospho-STAT3 (p-STAT3), whereas deletion of GdX results in a high level of p-STAT3 and accelerated colorectal tumorigenesis induced by AOM/DSS. Thus, GdX converts TC45, a nonspecific phosphatase, into a STAT3-specific phosphatase by bridging an association between TC45 and STAT3.
Publisher: Springer Science and Business Media LLC
Date: 26-05-0001
Publisher: American Association for Cancer Research (AACR)
Date: 04-2018
DOI: 10.1158/0008-5472.CAN-17-2403
Abstract: 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, G1–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 β-catenin protein ubiquitination and degradation independently of GSK-3β. 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 β-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 β-catenin in gastric cancer, blunting Wnt signaling and suppressing carcinogenesis. Cancer Res 78(7) 1643–56. ©2018 AACR.
Publisher: Informa UK Limited
Date: 02-01-2016
Publisher: Wiley
Date: 13-05-2007
DOI: 10.1111/J.1440-1746.2007.04952.X
Abstract: The risk factors and settings for non-alcoholic fatty liver disease (NAFLD) in Asians are reviewed comprehensively. Based particularly on large community-based studies using ultrasonography, case-control series and prospective longitudinal studies, the prevalence of NAFLD in Asia is between 12% and 24%, depending on age, gender, locality and ethnicity. Further, the prevalence in China and Japan has nearly doubled in the last 10-15 years. A detailed analysis of these data shows that NAFLD risk factors for Asians resemble those in the West for age at presentation, prevalence of type 2 diabetes mellitus (T2DM) and hyperlipidemia. The apparent differences in prevalence of central obesity and overall obesity are related to criteria used to define waist circumference and body mass index (BMI), respectively. The strongest associations are with components of the metabolic syndrome, particularly the combined presence of central obesity and obesity. Non-alcoholic fatty liver disease appears to be associated with long-standing insulin resistance and likely represents the hepatic manifestation of metabolic syndrome. Not surprisingly therefore, Asians with NAFLD are at high risk of developing diabetes and cardiovascular disease. Conversely, metabolic syndrome may precede the diagnosis of NAFLD. The increasing prevalence of obesity, coupled with T2DM, dyslipidemia, hypertension and ultimately metabolic syndrome puts more than half the world's population at risk of developing NAFLD/non-alcoholic steatohepatitis/cirrhosis in the coming decades. Public health initiatives are clearly imperative to halt or reverse the global 'diabesity' pandemic, the underlying basis of NAFLD and metabolic syndrome. In addition, a perspective of NAFLD beyond its hepatic consequences is now warranted this needs to be considered in relation to management guidelines for affected in iduals.
Publisher: Springer Science and Business Media LLC
Date: 15-04-2016
DOI: 10.1038/SREP24466
Abstract: MicroRNAs (miRNAs) are aberrantly expressed in virtually all cancer types, including digestive cancers. Herein, we aggregated and systematically analyzed miRNA expression profiles of 1765 tumor s les, including esophageal, gastric, liver, pancreatic, colon and rectal cancers, obtained through small RNA sequencing by The Cancer Genome Atlas. We found that digestive cancers of different tissue origins could be differentiated according to their miRNA expression profiles. In particular, esophageal squamous cell carcinoma and esophageal adenocarcinoma exhibited distinct miRNA expression patterns. Thirteen (e.g. miR-135b, miR-182) and sixteen (e.g. miR-139, miR-133a-1, miR-490) miRNAs were commonly upregulated and downregulated in more than four cancer types, respectively. Pertinent to pathological features, low miR-181d expression was associated with microsatellite instability in colon and gastric cancers whereas low miR-106a expression was associated with hepatitis B virus infection in hepatocellular carcinoma. Progression in colon cancer could also be predicted by low let-7f-2 and high miR-106a expression. Molecular subtypes with distinct prognostic outcomes independent of tumor-node-metastasis staging were identified in hepatocellular carcinoma and colon cancer. In total, 4 novel and 6 reported associations between specific miRNAs and patients’ survival were identified. Collectively, novel miRNA markers were identified to stratify digestive cancers with different pathological features and survival outcomes.
Publisher: Wiley
Date: 25-08-2017
Publisher: Wiley
Date: 23-06-2015
DOI: 10.1002/JCP.24967
Abstract: Hepatitis B virus (HBV) and one of its encoded proteins, HBV X protein (HBx), have been shown to induce autophagy in hepatoma cells. Substantial evidence indicates that autophagy is a potent suppressor of inflammation. However, sporadic reports suggest that autophagy could promote pro-inflammatory cytokine expression and inflammation in some biological contexts. Here, we show that overexpression of HBx induces LC3B-positive autophagosome formation, increases autophagic flux and enhances the expression of ATG5, ATG7, and LC3B-II in normal hepatocytes. Abrogation of autophagy by small interfering RNA against ATG5 and ATG7 prevents HBx-induced formation of autophagosomes. Autophagy inhibition also abrogates HBx-induced activation of nuclear factor-κB (NF-κB) and production of interleukin-6 (IL-6), IL-8, and CXCL2. These findings suggest that autophagy is required for HBx-induced NF-κB activation and pro-inflammatory cytokine production and could shed new light on the complex role of autophagy in the modulation of inflammation.
Publisher: American Society for Clinical Investigation
Date: 08-2011
DOI: 10.1172/JCI45967
Publisher: Springer Science and Business Media LLC
Date: 05-02-2010
Abstract: Nuclear factor of kappa B inhibitor alpha (IκBα) protein is implicated in regulating a variety of cellular process from inflammation to tumorigenesis. The objective of this study was to investigate the susceptibility of rs2233408 T/C genotype in the promoter region of IκBα to gastric cancer and the association of this polymorphism with clinicopathologic variables in gastric cancer patients. A population-based case-control study was conducted between 1999 and 2006 in Guangdong Province, China. A total of 564 gastric cancer patients and 566 healthy controls were enrolled in this study. rs2233408 genotypes in IκBα were analyzed by TaqMan SNP genotyping assay. Both rs2233408 T homozygote (TT) and T heterozygotes (TC and TT) had significantly reduced gastric cancer risk (TT: OR = 0.250, 95% CI = 0.069-0.909, P = 0.035 TC and TT: OR = 0.721, 95% CI = 0.530-0.981, P = 0.037), compared with rs2233408 C homozygote (CC). rs2233408 T heterozygotes were significantly associated with reduced risk of intestinal-type gastric cancer with ORs of 0.648 (95% CI = 0.459-0.916, P = 0.014), but not with the diffuse or mix type of gastric cancer. The association between rs2233408 T heterozygotes and gastric cancer appeared more apparent in the older patients (age ) (OR = 0.674, 95% CI = 0.484-0.939, P = 0.02). rs2233408 T heterozygotes was associated with non-cardiac gastric cancer (OR = 0.594, 95% CI = 0.411-0.859, P = 0.006), but not with cardiac gastric cancer. However, rs2233408 polymorphism was not associated with the prognosis of gastric cancer patients. IκBα rs2233408 T heterozygotes were associated with reduced risk of gastric cancer, especially for the development of certain subtypes of gastric cancer in Chinese population.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 23-03-2020
DOI: 10.1002/HEP.24124
Abstract: The paired box 5 (PAX5) is a member of PAX transcription factors family involved in the regulation of embryonic development. However, the role of PAX5 in carcinogenesis is largely unclear. We identified that PAX5 is involved in human cancer by methylation-sensitive representational difference analysis. We examined the biological functions and related molecular mechanisms of PAX5 in hepatocellular carcinoma (HCC). Promoter methylation of PAX5 was evaluated by methylation-specific polymerase chain reaction (PCR) and bisulfite genomic sequencing (BGS). The functions of ectopic PAX5 expression were determined by viability assay, colony formation, and cell cycle analyses, along with in vivo tumorigenicity assays. The PAX5 target signal pathway was identified by promoter luciferase assay, chromosome immunoprecipitation (ChIP), and pathway PCR array. PAX5 is expressed in normal human liver tissue, but silenced or down-regulated in 83% (10/12) of HCC cell lines. The mean expression level of PAX5 was significantly lower in primary HCCs as compared to their adjacent normal tissues (P < 0.0001). The promoter methylation contributes to the inactivation of PAX5. Restoring PAX5 expression in silenced HCC cell lines suppressed cell proliferation, induced apoptosis in vitro, and inhibited tumor growth in nude mice (P < 0.0001). The pathway luciferase reporter assay indicated that PAX5 activated p53 and p21 signaling. ChIP analysis demonstrated that PAX5 directly bound to the p53 promoter. The antitumorigenic function of PAX5 was at least up-regulated by p53 and its downstream targets including tumor necrosis factor, Fas ligand, leucine-rich repeats, and death domain-containing, poly(rC) binding protein 4, p21, and growth arrest and DNA-damage-inducible alpha. PAX5 is frequently inactivated by promoter methylation in HCC. PAX5 appears to be a functional tumor suppressor involved in liver carcinogenesis through direct regulation of the p53 signaling pathway.
Publisher: Public Library of Science (PLoS)
Date: 21-02-0007
Publisher: Elsevier BV
Date: 07-2022
DOI: 10.1016/J.GIE.2022.01.020
Abstract: The aim of this study was to evaluate the safety and effectiveness of Hemospray (Cook Medical, Winston-Salem, NC, USA), a hemostatic powder, as monotherapy for active peptic ulcer bleeding. In this prospective, multicenter, single-arm study, patients with Forrest Ia or Ib peptic ulcers underwent endoscopic application of Hemospray as treatment of first intent. Effectiveness endpoints were successful hemostasis at the end of the index endoscopy, recurrent bleeding within 72 hours and from 72 hours to 30 days, adverse events requiring reintervention or resulting in morbidity or mortality, and 30-day mortality. Hemospray was successfully administered in 98.5% of patients (66/67). Hemostasis was achieved at the index endoscopy in 90.9% of patients (60/66) with Hemospray alone and in an additional 4 patients treated with additional modalities, yielding an overall hemostasis rate of 97.0% (64/66). Rebleeding occurred in 13.3% of patients (8/60), 5 within 72 hours and 3 between 72 hours and 30 days. Two cases of perforation and 2 patient deaths occurred during the study, but none of these cases or any other adverse events were attributed to the use of Hemospray. The rate of early rebleeding was significantly higher in patients with Forrest Ia ulcers compared with patients with Forrest Ib ulcers. Higher rates of early bleeding in patients with Forrest Ia ulcers is consistent with results from studies where Hemospray was used as rescue after failure of conventional methods. Hemospray is an effective initial treatment for patients with active peptic ulcer bleeding, but care should be taken to monitor for recurrent bleeding. (Clinical trial registration number: NCT01306864.).
Publisher: Oxford University Press (OUP)
Date: 04-2009
DOI: 10.1002/IBD.20804
Abstract: According to the Montreal Classification, upper gastrointestinal tract phenotype L4 is uncommon in Caucasian patients with Crohn's disease (CD) but carries excess risk of recurrence. We studied the clinical course of CD in Chinese patients presenting with the L4 phenotype and factors predicting its occurrence upon longitudinal follow-up. This prospective cohort study included 132 Chinese CD patients (median age at diagnosis, 30.0 years, range: 14.0-77.0 years) who were followed for 770 person-years. Demographic data including disease behavior and location, details of surgery, and hospitalization were collected. The Kaplan-Meier method was used to estimate the probabilities of further hospitalization and major surgery followed by Cox proportional hazards regression to determine if clinical variables independently predicted the endpoints. The L4 phenotype was found in 30 (22.7%) patients at presentation. There were significantly more stricturing (46.7% versus 18.6%) and penetrating (30.0% versus 3.9%) phenotypes in the L4 group than in the non-L4 group (P < 0.0001). The 3-year cumulative probability of further hospitalization was 86.9% (95% confidence interval [CI]: 73.8%-100.0%) in the L4 group as compared with 49.3% (95% CI: 39.3%-59.3%) in the non-L4 group (log-rank test, P < 0.0001). The L4 phenotype independently predicted further hospitalization (adjusted hazards ratio [HR]: 2.1 95% CI: 1.3-3.5). The cumulative probability of major surgery was significantly higher in the L4 than in the non-L4 group (P < 0.0001). Eighteen (17.6%) patients developed the L4 phenotype on follow-up and the stricturing phenotype predicted its occurrence (adjusted HR: 5.5 95% CI: 2.2-14.0). Chinese CD patients more often had the L4 phenotype, which predicted the need of subsequent hospitalization.
Publisher: Elsevier BV
Date: 10-2009
Publisher: Springer Science and Business Media LLC
Date: 14-03-2018
DOI: 10.1038/S41598-018-19819-8
Abstract: 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 in iduals at increased risk for primary prevention.
Publisher: Springer Science and Business Media LLC
Date: 12-05-2008
DOI: 10.1038/ONC.2008.147
Abstract: 16q24 is frequently deleted in multiple tumors including cancers of nasopharynx, esophagus, breast, prostate and liver. By array comparative genomic hybridization (aCGH), we refined a 16q24 hemizygous deletion in nasopharyngeal carcinoma (NPC) cell lines. Semi-quantitative RT-PCR analysis revealed interferon regulatory factor 8 (IRF8) as the only downregulated gene within this deletion. IRF8 belongs to a family of interferon (IFN) regulatory factors that modulate various important physiologic processes including host defense, cell growth and differentiation and immune regulation. In contrast to the broad expression of IRF8 in normal adult and fetal tissues, transcriptional silencing and promoter methylation of IRF8 were frequently detected in multiple carcinoma (except for hepatocellular) cell lines (100% in NPC, 88% in esophageal and 18-78% in other carcinoma cell lines) and in a large collection of primary carcinomas (78% in NPC, 36-71% in other carcinomas). Methylation of the IRF8 promoter led to the disruption of its response to IFN-gamma stimulation. Pharmacological and genetic demethylation could restore IRF8 expression, indicating a direct epigenetic mechanism. Ectopic expression of IRF8 in tumor cells lacking its expression strongly inhibited their clonogenicity, confirming its tumor suppressor function. Thus, IRF8 was identified as a functional tumor suppressor, which is frequently silenced by epigenetic mechanism in multiple carcinomas.
Publisher: Radiological Society of North America (RSNA)
Date: 11-2004
Publisher: BMJ
Date: 19-03-2014
DOI: 10.1136/GUTJNL-2013-306503
Abstract: Since the publication of the first Asia Pacific Consensus on Colorectal Cancer (CRC) in 2008, there are substantial advancements in the science and experience of implementing CRC screening. The Asia Pacific Working Group aimed to provide an updated set of consensus recommendations. Members from 14 Asian regions gathered to seek consensus using other national and international guidelines, and recent relevant literature published from 2008 to 2013. A modified Delphi process was adopted to develop the statements. Age range for CRC screening is defined as 50-75 years. Advancing age, male, family history of CRC, smoking and obesity are confirmed risk factors for CRC and advanced neoplasia. A risk-stratified scoring system is recommended for selecting high-risk patients for colonoscopy. Quantitative faecal immunochemical test (FIT) instead of guaiac-based faecal occult blood test (gFOBT) is preferred for average-risk subjects. Ancillary methods in colonoscopy, with the exception of chromoendoscopy, have not proven to be superior to high-definition white light endoscopy in identifying adenoma. Quality of colonoscopy should be upheld and quality assurance programme should be in place to audit every aspects of CRC screening. Serrated adenoma is recognised as a risk for interval cancer. There is no consensus on the recruitment of trained endoscopy nurses for CRC screening. Based on recent data on CRC screening, an updated list of recommendations on CRC screening is prepared. These consensus statements will further enhance the implementation of CRC screening in the Asia Pacific region.
Publisher: Wiley
Date: 10-10-2021
DOI: 10.1111/JGH.15690
Abstract: Protein O ‐GlcNAcylation is a critical post‐translational modification regulating gene expression and fundamental cell functions. O ‐GlcNAc transferase (OGT) emerged as a key regulator of liver pathophysiology and disease. In this study, we aimed to evaluate the role of OGT in hepatic stellate cells (HSCs) and its consequent role in liver fibrosis. Primary HSCs were isolated from C57/B6 mice. Cell morphology and αSMA immunofluorescence staining were observed under scanning confocal microscope. Transcriptomic profile was evaluated by RNAseq (Illumina). Promoter activity was examined by luciferase and β‐Galactosidase reporter assays. Liver fibrosis mouse models were induced either by intraperitoneal injection of CCl 4 at 3 times/week for 4 weeks or by feeding with methionine and choline deficient (MCD) diet for 4 weeks. OGT protein expression and protein O ‐GlcNAcylation were significantly decreased in CCl 4 − or MCD diet‐induced liver fibrosis as compared with normal liver in mice. OGT expression and protein O ‐GlcNAcylation were also decreased in primary HSCs isolated from liver with CCl 4 ‐induced fibrosis compared with those from normal liver. RNA‐seq showed that OGT knockdown in HSCs modulated key signaling pathways involved in HSC activation. Promoter sequence analysis of the differentially expressed genes predicted serum response factor (SRF) as a key transcription factor regulated by OGT. Luciferase reporter assay confirmed that OGT repressed activity of SRF to induce α‐SMA transcription. Mutations of specific O ‐GlcNAcylation sites on SRF increased its transcriptional activity, validating negative regulation of SRF by OGT‐mediated O ‐GlcNAcylation. Our results suggest that OGT functions as a negative regulator of HSC activation by promoting SRF O ‐GlcNAcylation to protect against liver fibrosis.
Publisher: American Association for Cancer Research (AACR)
Date: 15-06-2009
DOI: 10.1158/0008-5472.CAN-08-3694
Abstract: Closely located at the tumor suppressor locus 16q22.1, CKLF-like MARVEL transmembrane domain-containing member 3 and 4 (CMTM3 and CMTM4) encode two CMTM family proteins, which link chemokines and the transmembrane-4 superfamily. In contrast to the broad expression of both CMTM3 and CMTM4 in normal human adult tissues, only CMTM3 is silenced or down-regulated in common carcinoma (gastric, breast, nasopharyngeal, esophageal, and colon) cell lines and primary tumors. CMTM3 methylation was not detected in normal epithelial cell lines and tissues, with weak methylation present in only 5 of 35 (14%) gastric cancer adjacent normal tissues. Furthermore, immunohistochemistry showed that CMTM3 protein was absent in 12 of 35 (34%) gastric and 1 of 2 colorectal tumors, which was well correlated with its methylation status. The silencing of CMTM3 is due to aberrant promoter CpG methylation that could be reversed by pharmacologic demethylation. Ectopic expression of CMTM3 strongly suppressed the colony formation of carcinoma cell lines. In addition, CMTM3 inhibited tumor cell growth and induced apoptosis with caspase-3 activation. Thus, CMTM3 exerts tumor-suppressive functions in tumor cells, with frequent epigenetic inactivation by promoter CpG methylation in common carcinomas. [Cancer Res 2009 (12):5194–201]
Publisher: Elsevier BV
Date: 12-2001
Publisher: Wiley
Date: 26-01-2023
DOI: 10.1111/AOGS.14508
Abstract: Interventional radiology (IR) is a technique for controlling hemorrhage and preserving fertility for women with serious obstetric conditions such as placenta accreta spectrum (PAS) or postpartum hemorrhage. This study examined maternal, pregnancy and hospital characteristics and outcomes for women receiving IR in pregnancy and postpartum. A population‐based record linkage study was conducted, including all women who gave birth in hospital in New South Wales or the major tertiary hospital in the neighboring Australian Capital Territory, Australia, between 2003 and 2019. Data were obtained from birth and hospital records. Characteristics and outcomes of women who underwent IR in pregnancy or postpartum are described. Outcomes following IR were compared in a high‐risk cohort of women: those with PAS who had a planned cesarean with hysterectomy. Women were grouped by those who did and those who did did not have IR and were matched using propensity score and other factors. We identified IR in 236 pregnancies of 1 584 708 (15.0 per 100 000), including 208 in the delivery and 26 in a postpartum admission. Two‐thirds of women receiving IR in the birth admission received a transfusion of red cells or blood products, 28% underwent hysterectomy and 12.5% were readmitted within 6 weeks. Other complications included: severe maternal morbidity (29.8%), genitourinary tract trauma/repair (17.3%) and deep vein thrombosis ulmonary embolism (4.3%). Outcomes for women with PAS who underwent planned cesarean with hysterectomy were similar for those who did and did not receive IR, with a small reduction in transfusion requirement for those who received IR. Interventional radiology is infrequently used in pregnant women. In our study it was performed at a limited number of hospitals, largely tertiary centers, with the level of adverse outcomes reflecting use in a high‐risk population. For women with PAS undergoing planned cesarean with hysterectomy, most outcomes were similar for those receiving IR and those not receiving IR, but IR may reduce bleeding.
Publisher: Elsevier BV
Date: 06-2005
DOI: 10.1016/J.CANLET.2004.09.052
Abstract: Peroxisome proliferator-activated receptor delta (PPARdelta) is ligand-activated transcription factor of the nuclear receptor superfamily which is recently implicated in carcinogenesis. We examined the expression profiles of PPARdelta in human gastric cancer, normal gastric mucosa and gastric cancer cell lines by RT-PCR, Western blot and immunohistochemistry. PPARdelta mRNA and protein was found to be ubiquitously expressed in all 5 gastric cancer cell lines, 40 gastric cancer s les and 10 normal gastric mucosa from non-cancer patients. Positive immunoreactivity was detected in the nuclei of normal and malignant gastric epithelium. Treatment of gastric cell line MKN45 that overexpressed cyclooxygenase-2 (COX-2) with specific COX-2 inhibitor NS398 resulted in a time- and dose-dependent suppression of PPARdelta expression. In contrast, there was no suppression of PPARdelta in MKN28 gastric cell line with low COX-2 expression. Our results demonstrated the ubiquitous expression of PPARdelta in normal and cancer gastric epithelium. Suppression of PPARdelta may be one of the mechanisms underlying the chemopreventive effects of COX-2 inhibitor.
Publisher: American Association for Cancer Research (AACR)
Date: 15-12-2012
DOI: 10.1158/0008-5472.CAN-12-2359
Abstract: Cathelicidins are a family of bacteriocidal polypeptides secreted by macrophages and polymorphonuclear leukocytes (PMN). LL-37, the only human cathelicidin, has been implicated in tumorigenesis, but there has been limited investigation of its expression and function in cancer. Here, we report that LL-37 activates a p53-mediated, caspase-independent apoptotic cascade that contributes to suppression of colon cancer. LL-37 was expressed strongly in normal colon mucosa but downregulated in colon cancer tissues, where in both settings its expression correlated with terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling-positive apoptotic cells. Exposure of colon cancer cells to LL-37 induced phosphatidylserine externalization and DNA fragmentation in a manner independent of caspase activation. Apoptogenic function was mediated by nuclear translocation of the proapoptotic factors, apoptosis-inducing factor (AIF) and endonuclease G (EndoG), through p53-dependent upregulation of Bax and Bak and downregulation of Bcl-2 via a pertussis toxin–sensitive G-protein–coupled receptor (GPCR) pathway. Correspondingly, colonic mucosa of cathelicidin-deficient mice exhibited reduced expression of p53, Bax, and Bak and increased expression of Bcl-2 together with a lower basal level of apoptosis. Cathelicidin-deficient mice exhibited an increased susceptibility to azoxymethane-induced colon tumorigenesis, establishing pathophysiologic relevance in colon cancer. Collectively, our findings show that LL-37 activates a GPCR-p53-Bax/Bak/Bcl-2 signaling cascade that triggers AIF/EndoG–mediated apoptosis in colon cancer cells. Cancer Res 72(24) 6512–23. ©2012 AACR.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 05-2003
Abstract: Purpose: Beta-catenin (β-catenin) participates in intercellular adhesion and is an integral part of the Wnt signaling pathway. The role of β-catenin in the pathogenesis of gastric cancer and its metastasis is largely unknown. Patients and Methods: Immunohistochemistry and Western blot analysis were used to analyze the expression of β-catenin in 87 human gastric cancers, in metastasis and cancer cell lines. The β-catenin and the adenomatous polyposis coli (APC) genes were analyzed for gene mutations. Furthermore, methylation of the β-catenin promoter in cell lines was assessed by treatment with 5′-azadeoxycytidine and sodium bisulfite genomic sequencing. Results: β-Catenin expression was present at either the cell membrane or the cytoplasm in 34 of 75 primary gastric cancers. Expression of β-catenin was significantly more frequent in intestinal-type (P = .0049) and well-differentiated gastric cancers (P .001). There were no quantitative differences between gastric cancers and the nonmalignant gastric tissues, as determined by Western blot analysis. One of 18 metastatic cancer lesions and four of five gastric cancer cell lines expressed β-catenin protein. N87 cells, derived from the liver metastasis of a gastric cancer, did not express β-catenin. Treatment with 5′-azadeoxycytidine restored β-catenin protein levels in this cell line, which exhibited significantly more 5-methylcytosines in the β-catenin promoter compared with the other cell lines. Conclusion: β-Catenin expression is lost in a subgroup of primary gastric cancers, is frequently absent in metastases, and exhibits nuclear localization in cancers with either β-catenin or APC gene mutations. Interestingly, the loss of β-catenin expression in metastatic gastric cancers may result from hypermethylation of the β-catenin promoter.
Publisher: Elsevier BV
Date: 2021
Publisher: BMJ
Date: 05-2007
Publisher: Springer Science and Business Media LLC
Date: 31-08-2004
Publisher: Wiley
Date: 22-03-2004
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2004
DOI: 10.1097/00004836-200411003-00004
Abstract: To estimate and compare the direct medical cost in the management of chronic hepatitis B (CHB) infection and its complications from the perspective of public health organizations in Hong Kong and Singapore. Hong Kong and Singapore are endemic hepatitis B virus areas with about 10% and 5%, respectively, of the population estimated as hepatitis B virus infected. The medical histories of 660 patients with CHB who received medical services over 5 years from three major public hospitals in Hong Kong and Singapore were studied retrospectively. Costs were analyzed according to the five disease states and estimated in Hong Kong dollars (HKD) and Singapore dollars (SGD). In both Hong Kong and Singapore, the per-patient total annual cost increased with the severity of the disease. CHB cost HKD 6318 (US 810 dollars) in Hong Kong and SGD 718.15 (US 410.37 dollars) in Singapore. Compensated cirrhosis cost HKD 10,304 (US 1321 dollars) in Hong Kong and SGD 1,175.34 (US 671.62 dollars) in Singapore. Decompensated cirrhosis cost HKD 58,428 (US 7490 dollars) in Hong Kong and SGD 15,389.84 (US 8794.19 dollars) in Singapore. Hepatocellular carcinoma cost HKD 121,822 (US 15,618 dollars) in Hong Kong and SGD 12314.04 (US 7036.59 dollars) in Singapore. Each case of liver transplant was estimated to cost HKD 514,498 (US 65,961 dollars) in Hong Kong and SGD 86,369.28 (US 49,353.87 dollars) in Singapore. CHB in Hong Kong accounted for about 4% of the healthcare expenditure. This study confirms that CHB and its liver disease complications are a significant economic burden to the healthcare budgets of Hong Kong and Singapore, and indicates that effective therapy that arrests or reverses the progression of liver disease would be highly cost-effective.
Publisher: Elsevier BV
Date: 06-2006
Publisher: Elsevier BV
Date: 10-2005
Publisher: Springer Science and Business Media LLC
Date: 05-11-2015
DOI: 10.1038/NRDP.2015.65
Publisher: BMJ
Date: 06-04-2011
Abstract: Upper gastrointestinal bleeding (UGIB), especially peptic ulcer bleeding, remains one of the most important cause of hospitalisation and mortality world wide. In Asia, with a high prevalence of Helicobacter pylori infection, a potential difference in drug metabolism, and a difference in clinical management of UGIB due to variable socioeconomic environments, it is considered necessary to re-examine the International Consensus of Non-variceal Upper Gastrointestinal Bleeding with emphasis on data generated from the region. The working group, which comprised experts from 12 countries from Asia, recommended the use of the Blatchford score for selection of patients who require endoscopic intervention and which would allow early discharge of patients at low risk. Patients' comorbid conditions should be included in risk assessment. A pre-endoscopy proton pump inhibitor (PPI) is recommended as a stop-gap treatment when endoscopy within 24 h is not available. An adherent clot on a peptic ulcer should be treated with endoscopy combined with a PPI if the clot cannot be removed. Routine repeated endoscopy is not recommended. High-dose intravenous and oral PPIs are recommended but low-dose intravenous PPIs should be avoided. COX-2 selective non-steroidal anti-inflammatory drugs combined with a PPI are recommended for patients with very high risk of UGIB. Aspirin should be resumed soon after stabilisation and clopidogrel alone is no safer than aspirin plus a PPI. When dual antiplatelet agents are used, prophylactic use of a PPI reduces the risk of adverse gastrointestinal events.
Publisher: BMJ
Date: 10-2002
DOI: 10.1136/GUT.51.4.480
Abstract: Helicobacter pylori blood group antigen binding adhesin (BabA) mediates bacterial adherence to human blood group antigens on gastric epithelium. Although strains harbouring babA2 were recently found to be associated with peptic ulcer and gastric cancer, the role of babA2 in cellular turnover, severity of gastritis, and premalignant changes is poorly understood. We correlated H pylori babA2, vacuolating toxin (vacA), and cytotoxin associated gene A (cagA) genotypes with the severity of gastric inflammation and epithelial cell turnover in a group of Chinese patients from an area with a high incidence of gastric cancer. H pylori isolates were obtained from 104 Chinese patients who participated in a gastric cancer prevention programme. Genotype variants of babA2, vacA, and cagA were determined by polymerase chain reaction. Antrum and corpus histopathology was examined according to the updated Sydney classification. Apoptosis was scored by terminal uridine deoxynucleotidyl nick end labeling (TUNEL) and proliferation by Ki-67 immunostaining. Of the 104 patients, 102 (98.1%) harboured cagA(+) strains and all had vacA s1 genotype. The babA2(+) strains were found in 83 (79.8%) patients and were associated with higher lymphocytic infiltration (p=0.028), presence of glandular atrophy (odds ratio (OR) 7.5, 95% confidence interval (CI) 2.3-24.3), and intestinal metaplasia (OR 7.4, 95% CI 2.2-25.3) in the antrum. Increased epithelial proliferation was also noted in in iduals infected with babA2(+) strains (p=0.025). Strains harbouring cagA(+)/vacA s1 genotypes lacked this association in the absence of babA2. The presence of babA2(+) H pylori strains alone or in combination with cagA(+) and vacA s1 was associated with the presence of preneoplastic gastric lesions.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2006
DOI: 10.1111/J.1572-0241.2006.00503.X
Abstract: Crohn's disease (CD) is a heterogenous disease characterized by variable manifestations and outcomes, and increasing in incidence in China. Phenotypic classification has been proposed to assist in subtyping of disease. Non-caseating intestinal granulomas are a hallmark of CD, but whether intestinal granulomas help predict Chinese CD phenotypes or determine severity, is not known. To determine the association between intestinal granulomas with CD phenotype, severity, risk factors, and serological markers. This was a single-centre study of consecutive definite Chinese CD cases. Granulomas were diagnosed by an experienced GI pathologist. Correlation with the Vienna Classification and other parameters was performed. Eighty Chinese CD patients were recruited, 40 (50%) of whom had intestinal granulomas. Intestinal granulomas were independently associated with the stricturing behavior (OR: 4.71 95% CI: 1.41-15.72), colonic location of disease (OR: 26.96 95% CI: 2.68-271.14), but not with age of CD diagnosis. Current or previous smoking protected against the development of granulomas (OR: 0.16 95% CI: 0.04-0.59). Granulomas were not associated with peri-anal involvement, extra-intestinal manifestations, anti-neutrophil cytoplasmic antibody or anti-Saccharomyces cerevisiae antibody serology, or severity of CD gauged by the requirement of major intestinal surgery or immunomodulating therapy. Intestinal granulomas in the setting of CD may be helpful in determining phenotypic subtypes of CD, but is unhelpful in predicting disease severity. Smoking impairs the formation of granulomas in CD.
Publisher: BMJ
Date: 02-2004
Abstract: The role of Helicobacter pylori eradication in the management of gastro-oesophageal reflux disease (GORD) is controversial. We hypothesised that H pylori eradication leads to worsened control of reflux disease. Consecutive patients with weekly reflux symptoms were prospectively recruited for endoscopy and symptom evaluation. Patients were enrolled if they had H pylori infection and required long term acid suppressants. Eligible patients were randomly assigned to omeprazole triple therapy (HpE group) or omeprazole with placebo antibiotics (Hp+ group) for one week. Omeprazole 20 mg daily was given for eight weeks for healing of oesophagitis and symptom relief. This was followed by a maintenance dose of 10 mg daily for up to 12 months. The primary study end point was the probability of treatment failure within 12 months, which was defined as either incomplete resolution of symptoms or oesophagitis at the initial treatment phase, or relapse of symptoms and oesophagitis during the maintenance phase. Predictors of treatment failure were determined by Cox's proportional hazards model. A total of 236 GORD patients were screened and 113 (47.9%) were positive for H pylori 104 (92%) patients were included in the intention to treat analysis (53 in the HpE group and 51 in the Hp+ group). Thirty one patients (30%) had erosive oesophagitis at baseline. H pylori was eradicated in 98% of the HpE group and in 3.9% of the Hp+ group. Overall, 15 patients (28.3%) in the HpE group and eight patients (15.7%) in the Hp+ group had treatment failure. The 12 month probability of treatment failure was 43.2% (95% confidence interval (CI) 29.9-56.5%) in the HpE group and 21.1% (95% CI 9.9-32.3%) in the Hp+ group (log rank test, p = 0.043). In the Cox proportional hazards model, after adjustment for the covariates age, sex, erosive oesophagitis, hiatus hernia, degree of gastritis, and severity of symptoms at baseline, H pylori eradication was the only predictor of treatment failure (adjusted hazard ratio 2.47 (95% CI 1.05-5.85)). H pylori eradication leads to more resilient GORD.
Publisher: Wiley
Date: 26-09-2005
Publisher: Oxford University Press (OUP)
Date: 16-11-2010
Abstract: Colon carcinogenesis represents a stepwise progression from benign polyps to invasive adenocarcinomas and distant metastasis. It is believed that these pathologic changes are contributed by aberrant activation or inactivation of protein-coding proto-oncogenes and tumor suppressor genes. However, recent discoveries in microRNA (miRNA) research have reshaped our understanding of the role of non-protein-coding genes in carcinogenesis. In this regard, a remarkable number of miRNAs exhibit differential expression in colon cancer tissues. These miRNAs alter cell proliferation, apoptosis and metastasis through their interactions with intracellular signaling networks. From a clinical perspective, polymorphisms within miRNA-binding sites are associated with the risk for colon cancer, whereas miRNAs isolated from feces or blood may serve as biomarkers for early diagnosis. Altered expression of miRNA or polymorphisms in miRNA-related genes have also been shown to correlate with patient survival or treatment outcome. With further insights into miRNA dysregulation in colon cancer and the advancement of RNA delivery technology, it is anticipated that novel miRNA-based therapeutics will emerge.
Publisher: Elsevier BV
Date: 18-11-2006
DOI: 10.1016/J.CANLET.2005.11.039
Abstract: Peroxisome proliferator-activated receptor gamma (PPARgamma) ligands have been shown to inhibit angiogenesis. We showed that treatment with 15d-PGJ(2), a PPARgamma ligand, downregulate the expressions of angiopoietin-1 (Ang-1) in gastric cancer cells MKN45. The medium of MKN45 cells treated with 15d-PGJ(2) significantly inhibited the migration and tube formation of human umbilical vein endothelial cells (HUVECs). Moreover, Matrigel plug assay revealed that 15d-PGJ(2) reduced in vivo angiogenesis induced by MKN45 cells. These modulations were restored by the addition of recombinant Ang-1. Our findings supported that 15d-PGJ(2) suppressed angiogenesis of gastric cancer cells by downregulation of Ang-1.
Publisher: Elsevier BV
Date: 04-2011
DOI: 10.1016/J.LFS.2011.02.016
Abstract: Nuclear factor-kappa B inhibitor alpha (IκBα) polymorphisms were found to be associated with inflammatory diseases. However, the association between IκBα polymorphisms with gastric cancer is still unknown. We aim to investigate the association between IκBα polymorphisms and gastric cancer risk in a large population-based case-control study among southern Chinese. A population-based case-control study was conducted between 1999 and 2006 in Guangdong Province, China. A total of 1010 gastric cancer patients and 1500 healthy controls were enrolled in this study. IκBα polymorphisms were identified by sequencing of IκBα gene ranging from the 2kb promoter region to the 3.5kb genomic region. Polymorphisms in IκBα were analyzed by TaqMan SNP genotyping assay. rs17103265 deletion homozygote (-/-) had significantly increased gastric cancer risk (OR=2.11, 95% CI=1.17-3.83, P=0.01), compared with rs17103265 T homozygote (TT). rs17103265 (-/-) genotype was significantly associated with increased risk of intestinal-type gastric cancer with (OR=2.21, 95% CI=1.19-4.08, P=0.01), but not with the diffuse or mix type of gastric cancer. rs17103265 (-/-) was associated with poorly differentiated gastric cancer (OR=2.05, 95% CI=1.07-3.94, P=0.03), but not with moderately or well differentiated gastric cancer. A significant decrease in luciferase activity was observed in rs17103265 deletion allele as compared with the vector containing the rs17103265 T allele (P<0.0001). rs17103265 polymorphism was not associated with the prognosis of gastric cancer patients. IκBα rs17103265 deletion homozygote is a novel genetic risk factor for gastric carcinogenesis, especially for the development of certain subtypes of gastric cancer in southern Chinese population.
Publisher: Elsevier BV
Date: 12-2013
DOI: 10.1016/J.SEMCANCER.2013.09.005
Abstract: Colorectal cancer is a leading cause of morbidity and mortality worldwide. Understanding its genetic mechanisms is key to improving risk prediction, prognostication and treatment. Results from genome-wide association studies have engendered a growing list of colorectal cancer susceptibility genes whereas the application of genome-wide mutational analysis has enabled the depiction of mutational landscape of colorectal cancer at high resolution. The development of novel technologies, such as metagenomic and single-cell sequencing, is expected to have positive impact on future genetic studies. However, challenges remain to address the changing epidemiology of colorectal cancer, issues on genetic testing, and clinical utilization of genomic data.
Publisher: BMJ
Date: 25-07-2023
DOI: 10.1136/GUTJNL-2023-330291
Abstract: Roseburia intestinalis is a probiotic species that can suppress intestinal inflammation by producing metabolites. We aimed to study the role of R. intestinalis in colorectal tumourigenesis and immunotherapy. R. intestinalis abundance was evaluated in stools of patients with colorectal cancer (CRC) (n=444) and healthy controls (n=575). The effects of R. intestinalis were studied in Apc Min/+ or azoxymethane (AOM)-induced CRC mouse models, and in syngeneic mouse xenograft models of CT26 (microsatellite instability (MSI)-low) or MC38 (MSI-high). The change of immune landscape was evaluated by multicolour flow cytometry and immunohistochemistry staining. Metabolites were profiled by metabolomic profiling. R. intestinalis was significantly depleted in stools of patients with CRC compared with healthy controls. R. intestinalis administration significantly inhibited tumour formation in Apc Min/+ mice, which was confirmed in mice with AOM-induced CRC. R. intestinalis restored gut barrier function as indicated by improved intestinal permeability and enhanced expression of tight junction proteins. Butyrate was identified as the functional metabolite generated by R. intestinalis. R. intestinalis or butyrate suppressed tumour growth by inducing cytotoxic granzyme B + , interferon (IFN)-γ + and tumour necrosis factor (TNF)-α + CD8 + T cells in orthotopic mouse models of MC38 or CT26. R. intestinalis or butyrate also significantly improved antiprogrammed cell death protein 1 (anti-PD-1) efficacy in mice bearing MSI-low CT26 tumours. Mechanistically, butyrate directly bound to toll-like receptor 5 (TLR5) receptor on CD8 + T cells to induce its activity through activating nuclear factor kappa B (NF-κB) signalling. R. intestinalis protects against colorectal tumourigenesis by producing butyrate, which could also improve anti-PD-1 efficacy by inducing functional CD8 + T cells. R. intestinalis is a potential adjuvant to augment anti-PD-1 efficacy against CRC.
Publisher: American Society for Microbiology
Date: 15-09-2006
DOI: 10.1128/JVI.00649-06
Abstract: Estimates of seropositivity to a new infectious agent in a community are useful to public health. For severe acute respiratory syndrome (SARS), the figures are conflicting. Herein, we screened 12,000 people in a community stricken by SARS 10 months previously and found 53 in iduals (0.44%) who had immunoglobulin G antibodies to the SARS coronavirus (SARS-CoV) nucleocapsid (N) produced in bacteria. However, only seven of these (group 1) had sera which also reacted with the native N antigen expressed in SARS-CoV-infected Vero cells, N-transfected 293T cells, and tissues of infected SARS patients. Of these, six in iduals had had SARS previously. The remaining person, as well as the 46 other in iduals (group 2), were healthy and had no history of SARS. Group 1 antibodies recognized epitopes located slightly differently in N from those of group 2 antibodies, and a mouse hybridoma antibody resembling the former type was generated. Unusually, group 2 antibodies appeared to recognize cross-reactive bacterial epitopes that presumably were posttranslationally modified in eukaryotes and hence were probably not induced by SARS-CoV or related coronaviruses but rather by bacteria. The N antigen is thus highly unique. The extremely low rate (0.008%) of asymptomatic SARS infection found attests to the high virulence of the SARS-CoV virus.
Publisher: Elsevier BV
Date: 09-2010
DOI: 10.1016/J.CANLET.2010.03.015
Abstract: The use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with lower risks for esophageal, gastric and colon cancers as well as other solid tumors. The antitumor effect of NSAIDs is mediated through cyclooxygenase-2 (COX-2)-dependent and -independent regulation of oncogenic and tumor-suppressive pathways. Recent discoveries have shed new light on the regulation of COX-2 at the molecular level in these cancers. Moreover, prostaglandin E(2) (PGE(2)), a COX-2-derived eicosanoid, has been found to affect numerous tumorigenic processes. In this connection, PGE(2) activates multiple intracellular signaling pathways, including (1) transactivation of epidermal growth factor receptor (EGFR) (2) protein kinase C-dependent, EGFR-independent activation of extracellular signal-regulated kinase (ERK) and the transcription factors activator protein-1 and c-Myc (3) G-protein-mediated activation of beta-catenin/TCF-dependent transcription. Activation of these signaling pathways by PGE(2) is mediated by EP receptors whose inhibitors suppress gastrointestinal carcinogenesis. Taken together, COX-2 expression is dysregulated in many types of cancer and COX-2-derived PGE(2) elicits multiple oncogenic signals to promote carcinogenesis. Targeting PGE(2) signaling by EP receptor antagonists holds promise for the development of targeted therapy for the treatment of cancer.
Publisher: Elsevier BV
Date: 11-2003
Publisher: Wiley
Date: 25-01-2011
DOI: 10.1002/MC.20718
Abstract: A recent genome-wide study identified a strong association between polymorphisms in the prostate stem cell antigen (PSCA) gene and the risk of diffuse-type of gastric cancer in Japanese and Korean population. In this case-control study, we aimed to investigate the possible association between PSCA rs2294008 C/T with clinicopathological features and the prognosis of gastric cancer in a Southern Chinese population. Genotypes of 460 gastric cancer patients and 549 controls were determined by PCR-restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing. We found that in iduals with at least one copy of the rs2294008T allele (CT or TT genotype) had an increased risk for gastric cancer compared with CC genotype (OR = 1.42, 95% CI = 1.10-1.82, P = 0.006). Further stratification analyses indicated that the effect of PSCA rs2294008T carriers was noteworthy in intestinal type (OR = 1.55, 95% CI = 1.18-2.04, P = 0.002), poorly differentiated (OR = 1.59, 95% CI = 1.19-2.13, P = 0.002), noncardia (OR = 1.55, 95% CI = 1.17-2.04, P = 0.002) subtypes of gastric cancer. Cox proportional hazards analyses demonstrated that TT genotype (HR = 2.12, 95% CI = 1.22-3.69, P = 0.008) as well as TNM staging were prognostic factors of gastric cancer patients. In conclusion, The T allele of PSCA rs2294008 is associated with increased risk of gastric cancer, especially intestinal type, poorly differentiated, early onset, and noncardia gastric cancer in Chinese population. TNM staging and TT genotype might be involved in the prognosis of gastric cancer patients.
Publisher: BMJ
Date: 12-09-2014
DOI: 10.1136/GUTJNL-2014-307410
Abstract: The rising incidence of inflammatory bowel disease in Asia supports the importance of environmental risk factors in disease aetiology. This prospective population-based case-control study in Asia-Pacific examined risk factors prior to patients developing IBD. 442 incident cases (186 Crohn's disease (CD) 256 UC 374 Asians) diagnosed between 2011 and 2013 from eight countries in Asia and Australia and 940 controls (frequency-matched by sex, age and geographical location 789 Asians) completed an environmental factor questionnaire at diagnosis. Unconditional logistic regression models were used to estimate adjusted ORs (aOR) and 95% CIs. In multivariate model, being breast fed >12 months (aOR 0.10 95% CI 0.04 to 0.30), antibiotic use (aOR 0.19 0.07 to 0.52), having dogs (aOR 0.54 0.35 to 0.83), daily tea consumption (aOR 0.62 0.43 to 0.91) and daily physical activity (aOR 0.58 0.35 to 0.96) decreased the odds for CD in Asians. In UC, being breast fed >12 months (aOR 0.16 0.08 to 0.31), antibiotic use (aOR 0.48 0.27 to 0.87), daily tea (aOR 0.63 0.46 to 0.86) or coffee consumption (aOR 0.51 0.36 to 0.72), presence of hot water tap (aOR 0.65 0.46 to 0.91) and flush toilet in childhood (aOR 0.71 0.51 to 0.98) were protective for UC development whereas ex-smoking (aOR 2.02 1.22 to 3.35) increased the risk of UC. This first population-based study of IBD risk factors in Asia-Pacific supports the importance of childhood immunological, hygiene and dietary factors in the development of IBD, suggesting that markers of altered intestinal microbiota may modulate risk of IBD later in life.
Publisher: Oxford University Press (OUP)
Date: 25-01-2019
Publisher: Elsevier BV
Date: 2012
DOI: 10.1016/J.CCR.2011.12.016
Abstract: Tumorigenesis is caused by an uncontrolled cell cycle and the altered expression of many genes. Here, we report a gene CREPT that is preferentially expressed in erse human tumors. Overexpression of CREPT accelerates tumor growth, whereas depletion of CREPT demonstrates a reversed effect. CREPT regulates cyclin D1 expression by binding to its promoter, enhancing its transcription both in vivo and in vitro, and interacting with RNA polymerase II (RNAPII). Interestingly, CREPT promotes the formation of a chromatin loop and prevents RNAPII from reading through the 3' end termination site of the gene. Our findings reveal a mechanism where CREPT increases cyclin D1 transcription during tumorigenesis, through enhancing the recruitment of RNAPII to the promoter region, possibly, as well as chromatin looping.
Publisher: Oxford University Press (OUP)
Date: 15-04-2008
DOI: 10.1086/533477
Publisher: SAGE Publications
Date: 2020
Abstract: The association between the survival or efficacy of chemotherapy and the Lauren subtype of gastric cancer (GC) remains unclear. We aimed to clarify whether patients with different Lauren subtypes have different survival after treatment with systemic chemotherapy: intestinal gastric cancer (IGC) patients survived better than patients with mixed type gastric cancer (MGC) or diffuse gastric cancer (DGC) after treatment with systemic chemotherapy. Relevant studies for the meta-analysis were identified through searching Pubmed, Embase, Cochrane and Ovid up to March 2020. We also included our own prospectively collected cohort of patients that were followed over a 10-year period. Sub-group and sensitivity analyses were also performed. In our prospective cohort, the overall survival (OS) of IGC patients receiving systemic chemotherapy (chemoIGC) [median OS 5.01 years, interquartile range (IQR) 2.63–6.71] was significantly higher than that of DGC patients receiving the same chemotherapy (chemoDGC) (median OS 1.33 years, IQR 0.78–3.33, p = 0.0001). After adjusting for age, gender and cancer stage, there was a significant difference in OS in patients treated with chemotherapy based on the Lauren classification of GC {hazard ratio (HR) for OS of the IGC versus DGC 0.33, [95% confidence interval (CI), 0.17–0.65 p 0.001]}. In the IGC patients, the adjusted HR associated with chemotherapy was 0.26 (95% CI, 0.12–0.56 p = 0.001), whereas the association was 0.64 (95% CI, 0.30–1.33 p = 0.23) in the DGC patient group. In our meta-analysis, 33 studies comprising 10,246 patients treated with systemic chemotherapy (chemoIGC n = 4888, chemoDGC n = 5358) met all the selection criteria. While we accounted for much of the heterogeneity in these studies, we found that chemoIGC patients showed significantly improved OS [HR, 0.76 (95% CI, 0.71–0.82) p 0.00001] when compared with similarly treated chemoDGC patients. Our results support the consideration of Lauren subtype when prescribing systemic chemotherapy for GC, particularly for MGC or DGC, which may not benefit from chemotherapy. Lauren classification should be considered to stratify chemotherapy regimens to GC patients in future clinical trials, with particular relevance to MGC or DGC, which is more difficult to treat with current regimens.
Publisher: BMJ
Date: 02-2004
Abstract: Overexpression of cyclooxygenase 2 (COX-2) is frequently detected in gastric cancer and is believed to play a crucial role in gastric carcinogenesis. We examined the chemopreventive effect of a COX-2 inhibitor in an animal model of stomach carcinogenesis. Eighty six male Wistar rats were ided into six different treatment groups: group A, water alone (n = 5) group B, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG 100 micro g/ml) (n = 16) group C, indomethacin (3 mg/kg/day) (n = 16) group D, celecoxib (5 mg/kg/day) (n = 17) group E, celecoxib (10 mg/kg/day) (n = 16) and group F, celecoxib (20 mg/kg/day) (n = 16). Group B-F animals were treated with 10% sodium chloride (in the initial six weeks) and MNNG in drinking water to induce adenocarcinoma in the stomach. All animals received treatment for 40 weeks, and were sacrificed after death or at 48 weeks. Gastric neoplasm was evaluated by histology. The incidences of gastric cancer were 0% in group A, 75% in group B, 68.8% in group C, 70.6% in group D, 18.8% in group E, and 31.3% in group F (p = 0.002, ANOVA). Compared with MNNG controls, treatment with celecoxib 10 mg/kg/day also showed lower tumour multiplicity (0.19 (0.40) v 1.00 (0.73) p = 0.004) and lower mean tumour volume (2.4 v 2805 mm(3) p = 0.02). Although tumours had significantly higher COX-2 expression than their adjacent normal tissues (p<0.02), there was no significant difference in COX-2 levels among tumours in the different treatment groups. The lowest tumour prostaglandin E(2) level was found in the indomethacin treated group, suggesting that the chemopreventive effect of celecoxib may be mediated by a COX independent pathway. While treatment with indomethacin had no significant effect on tumour development, treatment with celecoxib reduced gastric cancer incidence and growth in rats.
Publisher: Springer Science and Business Media LLC
Date: 03-2011
DOI: 10.1038/BJC.2011.57
Publisher: Microbiology Society
Date: 07-2005
Abstract: An outbreak of severe acute respiratory syndrome (SARS) occurred in China and the first case emerged in mid-November 2002. The aetiological agent of this disease was found to be a previously unknown coronavirus, SARS-associated coronavirus (SARS-CoV). The detailed pathology of SARS-CoV infection and the host response to the viral infection are still not known. The 3a gene encodes a non-structural viral protein, which is predicted to be a transmembrane protein. In this study, it was shown that the 3a protein was expressed in the lungs and intestinal tissues of SARS patients and that the protein localized to the endoplasmic reticulum in 3a -transfected monkey kidney Vero E6 cells. In vitro experiments of chromatin condensation and DNA fragmentation suggested that the 3a protein may trigger apoptosis. These data showed that overexpression of a single SARS-CoV protein can induce apoptosis in vitro .
Publisher: BMJ
Date: 05-2005
Publisher: Elsevier BV
Date: 09-2010
DOI: 10.1016/J.CANLET.2010.04.025
Abstract: The pathogenesis of gastric cancer is complex and related to multiple factors. Dysregulation of intracellular signaling pathways represents a common pathogenic mechanism and may be amenable to drug targeting. Multiple well-established oncogenic pathways, such as those mediated by cell cycle regulators, nuclear factor-kappaB, cyclooxygenase-2 and epidermal growth factor receptor are implicated in gastric carcinogenesis. Emerging evidence also underscores the importance of signaling pathways involved in the developmental process, including transforming growth factor-beta/bone morphogenetic protein signaling, Wnt/beta-catenin signaling, Hedgehog signaling and Notch signaling. Understanding their biological significance will provide a rational basis for drug development. Their relative importance and cross-talk in gastric carcinogenesis, however, are still not completely understood and warrant further investigation.
Publisher: Wiley
Date: 10-11-2009
DOI: 10.1002/IJC.25027
Abstract: Chronic inflammation is the hallmark of the pathogenesis of Helicobacter pylori-induced gastric cancer. Interleukin (IL)-17A and IL-17F are inflammatory cytokines expressed by a novel subset of CD4+ Th cells and play critical function in inflammation and probably in cancer. We conducted a case-control study including 1,010 gastric cancer patients and 800 healthy controls to assess the association between IL-17A G197A and IL-17F A7488G polymorphisms and risk of gastric cancer. Genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing. Logistic regression and Cox-proportional hazards analyses were used to evaluate the associations between polymorphisms and gastric cancer susceptibility, clinicopathological features and survival. After adjusted for age and gender, IL-17F 7488GA and GG genotypes were associated with an increased risk of gastric cancer compared with AA genotype [OR 1.51, 95% confidence interval (CI): 1.22-1.87 for GA OR 1.61, 95% CI: 1.03-2.51 for GG]. Further stratification analyses indicated that the effect of IL-17F 7488GA genotype was noteworthy in gastric cancer patients of noncardia, intestinal type, poorly and moderately differentiated, age older than 40, large tumor size and lymph node metastasis. IL-17A 197AG genotype was associated with increased risk of poorly differentiated, TNM I/II, age of 40-65-year subtypes of gastric cancer, but not with total gastric cancer risk (p = 0.098). No significant relationship was observed between polymorphisms and survival of gastric cancer patients. These findings suggest that polymorphism of IL-17F 7488 involved in susceptibility to gastric cancer, which also influenced certain subtypes according to clinicopathological features, whereas IL-17A 197 may be less relevant.
Publisher: Springer Science and Business Media LLC
Date: 04-2012
DOI: 10.1038/BJC.2012.130
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2005
DOI: 10.1111/J.1572-0241.2005.41465.X
Abstract: Upper gastrointestinal (GI) symptoms are common in patients using non-steroidal antiinflammatory drugs (NSAIDs) including selective cyclooxygenase (COX)-2 inhibitors and may be acid related. We therefore assessed esomeprazole treatment for upper GI symptoms in these patients. A total of 794 and 848 continuous NSAID users, free of gastroduodenal ulcers, erosive esophagitis, and Helicobacter pylori, were enrolled into two identical, multinational, multicenter double-blind studies (NASA1, SPACE1). Moreover, 608 and 556 patients were randomized to receive 4 wk esomeprazole 20 mg, or 40 mg, or placebo once daily. The primary variable was the patient-reported change in the upper GI symptom (pain, discomfort, or burning in the upper abdomen) score on a 7-graded severity scale (0-6) from the 7 days prior to treatment to the last 7 days in the study. Esomeprazole was associated with highly significant symptom improvement compared to placebo. Symptom improvements were 2.30 mean [SD 1.63] on esomeprazole 20 mg and 2.03 [1.56] on esomeprazole 40 mg versus 1.64 [1.57] on placebo in NASA1 and 2.17 [1.34] and 2.12 [1.48]versus 1.56 [1.26], respectively, in SPACE1 (all placebo comparisons at least p < 0.001). Esomeprazole-improved symptoms in patients taking selective COX-2 inhibitors, with changes of 2.21 [1.46] and 1.92 [1.38]versus 1.64 [1.46] in NASA1 and 2.20 [1.26] and 2.24 [1.62]versus 1.58 [1.37] in SPACE1 (all placebo comparisons at least p < 0.05), as well as those on non-selective NSAIDs. Esomeprazole was well tolerated and associated with significant improvements in HRQL. Esomeprazole 20 mg and 40 mg improve upper GI symptoms associated with continuous, daily NSAID therapy, including selective COX-2 inhibitors.
Publisher: Wiley
Date: 20-05-2003
DOI: 10.1002/MC.10124
Abstract: Helicase-like transcription factor (HLTF), a member of the SWI/SNF (mating type switching/sucrose nonfermenting) chromatin-remodeling complex, is recently found to be inactivated by promoter hypermethylation in human colorectal cancer. However, the role of this putative tumor suppressor gene in other tumors has not been determined. We evaluated the role of HLTF promoter hypermethylation in gastric cancer. Expression of HLTF was examined by reverse-transcription (RT)-polymerase chain reaction (PCR), and promoter hypermethylation in HLTF was determined by methylation-specific PCR. Bisulfite DNA sequencing was performed to determine the detailed methylation profiles of the promoter region. HLTF expression was lost in two of five gastric cell lines and in 13 (28%) of 46 primary gastric cancers. Accordingly, promoter hypermethylation was detected in the two cell lines and in nine of 13 gastric cancer s les. Of the ten normal gastric specimens and ten paired adjacent nonneoplastic tissues, methylation was detected in only one adjacent nonneoplastic tissue. Bisulfite DNA sequencing of the promoter region of HLTF showed that the CpG island was densely methylated in cell lines and cancer s les this also appeared to correlate with expression level. Treatment of gastric cell lines that lacked HLTF expression with the demethylating agent 5-azacytidine (5-azaDC) restored HLTF expression. These results suggest that HLTF promoter hypermethylation is frequently demonstrated in human gastric cancer, and inactivation of HLTF or the chromatin-remodeling complex may play a crucial role in gastric carcinogenesis.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 21-12-2007
DOI: 10.1002/HEP.22039
Abstract: Hepatic oxidative stress plays a critical role in metabolic forms of steatohepatitis. Phyllanthus urinaria, an herbal medicine, has been reported to have potential antioxidant properties. We tested the effects of P. urinaria on nutritional steatohepatitis both in vitro and in vivo. Immortalized normal hepatocytes (AML-12) or primary hepatocytes were exposed to control, the methionine-and-choline-deficient (MCD) culture medium, in the presence or absence of P. urinaria for 24 hours. Hepatocyte triglyceride, release of alanine aminotransferase, lipoperoxides, and reactive oxygen species production were determined. Age-matched C57BL/6 and db/db mice were fed control or MCD diet for 10 days with or without P. urinaria. Hepatic steatosis, necroinflammation, triglycerides, and lipid peroxide levels were determined. Hepatic expression of inflammatory factors and lipid regulatory mediators were assayed. P. urinaria reduced steatosis and alanine aminotransferase (ALT) levels in culture of hepatocytes in a dose-dependent manner. Phyllanthus prevented MCD-induced hepatic fat accumulation and steatohepatitis in mice. This effect was associated with repressed levels of hepatic lipid peroxides, reduced expression of cytochrome P450-2E1, pro-inflammatory tumor necrosis factor alpha, interleukin-6, d ened activation of inflammatory c-Jun N-terminal kinase (JNK) and nuclear factor kappa B (NF-kappaB), increased expression of lipolytic cytochrome P450 (Cyp4a10), and suppressed transcriptional activity of lipogenic CCAAT/enhancer binding protein beta (C/EBPbeta). Hepatic acyl co-enzyme A oxidase that regulated hepatic beta-oxidation of fatty acid and other lipid regulators were not affected by P. urinaria. In conclusion, P. urinaria effectively alleviated the steatohepatitis induced by the MCD, probably through d ening oxidative stress, ameliorating inflammation, and decreasing lipid accumulation.
Publisher: SAGE Publications
Date: 16-02-2023
DOI: 10.1177/09562478221149915
Abstract: Citywide inclusive sanitation (CWIS) is becoming the dominant paradigm for achieving safe sanitation for all by 2030. Its technical benefits have been explored, but the bargaining over financial and organizational changes CWIS entails have not yet been adequately addressed. Our case study explains the stalled rollout of CWIS in Dhaka, Bangladesh. We analyse policy pathways over the past 30 years through a combined territorial political economy and power perspective to understand their effects on equality. We highlight how donors link the introduction of CWIS to the organization of sanitation through a market how the utility uses CWIS as an opportunity to avoid costly responsibilities in non-sewered sanitation and how service co-production through community-based solutions is neglected. CWIS has successfully overcome the dogmatic technological focus in the sanitation system, but for citywide sanitation to be scaled inclusively, the dogmatic focus in the organization and financing of the sanitation sector must also be overcome.
Publisher: Georg Thieme Verlag KG
Date: 30-08-2010
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2010
DOI: 10.1038/AJG.2009.644
Abstract: The association of interleukin-1B (IL-1B)-511 polymorphism with gastric cancer is still controversial, and the association of IL-1B-511 polymorphism with subtypes of gastric cancer is still largely unknown. We investigated whether the association between IL-1B-511 polymorphism and gastric cancer risk varies by clinically important tumor characteristics and the prognostic value of this polymorphism in a large population-based case-control study among Chinese. A population-based case-control study was conducted between 1999 and 2006 in Guangdong Province, China. A total of 1,010 gastric cancer patients and 1,500 healthy controls were enrolled in this study. Polymorphism in IL-1B-511 was analyzed by PCR-restriction fragment length polymorphism on 501 gastric cancers and 500 healthy controls. Compared with the CC genotype, carriers of IL-1B-511 TT genotype had an increased gastric cancer risk (odds ratio (OR)=1.97, 95% confidence interval (CI)=1.29-3.01, P=0.0016). TT genotype was significantly associated with intestinal type of gastric cancer (OR=3.16, 95% CI=1.74-5.71, P=0.0001) but not with diffuse or mixed-type gastric cancer. The test for OR heterogeneity between the intestinal-type and non-intestinal-type gastric cancers was statistically significant (P=0.02). In subgroup analyses, TT genotype was found to be associated with poorly differentiated gastric cancer (OR=3.31, 95% CI=1.43-3.60, P<0.0001), but not with moderately or well-differentiated gastric cancer. IL-1B-511 genotypes were not associated with the prognosis of gastric cancer patients. IL-1B polymorphism influences certain subtypes of gastric cancer according to the clinical and pathological features. Understanding the etiologic heterogeneity of gastric cancer may result in improvements in controlling this disorder.
Publisher: Elsevier BV
Date: 09-2020
Publisher: Wiley
Date: 02-2016
DOI: 10.1002/CNCR.29865
Publisher: Springer Science and Business Media LLC
Date: 23-01-2004
Publisher: Elsevier BV
Date: 04-2003
Publisher: Wiley
Date: 06-2003
DOI: 10.1046/J.1365-2036.2003.01607.X
Abstract: Crohn's disease affects people world-wide, but the incidence in Asia is lower than in Western countries. This difference may be due to genetic and/or environmental factors. Three single nucleotide polymorphisms (SNPs) of the NOD2/CARD15 gene have been identified to be independently associated with the development of Crohn's disease in Caucasians. Whether these SNPs are involved in the pathogenesis of Crohn's disease in the Chinese population is unknown. To determine if NOD2/CARD15 gene polymorphisms are found in Chinese patients with Crohn's disease. Sixty-five consecutive Chinese Crohn's disease patients had genotyping performed using sequence-specific PCR directed against the wild-type and the Arg702Trp, Gly908Arg and 3020insC variants of the NOD2/CARD15 gene. Controls consisted of 63 patients with ulcerative colitis and 70 patients with dyspepsia. None of the patients with Crohn's disease had heterozygous or homozygous SNP variants. Similarly none of the ulcerative colitis or dyspeptic controls had these SNPs. The three previously described SNPs associated with the development of Crohn's disease in Caucasians are not found in Chinese patients with Crohn's disease.
Publisher: The American Association of Immunologists
Date: 15-02-2016
Abstract: The antimicrobial peptide cathelicidin is critical for protection against different kinds of microbial infection. This study sought to elucidate the protective action of cathelicidin against Helicobacter pylori infection and its associated gastritis. Exogenous cathelicidin was found to inhibit H. pylori growth, destroy the bacteria biofilm, and induce morphological alterations in H. pylori membrane. Additionally, knockdown of endogenous cathelicidin in human gastric epithelial HFE-145 cells markedly increased the intracellular survival of H. pylori. Consistently, cathelicidin knockout mice exhibited stronger H. pylori colonization, higher expression of proinflammatory cytokines IL-6, IL-1β, and ICAM1, and lower expression of the anti-inflammatory cytokine IL-10 in the gastric mucosa upon H. pylori infection. In wild-type mice, H. pylori infection also stimulated gastric epithelium-derived cathelicidin production. Importantly, pretreatment with bioengineered Lactococcus lactis that actively secretes cathelicidin significantly increased mucosal cathelicidin levels and reduced H. pylori infection and the associated inflammation. Moreover, cathelicidin strengthened the barrier function of gastric mucosa by stimulating mucus synthesis. Collectively, these findings indicate that cathelicidin plays a significant role as a potential natural antibiotic for H. pylori clearance and a therapeutic agent for chronic gastritis.
Publisher: Elsevier BV
Date: 12-2001
DOI: 10.1016/S0024-3205(01)01422-9
Abstract: Wnt signaling pathway is important for development and carcinogenesis. Alterations of this pathway, such as mutations in adenomatous polyposis coli (APC) gene and activation mutations of beta-catenin, would result in stabilization of beta-catenin and subsequent translocation to nucleus where genes are transcribed. Recently, a receptor of Wnt, FzE3 was found to be up-regulated in esophageal carcinoma while a non-receptor antagonist of Wnt, secreted frizzled related protein (hsFRP) was found to be down-regulated in some cancer. These findings suggested that FzE3 is a potential oncogene while hsFRP is a potential tumor suppressor gene. We aimed to investigate whether FzE3 and hsFRP were altered in gastric cancer. Twelve cases of gastric cancer, including 7 cases of intestinal type, 4 cases of diffuse type and I case of mixed type, were studied. FzE3 and hsFRP mRNAs were expressed in most of the paired normal gastric tissues. FzE3 was over-expressed in 9 cases (75%) of gastric carcinoma tissues while hsFRP was down-regulated in 2 cases (16%). Beta-catenin nuclear staining was identified in 3 cases (27%) and cyclin D1 was expressed in 5 cases (41%) of cancer s les. All these cases were associated with either up-regulation of FzE3 or down-regulation of hsFRP. Our results suggested that alterations of FzE3 or hsFRP were frequent in gastric cancer. These provide alternative mechanisms leading to activation of Wnt signaling pathway in gastric carcinogenesis.
Publisher: Ivyspring International Publisher
Date: 2018
DOI: 10.7150/THNO.22010
Publisher: BMJ
Date: 03-2004
Abstract: Although peroxisome proliferator activated receptor gamma (PPARgamma) agonists have been implicated in differentiation and growth inhibition of cancer cells, the potential therapeutic and chemopreventive effects on gastric cancer are poorly defined. We examined the in vitro and in vivo effects of PPARgamma ligands on growth of gastric cancer, and the effect of PPARgamma activation on expression of cyclooxygenase 2 (COX-2) and cancer related genes. Gastric cell lines (MKN28 and MKN45) were treated with two specific PPARgamma ligands: ciglitazone and 15-deoxy-Delta(12,)(14)-prostaglandin J(2). Cell growth was determined by bromodeoxyuridine incorporation assay and apoptosis was measured by DNA fragmentation. Expression of COX-2 was determined by western blot and real time quantitative polymerase chain reaction (PCR). Expression profiles of cancer related genes were screened with cDNA array. In vivo growth of implanted MKN45 cells in nude mice was monitored after oral treatment with rosiglitazone. PPARgamma ligands suppressed the in vitro growth of MKN45 cells in a dose dependent manner whereas prostacyclin, a PPARdelta agonist, had no growth inhibitory effect. Growth inhibition was more pronounced in MKN45 cells, which was accompanied by DNA fragmentation and downregulation of COX-2. Screening by cDNA microarray showed that PPARgamma ligand treatment was associated with upregulation of bad and p53, and downregulation of bcl-2, bcl-xl, and cyclin E1 in MKN45 cells, which was confirmed by quantitative real time PCR. In contrast, MKN28 cells with lower PPARgamma and COX-2 expression levels had lower growth inhibitory responses to PPARgamma ligands. Microarray experiments only showed induction of the bad gene in MKN28 cells. In vivo growth of MKN45 cells in nude mice was retarded by rosiglitazone. Mean tumour volume in rosiglitazone treated mice was significantly lower than controls at six weeks (p = 0.019) and seven weeks (p = 0.001) after treatment. PPARgamma ligands suppress both in vitro and in vivo growth of gastric cancer and may play a major role in cancer therapy and prevention.
Publisher: Elsevier BV
Date: 10-2020
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-05-2014
Publisher: Wiley
Date: 27-09-2001
DOI: 10.1046/J.1365-2036.2001.01057.X
Abstract: Imbalance between apoptosis and proliferation may be one of the mechanisms underlying H. pylori associated gastric carcinogenesis. To examine the cell kinetics of gastric intestinal metaplasia and the effect of H. pylori eradication. Endoscopic gastric biopsies were obtained from 100 H. pylori-infected patients. Apoptosis was determined by triphosphate nick-end labelling (TUNEL) and apoptotic nuclei counting, whereas proliferation was assessed by Ki67 immunostaining. Gastric biopsies were repeated in a sub-group of intestinal metaplasia patients after H. pylori eradication. Antral apoptotic index was significantly lower in intestinal metaplasia than in non-intestinal metaplasia (0.19% vs. 0.51% P < 0.0001) whereas the level of proliferation was comparable (28% vs. 22%, P=0.15). Serial antral biopsies taken from 14 intestinal metaplasia patients before and 1 year after H. pylori eradication showed a significant drop in proliferation in both intestinal metaplasia (50% vs. 12%, P < 0.001) and non-intestinal metaplasia area (47% vs. 9%, P < 0.001). A similar fall in apoptosis was detected in non-metaplastic region (0.58% vs. 0.38%, P < 0.001) but not in intestinal metaplasia (0.24% vs. 0.27%, P=0.56), resulting in a significant increase in the apoptosis roliferation ratio (0.005-0.021 P=0.03). Dysregulation in apoptosis control of gastric intestinal metaplasia may contribute to gastric carcinogenesis, which may be retarded by clearance of H. pylori.
Publisher: Oxford University Press (OUP)
Date: 15-06-2005
DOI: 10.1086/430324
Abstract: We aimed to investigate the characteristics of hepatitis B virus (HBV) genotype C subgroups in Hong Kong and their relationship with HBV genotype C in other parts of Asia. Full-genome nucleotide sequences of 49 HBV genotype C isolates from Chinese patients with chronic hepatitis B were compared with the sequences of 69 HBV genotype C isolates and 12 non-genotype C isolates in the GenBank database. Phylogenetic analysis was performed to define the subgroups of HBV genotype C on the basis of >4% heterogeneity of the entire HBV genome. HBV in 80% of patients in Hong Kong belonged to a subgroup predominantly found in Southeast Asia (Vietnam, Thailand, Myanmar, and southern China) designated as HBV genotype "Cs," and HBV in the remaining 20% of patients belonged to another subgroup, predominantly found in the Far East (Korea, Japan, and northern China), designated as HBV genotype "Ce." Overall, the mean+/-SD nucleotide sequence difference between HBV genotype Cs and HBV genotype Ce was 4.2%+/-0.3%. When HBV genotype Cs and HBV genotype Ce were compared among patients in Hong Kong, HBV genotype Cs was associated with a higher tendency to develop basal core promoter mutations (80% vs. 50% P=.14), a higher prevalence of C at nucleotide 1858 (95% vs. 0% P<.001), and a lower prevalence of precore stop codon mutations (5% vs. 50% P=.002). HBV genotype C can be differentiated into 2 subgroups--namely, genotype Ce and genotype Cs--that have different epidemiological distributions and virological characteristics.
Publisher: Springer Science and Business Media LLC
Date: 09-09-2019
DOI: 10.1038/S41564-019-0541-3
Abstract: Emerging evidence implicates a role of the gut microbiota in colorectal cancer (CRC). Peptostreptococcus anaerobius (P. anaerobius) is an anaerobic bacterium selectively enriched in the faecal and mucosal microbiota from patients with CRC, but its causative role and molecular mechanism in promoting tumorigenesis remain unestablished. We demonstrate that P. anaerobius adheres to the CRC mucosa and accelerates CRC development in Apc
Publisher: Wiley
Date: 28-08-2013
DOI: 10.1002/IJC.28402
Publisher: Springer Science and Business Media LLC
Date: 08-04-2010
DOI: 10.1038/GT.2010.41
Abstract: Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a transcription factor that regulates lipid metabolism and inflammatory responses. Certain PPARgamma ligands improve nonalcoholic steatohepatitis (NASH). The role of PPARgamma itself in NASH remains poorly understood. The functional consequences of PPARgamma in the development of steatohepatitis through gene deficiency or gene overexpression of PPARgamma delivered by adenovirus (Ad-PPARgamma) were examined. Our results show that PPARgamma-deficient (PPARgamma(+/-)) mice fed the methionine- and choline-deficient (MCD) diet developed more severe steatohepatitis than wild-type mice, and were unaffected by PPARgamma ligand rosiglitazone. Overexpression of PPARgamma delivered by Ad-PPARgamma attenuated steatohepatitis. This effect was associated with redistribution of fatty acid from liver to adipose tissue by enhancing expression of fatty acid uptake genes (fatty acid binding protein-4 (aP2), fatty acid translocase (CD36), lipoprotein lipase (LPL) and fatty acid transport protein-1 (FATP-1)) and lipogenic genes (sterol regulatory element binding protein isoform-1 (SREBP-1) and stearoyl-CoA desaturase isoform-1 (SCD-1)) in adipose tissue and to a lesser extent in liver. The anti-steatohepatitis action of PPARgamma was also mediated via regulating adipokines through suppressing tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) and inducing adiponectin. Moreover, PPARgamma activation suppressed hepatic lipoperoxide and reduced hepatic pro-inflammatory cytokines (TNF-alpha and IL-6) production. In conclusion, PPARgamma is an important endogenous regulator and potential therapeutic target for nutritional steatohepatitis.
Publisher: Radiological Society of North America (RSNA)
Date: 06-2011
Abstract: To correlate spin-lattice relaxation time in the rotating frame (T1ρ) measurements with degree of liver fibrosis in a rat model. The protocols and procedures were approved by the local Animal Experimentation Ethics Committee. Liver fibrosis was induced with biliary duct ligation (BDL). Two studies, 1 month apart, were performed with a 3-T clinical imager. The first study involved longitudinal magnetic resonance (MR) imaging follow-up of BDL rats (n = 8) and control rats (n = 4) on days 8, 15, 21, and 29 after BDL. The second study involved MR imaging of another group of BDL and control rats (n = 5 for each) on days 24 and 38 after BDL. Hematoxylin-eosin and picrosirius red staining were performed in liver specimens from days 8, 15, 24, and 38 after BDL. Repeated-measures analysis of variance was used, and treatment groups were compared (Bonferroni adjustment). On day 8, there were proliferation of bile duct and inflammatory cell infiltration around portal triads. While there was overlap, BDL rats (n = 8) demonstrated higher mean liver T1ρ values than did control rats (n = 4) on day 8 (46.7 msec ± 2.9 [standard deviation] vs 44.7 msec ± 1.2, P = .4). On day 15, BDL rats demonstrated liver fibrosis with a background of inflammatory infiltration. On day 15, mean T1ρ values in BDL rats could be largely separated from those in control rats (52.6 msec ± 6.0 vs 43.8 msec ± 1.5, P = .02). On day 24, BDL rats had liver T1ρ values 23.5% higher than in control rats (n = 5 for each group, P = .0007). Histomorphometric analysis showed that collagen content increased after surgery from days 8 to 24 (n = 6 for each group, P .99). In this model, liver fibrosis was detected with T1ρ MR imaging the degree of fibrosis was correlated with degree of increase in T1ρ measurements. ookup/suppl/doi:10.1148/radiol.11101638/-/DC1.
No related grants have been discovered for Joseph J Y SUNG.