Key Laboratory of Gastroenterology and Hepatology

Shanghai, China

Key Laboratory of Gastroenterology and Hepatology

Shanghai, China

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Wang J.-L.,Shanghai JiaoTong University | Hu Y.,Shanghai JiaoTong University | Kong X.,Shanghai JiaoTong University | Wang Z.-H.,Shanghai JiaoTong University | And 5 more authors.
PLoS ONE | Year: 2013

Gastric cancer (GC) remains a major cause of morbidity and mortality worldwide and there is therefore a clear need to search for more sensitive early diagnostic biomarkers. We performed a systematic review of eight published miRNA profiling studies that compared GC tissues with adjacent noncancerous tissues. A miRNA ranking system was used that took the frequency of comparisons, direction of differential expression and total sample size into consideration. We identified five miRNAs that were most consistently reported to be upregulated (miR-21, miR-106b, miR-17, miR-18a and miR-20a) and two miRNAs that were downregulated (miR-378 and miR-638). Six of these were further validated in 32 paired sets of GC and adjacent noncancerous tissue samples using real-time PCR. MiR-21, miR-106b, miR-17, miR-18a and miR-20a were confirmed to be upregulatedin GC tissues, while the expression of miR-378 was decreased. Moreover, we found a significant association between expression levels of miR-21, miR-106b, miR-17, miR-18a and miR-20a and clinicopathological features of GC. These miRNAs may be used for diagnostic and/or prognostic biomarkers for GC and therefore warrant further investigation. © 2013 Wang et al.


Zhang W.,Shanghai JiaoTong University | Zhang W.,Key Laboratory of Gastroenterology and Hepatology | Chen Q.,Shanghai JiaoTong University | Chen Q.,Key Laboratory of Gastroenterology and Hepatology | And 9 more authors.
Gut | Year: 2015

Objective: To evaluate the efficacy and tolerability of replacing tetracycline with amoxicillin in bismuth quadruple therapy. Design: Subjects who were infected with Helicobacter pylori and naïve to treatment were randomly (1:1) assigned to receive a 14-day modified bismuth quadruple therapy: lansoprazole 30 mg, amoxicillin 1 g, bismuth potassium citrate 220 mg (elemental bismuth), twice a day with metronidazole 400 mg four times a day (metronidazole group) or clarithromycin 500 mg twice a day (clarithromycin group). Six weeks after treatment, H. pylori eradication was assessed by 13C-urea breath test. Antimicrobial susceptibility was assessed by the twofold agar dilution method. This was a non-inferiority trial. Results: Two hundred and fifteen subjects were randomised. Metronidazole and clarithromycin containing regimens achieved high cure rates: 94 of 97 (96.9%, 95% CI 93.5% to 100%) and 93 of 98 (94.9%, 95% CI 90.5% to 99.3%) by per-protocol and 88.9% (95% CI 83.0% to 94.8%) and 88.8% (95% CI 82.8% to 94.8%) by intention-to-treat, respectively. Amoxicillin, metronidazole and clarithromycin resistance rates were 1.5%, 45.5% and 26.5%, respectively. Only clarithromycin resistance reduced treatment success (eg, susceptible 98.6%, resistant 76.9%, p=0.001). Adverse events were more common in the metronidazole group. Conclusions: These results suggest that amoxicillin can substitute for tetracycline in modified 14 day bismuth quadruple therapy as first-line treatment and still overcome metronidazole resistance in areas with high prevalence of metronidazole and clarithromycin resistance. Using clarithromycin instead of metronidazole was only effective in the presence of susceptible strains. Trial registration number: NCT02175901. © 2015, BMJ Publishing Group. All rights reserved.


Li Y.-T.,Shanghai JiaoTong University | Li Y.-T.,Key Laboratory of Gastroenterology and Hepatology | Li Y.-T.,State Key Laboratory for Oncogenes and Related Genes | Cai H.-F.,Shanghai JiaoTong University | And 11 more authors.
Alimentary Pharmacology and Therapeutics | Year: 2016

Background Clostridium difficile infection is a major cause of nosocomial diarrhoea. Aim To evaluate long-term (≥90 days) efficacy and safety of faecal microbiota transplantation for C. difficile infection and explore the factors affecting the faecal microbiota transplantation outcomes. Methods MEDLINE, the Cochrane Library and EMBASE were searched and only observational studies that utilised faecal microbiota transplantation for C. difficile infection with long-term follow-up duration (≥90 days) were included. Primary cure rate, overall recurrence rate and early (<90 days) and late (≥90 days) recurrence rate were calculated. Results Eighteen observational studies with 611 patients were included. The primary cure rate was 91.2% (95% confidence interval, CI 86.7-94.8%). The overall recurrence rate was 5.5% (95% CI 2.2-10.3%). The early recurrence rate and late recurrence rate were 2.7% (95% CI 0.7-6.0%) and 1.7% (95% CI 0.4-4.2%) respectively. Most adverse events were expected, short-lived, self-limited and manageable. The association between faecal microbiota transplantation therapy and adverse events such as inflammatory bowel disease flare, infectious disease and autoimmune disease was a concern but remained insignificant. Old age (≥65 years) was identified as a risk factor for after faecal microbiota transplantation therapy. Upper gastrointestinal administration also results in less frequent primary cure. Conclusions Faecal microbiota transplantation seems to be a highly effective and robust therapy for recurrent C. difficile infection. However, more quality studies, such as randomised controlled trials and cohort studies with control groups, are needed to confirm its long-term efficacy and safety. © 2015 John Wiley & Sons Ltd.


Chen H.-M.,Shanghai JiaoTong University | Chen H.-M.,Key Laboratory of Gastroenterology and Hepatology | Chen H.-M.,Shanghai Institute of Digestive Disease | Yu Y.-N.,Shanghai JiaoTong University | And 23 more authors.
American Journal of Clinical Nutrition | Year: 2013

Background: Accumulating evidence indicates that diet is one of the most important environmental factors involved in the progression from advanced colorectal adenoma (A-CRA) to colorectal cancer. Objective: We evaluated the possible effects of dietary fiber on the fecal microbiota of patients with A-CRA. Design: Patients with a diagnosis of A-CRA by pathological examination were enrolled in the A-CRA group. Patients with no obvious abnormalities or histopathological changes were enrolled in the healthy control (HC) group. Dietary fiber intake was assessed in all patients. Short-chain fatty acids (SCFAs) in feces were detected by gas chromatography. The fecal microbiota community was analyzed by 454 pyrosequencing based on 16S ribosomal RNA. Results: Lower dietary fiber patterns and consistently lower SCFA production were observed in the A-CRA group (n = 344). Principal component analysis showed distinct differences in the fecal microbiota communities of the 2 groups. Clostridium, Roseburia, and Eubacterium spp. were significantly less prevalent in the A-CRA group (n = 47) than in the HC group (n = 47), whereas Enterococcus and Streptococcus spp. were more prevalent in the A-CRA group (n = 47) (all P<0.05). Butyrate and butyrate-producing bacteria were more prevalent in a subgroup of HC subjects with a high fiber intake than in those in both the low-fiber HC subgroup and the high-fiber A-CRA subgroup (all P<0.05). Conclusion: A high-fiber dietary pattern and subsequent consistent production of SCFAs and healthy gut microbiota are associated with a reduced risk of A-CRA. This trial was registered at www.chictr. org as ChiCTR-TRC-00000123. © 2013 American Society for Nutrition.


Hao Y.,Case Western Reserve University | Zhao S.,Case Western Reserve University | Zhao S.,Shanghai JiaoTong University | Zhao S.,Key Laboratory of Gastroenterology and Hepatology | Wang Z.,Case Western Reserve University
Toxicologic Pathology | Year: 2014

Phosphoinositide-3-kinase, catalytic, alpha polypeptide, which encodes the catalytic p110α subunit of phosphatidylinositol 3-kinase α, is the most frequently mutated oncogene in human cancers. Targeting mutant p110α holds great promise for cancer therapy. However, it is challenging to develop p110α isoform-specific inhibitors. Most p110α mutations occur at two hot spot regions: an acidic cluster (E542, E545, and Q546) in the helical domain and a histidine residue (H1047) in the kinase domain. We recently discovered that p110α helical domain mutant proteins, but not the kinase domain mutant proteins, directly associate with insulin receptor substrate 1 (IRS1). Moreover, we demonstrated that disruption of protein-protein interaction between p110α helical domain mutant and IRS1 inhibits the growth of tumors with such mutations. The direct protein interaction between IRS1 and p110α helical domain mutants may provide a more accessible target for developing novel precision cancer therapy. © 2013 by The Author(s).


Dore M.P.,University of Sassari | Dore M.P.,Baylor College of Medicine | Lu H.,Shanghai JiaoTong University | Lu H.,Key Laboratory of Gastroenterology and Hepatology | Graham D.Y.,Baylor College of Medicine
Gut | Year: 2016

In most regions of the world, antimicrobial resistance has increased to the point where empirical standard triple therapy for Helicobacter pylori eradication is no longer recommended. The treatment outcome in a population is calculated as the sum of the treatment success in the subpopulation with susceptible infections plus treatment success in the subpopulation with resistant infections. The addition of bismuth (ie, 14-day triple therapy plus bismuth) can improve cure rates despite a high prevalence of antimicrobial resistance. The major bismuth effect is to add an additional 30%-40% to the success with resistant infections. The overall result is therefore dependent on the prevalence of resistance and the treatment success in the subpopulation with resistant infections (eg, with proton-pump inhibitor-amoxicillin dual therapy). Here, we explore the contribution of each component and the mechanisms of how bismuth might enhance the effectiveness of triple therapy. We also discuss the limitations of this approach and provide suggestions how triple therapy plus bismuth might be further improved.


Xu J.,Renji Hospital | Li Z.,Vrije Universiteit Brussel | Wang J.,Renji Hospital | Chen H.,Renji Hospital | And 3 more authors.
Translational Oncology | Year: 2014

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor commonly inactivated in glioblastoma multiforme (GBM), but the prognostic significance of PTEN remains controversial. Here, we demon- strate significant prognostic value of combined PTEN mutation and expression for the survival of patients with GBM on the basis of analysis of large-scale cancer genomic data. PTEN nonsense mutations associated with significantly shorter disease-free survival and overexpression of PTEN protein linked to shorter disease-free and overall survival of patients with GBM. PTEN nonsense mutations correlated with decreased p53 and Gata3 protein levels and increased genomic instability in human GBM tissues. Expression of nonsense PTEN mutant decreased p53 and Gata3 levels, producing increased DNA damage both in vitro and in vivo. Mice carrying xenograft tumors with nonsense PTEN mutant displayed significantly shorter survival. Our data demonstrated the prognostic value of combined PTEN mutation and protein expression for patients with GBM and highlighted distinct biologic effects of nonsense and missense mutations of PTEN. © 2014 Neoplasia Press. All rights reserved.


Xu J.,Shanghai JiaoTong University | Xu J.,Key Laboratory of Gastroenterology and Hepatology | Qian J.,Shanghai JiaoTong University | Qian J.,Key Laboratory of Gastroenterology and Hepatology | And 9 more authors.
Scientific Reports | Year: 2014

Mutations of p53 cause not only loss of wild-type function but also gain of novel oncogenic functions (GOF). Accumulating evidence suggest that p53 hotspot mutations may confer different types and magnitudes of GOF. Here we add support to the heterogeneity of mutant p53 GOF by showing their unequal association with early tumor onset and spectrum of tumor types. We stratified Li-Fraumeni syndrome (LFS) patients according to carried p53 mutations using data from the updated p53 germline mutation database. When compared to loss-of-function nonsense mutations, the R282 GOF mutation associated with significantly earlier onset, while the G245 mutation displayed later onset. The R175, Y220, R248, R282 and nonsense mutations showed preferential distribution in certain cancer types, which varied in the age of onset. Multivariate COX regression model adjusting for cancer types and patient sex suggested that nonsense and G245 mutations had lower risk than R248 for early onset, suggesting unequal strengths of mutant GOF effects. Our results suggest that Li-Fraumeni syndrome can be subdivided into subtypes linking to unequal GOF effects of p53 mutations. These findings have potential implications in the prevention, early detection and targeted treatment of LFS tumors.


Hu Y.,Shanghai JiaoTong University | Hu Y.,Key Laboratory of Gastroenterology and Hepatology | Chen H.-Y.,Shanghai JiaoTong University | Chen H.-Y.,Key Laboratory of Gastroenterology and Hepatology | And 11 more authors.
Oncotarget | Year: 2014

Increasing evidence suggests long non-coding RNAs (lncRNAs) are frequently aberrantly expressed in cancers, however, few related lncRNA signatures have been established for prediction of cancer prognosis. We aimed to develop a lncRNA signature to improve prognosis prediction of colorectal cancer (CRC). Using a lncRNAmining approach, we performed lncRNA expression profiling in large CRC cohorts from Gene Expression Ominus (GEO), including GSE39582 test series(N=436), internal validation series (N=117); and two independent validation series GSE14333 (N=197) and GSE17536(N=145). We established a set of six lncRNAs that were significantly correlated with the disease free survival (DFS) in the test series. Based on this sixlncRNA signature, the test series patients could be classified into high-risk and lowrisk subgroups with significantly different DFS (HR=2.670; P<0.0001). The prognostic value of this six-lncRNA signature was confirmed in the internal validation series and another two independent CRC sets. Gene set enrichment analysis (GSEA) analysis suggested that risk score positively correlated with several cancer metastasis related pathways. Functional experiments demonstrated three dysregulated lncRNAs, AK123657, BX648207 and BX649059 were required for efficient invasion and proliferation suppression in CRC cell lines. Our results might provide an efficient classification tool for clinical prognosis evaluation of CRC.


Hu Y.,Shanghai JiaoTong University | Hu Y.,Key Laboratory of Gastroenterology and Hepatology | Hu Y.,State Key Laboratory of Oncogene and Related Genes | Yu C.-Y.,Shanghai JiaoTong University | And 12 more authors.
Scientific Reports | Year: 2014

MicroRNAs (miRNAs) participate in diverse biological pathways and may act as oncogenes or tumor suppressors. Single nucleotide polymorphisms (SNPs) in miRNAs (MirSNPs) might promote carcinogenesis by affecting miRNA function and/or maturation; however, the association between MirSNPs reported and cancer risk remain inconsistent. Here, we investigated the association between nine common MirSNPs and cancer risk using data from large scale case-control studies. Eight precursor-miRNA (pre-miRNA) SNPs (rs2043556/miR-605, rs3746444/miR-499a/b, rs4919510/miR-608, rs2910164/miR-146a, rs11614913/miR-196a2, rs895819/miR-27a, rs2292832/miR-149, rs6505162/miR-423) and one primary-miRNA (pri-miRNA) SNP (rs1834306/miR-100) were analyzed in 16399 cases and 21779 controls from seven published studies in eight common cancers. With a novel statistic, Cross phenotype meta-analysis (CPMA) of the association of MirSNPs with multiple phenotypes indicated rs2910164 C (P = 1.11E-03), rs2043556 C (P = 0.0165), rs6505162 C (P = 2.05E-03) and rs895819 (P = 0.0284) were associated with a significant overall risk of cancer. In conclusion, MirSNPs might affect an individual's susceptibility to various types of cancer.

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