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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.,State Key Laboratory for Oncogenes and Related Genes | Li Z.,Vrije Universiteit Brussel | Wang J.,Shanghai Institute of Digestive Disease | Chen H.,State Key Laboratory for Oncogenes and Related Genes | 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.

Lu H.,Key Laboratory of Gastroenterology and Hepatology | Zhang W.,Key Laboratory of Gastroenterology and Hepatology | Graham D.Y.,Baylor College of Medicine
European Journal of Gastroenterology and Hepatology | Year: 2013

Antimicrobial resistance has continued to undermine many popular anti-Helicobacter pylori therapies. Antibiotic resistance to commonly used anti-H. pylori drugs in China has increased markedly, making China an ideal site to identify regimens that remain effective despite widespread antimicrobial resistance. Bismuth is one of the few antimicrobials to which resistance does not develop. Factors contributing to H. pylori treatment success include host factors (e.g. genetic differences in the metabolism of the drugs used), bacterial factors (e.g. susceptibility), and details of the regimen (e.g. doses, dosing interval, dosing in relation to meals, formulation, etc.). We reviewed the recent experience in China with bismuth-containing quadruple therapies. The experience consists of 16 studies with 25 arms involving 1971 patients to identify successful regimens (defined as reliably obtaining 90% or greater eradication per protocol) deserving further study. Despite high rates of resistance to commonly used antimicrobials, several regimens could achieve high success. These were characteristically 14-day regimens containing a proton pump inhibitor and either tetracycline and metronidazole or furazolidone and amoxicillin. We propose approaches for further development including for optimization and simplification related to convenience and side effects (e.g. twice rather than three or four times daily or administration at the noon and evening meal instead of at breakfast and evening) while maintaining effectiveness of at least 90%. Studies in China identified regimens that were highly effective despite the high prevalence of resistance to metronidazole, fluoroquinolones, and macrolides. Multicenter randomized studies will be required to confirm which is the best. © 2013 Wolters Kluwer Health | Lippincott Williams and Wilkins.

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.

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.

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