Past Achievements

1. Clinical Trials on the Treatment of Helicobacter pylori Infection

In a recent multicenter randomized trial, we found that sequential therapy is more effective than triple therapy in the first line treatment (Lancet 2012;Nov 15, Epub). We further showed that antibiotic resistance is the most important factor leading to treatment failure. Based on the result of this study, we constructed a decision model to predict the efficacy of sequential therapy and triple therapy across a various range of antibiotic resistance (Lancet 2012;Nov 15, Epub; and http://hp-therapy.biomed.org.tw/). In another randomized trial with crossover design, we found that the use of clarithromycin-based triple therapy as the initial treatment and levofloxacin-based triple therapy as the rescue regimen achieved higher eradication rates than the reverse sequence (Gut 2010; 59:572-8). For second line treatment, we found that modified sequential therapy containing levofloxacin can achieve excellent eradication and its efficacy was not affected by levofloxacin resistance (J Antimicrob Chemother. 2011;66:1847-52). For patients who failed from at least two eradication therapies, genotypic resistance guided sequential therapy is effective in the third line treatment (J Antimicrob Chemother 2012;Oct 25, Epub). We also identified several important factors that might contribute to the pathogenesis and treatment of H. pylori related diseases. Early eradication of H. pylori decreases the risk of gastric cancer in patients with peptic ulcer disease (Gastroenterology. 2009;137:1641-8) and in the community (GUT 2012, Jun 14 Epub). In a nationwide population-based cohort study, we found that hospitalization for peptic ulcer disease was reduced with H pylori eradication and the use of proton pump inhibitor (Clin Gastroenterol Hepatol. 2009;7:427-31). More recently, we found that regular NSAID use may be a feasible way to prevent gastric cancer, at least in patients with gastric ulcers, and especially in H pylori-infected subjects (J Clin Oncol. 2010;28:2952-7).

2. Pathogenesis of gastric cancer and Proteomics utilization in HP-related diseases

We identified a secreted protein that could induce production of TGF-β. This protein might mediate the immune response and contribute to the pathogenesis of H. pylori infection (J Infect Dis 2007; 196:1386-1393). In an invited review, we suggested that the evolving technologies, such as proteomics, will reveal more useful markers for the diagnosis and prognosis of H. pylori-related gastroduodenal disease (Cancer Epidemiol Biomark Prev 2005; 14:1878-1882). We found that Helicobacter pylori (H. pylori) infection was inversely associated with morbid obesity (Arch Intern Med 2005; 165:1552-1555). We have demonstrated the potential role of H. pylori in morbid obesity in a case-control study and suggested H. pylori might act through the gastric ghrelin to modulate the effect on body weight (Arch Intern Med 2005; 165:1552-1555; Obes Surg 2006; 16:297-307; Obes Surg 2008;18:84-9). The prevalence of gastroesophageal reflux disease was also reduced after Roux-en-Y gastric bypass on in morbidly obese patients (Obes Surg 2009;19:565-70). We further demonstrated that visceral adiposity plays a crucial role in the pathogenesis of erosive esophagitis (Obesity 2010;18:2165-9).

To address the influence of oxidative stress and its underlying mechanisms, we have compared protein expression profiles of H. pylori incubated uncdr normal microaerophiclic (5% O2) and aerobic stress (20% O2) conditions. The results revealed that more than proteins were differentially expressed. Most notably, the protein expression levels of UreE (an essential methllochaperone for urease activity) and Ahpc (with antioxidant potential) are greatly decreased under stress conditions (Proteomics 2005; 5:3895-3901). We have further characterized Aphc, which has displayed both antioxidative activites and molecular chaperone properties (Proc Natl Acad Sci USA 2006; 103:2552-2557). In addition, by application of twe-dimensional electrophoresis nd immunoblotting, we have found GroES is differentially expressed between patients with gastric cancer, duodenal ulcer and non-ulcer dyspepsia (Mol Cell Proteomics 2006; 5:1484-1496). Collectively, these results indicated proteomics is a powerful tool in investigations of putative virulence factors of H. pylori-related gastroduodenal disease.

3. Signal transduction in HP-related gastroduodenal disease:

Cyclooxygenease-2 plays a crucial role in H. pylori-related gastric cancer. We have found H. pylori could induce COX-2 expression via activation of NF-κB, NF-interleukin 6, the CAMP response element. In NF-κB activation, H. pylori acts through TLR2/TLR9 to activate both the cascade of PI-PLCr/PKCα/c-Src/IKKα/β and the cascade of NIK/IKKα/β, resulting in the IκBα degradation and the expression of COX-2 gene (Mol Pharmacol 2004; 66:1465-1477). We have further demonstrated H. pylori acts throuth TLR2/TLR9 to activate MAPKs, especially p38, and their downstream transcription factors (CREB-1, AFT-2, c-Jun, c-fos), resulting in the activations of CRE and AP-1 on the COX-2 promoter. These intracellular networks drive the COX-2-dependent PGE2 release and contribute to cell invasion and angiogenesis (J Immunol 2005; 175:8242-8252). Recently, we also observed that cagA and bobA, but not sabA dependent activation of cyclin D1 and clarified their intracellular signaling pathways (Cell Microbiol 2006; 8:1740-1752). More importantly, we found that human alpha-L-fucosidase 2 (FUCA2) is essential for H. pylori adhesion which supports the idea that FUCA2 is a potential therapeutic target for H. pylori infection and its associated disease (Proc Natl Acad Sci U S A 2009;106:14581-6).We have established in vitro and in vivo models for investigation of angiogenesis and invasion in gastric cancer. Our results showed IL-6 can increase angiogenesis in gastric cancer and revealed its signaling pathways (J Biomed Sci 2004; 11:517-5271). In addition, we demonstrated COX-2 may increase hypoxia-inducible factor-1 and vascular endothelial growth factor to promote angiogenesis in gastric cancer (J Biomed Sci 2005; 12:229-241).

4. Genetic susceptibility and biomarkers in gastric malignancies:

We have found bloob levels of osteopontin (Gut 2007; 56:782-789) and IL-6 (Clin Candr Res 2008 in press) are associated with prognosis of gastric cancer. By case-control designs, we have demonstrated that certain HLA alleles (Cancer Sci 2002; 93:404-410), polymorphisms of xenobiotic-metabolizing enzyme genes (Int J Colorectal Dis 2002; 17:338-343), and E-cadherin gene (Cancer 2002; 94:1443-1448) are associated with the risk of gastric cancer. In addition, cytokine genes are also linked to the development of gastric cancer (J Infect Dis 2002; 185:106-109) and have synergistic effects with H. pylori infection and smoking (Int J Cancer 2003; 104:617-623). Recently, we have found genetic polymorphisms also play a crucial role in the development of gastric MALToma (Int J Cancer; 110:695-700; Haematologica 2004; 89:1015-1017; J Clin Oncol 2006; 24:3483-3489). We are also invited to write a review in genetic alterations and polymorphisms of gastric (J Formos Med Assoc 2003; 102:447-458).

5. Early detection and pathogenesis of colon cancer

We found that the diagnostic accuracy of NBI was better than that of conventional colonoscopy and equivalent to that of chromoendoscopy (Gut 2007;56:373-9). The immunochemical fecal occult blood test was specific for predicting lesions in the lower gastrointestinal tract. However, the test did not adequately predict lesions in the upper gastrointestinal tract (CMAJ 2011;183:1474-81). We showed that IGFBP-2 is a potential diagnostic and prognostic biomarker of CRC (J Clin Endocrinol Metab 2010;95:1717-25). LOI of IGF-II in tumours was also associated with more advanced diseases and poor prognosis (Eur J Cancer 2007;43:1276-82). Elevated plasma CRP levels are independently associated with an increased risk of colorectal neoplasia in men, but not in women (Am J Gastroenterol 2008;103:2317-25).