Harry H.X. Xia

Effects of selective COX-2 inhibitor and Helicobacter pylori eradication on precancerous gastric lesions

Objective Helicobacter pylori infection and overexpression of cyclo-oxygenase-2 (COX-2) are associated with gastric cancer and its precursors. To evaluate the effect of a selective COX-2 inhibitor alone and combined with H pylori eradication on the evolution of precancerous gastric lesions, a randomised, placebo-controlled trial was conducted in Linqu County, Shandong Province, China. Methods A total of 1024 participants aged 35–64 years with H pylori infection and advanced gastric lesions were randomly assigned in a factorial design to two interventions or placebo: anti-H pylori treatment for 7 days, and a COX-2 inhibitor (celecoxib) for 24 months. The effects of the interventions were evaluated by the regression or progression of advanced gastric lesions. Results Of the 1024 participants who received anti-H pylori treatment or placebo, 919 completed a subsequent 24-month treatment with celecoxib or placebo. The H pylori eradication rate by per-protocol analysis was 78.2%. Compared with placebo, the proportions of regression of gastric lesions significantly increased in the celecoxib treatment (52.8% vs 41.2%) and anti-H pylori treatment (59.3% vs 41.2%) group, and OR by per-protocol analysis was 1.72 (95% CI 1.07 to 2.76) for celecoxib and 2.19 (95% CI 1.32 to 3.64) for H pylori eradication. No statistically significant effect was found for H pylori eradication followed by celecoxib on the regression of advanced gastric lesions (OR 1.48, 95% CI 0.91 to 2.40). Conclusion This population-based intervention trial revealed that celecoxib treatment or H pylori eradication alone had beneficial effects on the regression of advanced gastric lesions. No favourable effects were seen for H pylori eradication followed by celecoxib treatment. Trial registration HARECCTR0500053 in accordance with WHO ICTRP requirements.

Antisense Targeting Protein Kinase C α and β1 Inhibits Gastric Carcinogenesis

Protein kinase C (PKC) family, which functions through serine/threonine kinase activity, is involved in signal transduction pathways necessary for cell proliferation, differentiation, and apoptosis. Its critical role in neoplastic transformation and tumor invasion renders PKC a potential target for anticancer therapy. In this study, we investigated the effect of targeting individual PKCs on gastric carcinogenesis. We established gastric cancer cell lines stably expressing antisense PKCα, PKCβ1, and PKCβ2 cDNA. These stable transfectants were characterized by cell morphology, cell growth, apoptosis, and tumorigenicity in vitro and in vivo. PKCα-AS and PKCβ1-AS transfectants showed a different morphology with flattened, long processes and decreased nuclear:cytoplasmic ratio compared with the control cells. Cell growth was markedly inhibited in PKCα-AS and PKCβ1-AS transfectants. PKCα-AS and PKCβ1-AS cells were more responsive to mitomycin C- or 5-fluorouracil-induced apoptosis. However, antisense targeting of PKCβ2 did not have any significant effect on cell morphology, cell growth, or apoptosis. Furthermore, antisense inhibition of PKCα and PKCβ1 markedly suppressed colony-forming efficiency in soft agar and in nude mice xenografts. Inhibition of PKCα or PKCβ1 significantly suppressed transcriptional and DNA binding activity of activator protein in gastric cancer cells, suggesting that PKCα or PKCβ1 exerts their effects on cell growth through regulation of activator protein activity. These data provide evidence that targeting PKCα and PKCβ1 by antisense method is a promising therapy for gastric cancer.

XAF1 mediates apoptosis through an extracellular signal-regulated kinase pathway in colon cancer

XIAP‐associated factor 1 (XAF1) negatively regulates the function of the X‐linked inhibitor of apoptosis protein (XIAP), a member of the IAP family that exerts antiapoptotic effects. The extracellular signal‐regulated kinase (ERK) pathway is thought to increase cell proliferation and to protect cells from apoptosis. The aim of the study was to investigate the correlation between the ERK1/2 signaling pathway and XAF1 in colon cancer.

Pathophysiology of Gastroesophageal Reflux Diseases in Chinese—Role of Transient Lower Esophageal Sphincter Relaxation and Esophageal Motor Dysfunction

BACKGROUND AND AIMS:Transient lower esophageal sphincter relaxation (TLESR) is the major mechanism for gastroesophageal reflux in the Western population. The major reflux mechanism in Chinese patients with GERD has not been studied before.METHODS:Fifty-four patients with GERD and 28 controls underwent stationary baseline manometry and the 24-h ambulatory esophageal pH monitoring. TLESRs were measured before and after an 850 kcal meal in the supine position. Primary peristalsis, secondary peristalsis, and esophageal acid clearance were measured by esophageal manometry.RESULTS:Total time esophageal pH ≤ 4 (7.3 vs 1.5, p = 0.001) was significantly higher in patients with GERD when compared to controls. Majority of acid reflux episodes was due to TLESR in both patients with GERD and controls. The frequency of TLESRs after meal was similar between patients with GERD and controls (1.0 vs 1.3/h, p = 0.34). There was no difference in the distribution of reflux mechanism between patients with GERD and controls. However, patients with GERD had a significantly lower successful primary peristalsis (59% vs 70%, p = 0.043) when compared to controls.CONCLUSION:The frequency of TLESRs was similar between patients with GERD and controls during stationary manometry. Primary peristalsis was impaired in Chinese patients with GERD. Esophageal motor dysfunction may contribute to the pathophysiology of GERD in the Chinese population.

Relationship between alcohol consumption and active Helicobacter pylori infection.

BACKGROUND Helicobacter pylori (H. pylori) is a cause of chronic gastritis and maybe responsible for functional dyspepsia in a subset of patients. Many risk factors, such as alcohol consumption and smoking, may contribute to the colonization and infection of H. pylori in humans. However, studies on the relationship between H. pylori infection and drinking or smoking have produced conflicting results. OBJECTIVE The aim of this study was to examine whether consumption of alcohol or smoking is associated with active H. pylori infection in functional dyspepsia patients. METHODS H. pylori infection was confirmed by CLOtest and histology on at least two biopsies. Active chronic gastritis was diagnosed using the updated Sydney system. In addition to gender and age, information on drinking and smoking habits was collected using a standard questionnaire. Functional dyspepsia was diagnosed according to the Rome II diagnostic criteria. RESULTS H. pylori infection was positive in 27.3% of the 139 functional dyspepsia patients. Both age and gender were not significantly associated with H. pylori infection. A multiple logistic model found that alcohol consumption (OR = 9.05, 95% CI: 1.05-77.98) and pathology (active gastritis) (OR = 595.39, 95% CI: 81.43-4353.33) were associated with H. pylori infection. Active gastritis was associated with alcohol consumption (OR = 2.89, 95% CI: 1.03-8.02), smoking (OR = 2.72, 95% CI: 1.22-6.05) and age (OR = 1.03, 95% CI: 1.01-1.06). CONCLUSIONS In patients with functional dyspepsia, there is no significant association between active H. pylori infection and smoking. However, alcohol consumption appears to be associated with H. pylori infection.

Inhibition of Akt/PKB by a COX-2 inhibitor induces apoptosis in gastric cancer cells.

Background/Aim: Inhibition of cyclooxygenase-2 has been proposed to be a potential mechanism for the chemoprevention of gastrointestinal tumors by nonsteroidal anti-inflammatory drugs. This study investigates the mechanisms by which the cyclooxygenase-2 inhibitor SC236 induces apoptosis of gastric cancer cell lines and its downstream signaling pathway. Methods: Two gastric cancer cell lines, AGS and MKN28, were treated with SC236 and assessed for cell growth and apoptosis. The involvement of mitogen-activated protein kinase and Akt kinase/protein kinase B (Akt/PKB) pathways and their downstream signalings were studied in the AGS cell line. Results: SC236 treatment induced apoptosis in gastric cancer cells and caused activation of p38 and stress-activated protein kinase/jun kinase, but down-regulated Akt/PKB. The specific p38 inhibitor SB203580 and the dominant-negative stress-activated protein kinase/jun kinase both failed, while the constitutively active form of Akt/PKB was able to block SC236-induced apoptosis. SC236-induced apoptosis was coupled with release of cytochrome c and activation of caspases. Conclusion: One of the pathways involved in SC-236-induced apoptosis in gastric cancer cells is through downregulation of Akt and then release of cytochrome c.

Pancreatic duodenal homeobox-1 (PDX1) functions as a tumor suppressor in gastric cancer

AIM Pancreatic duodenal homeobox-1 (PDX1) is a transcription factor of homeobox genes family important in differentiation and development of the pancreas, duodenum and antrum. This study aims to clarify the putative role of PDX1 in gastric carcinogenesis. METHODS PDX1 expression was detected in gastric tissues with chronic gastritis and cancer as well as gastric cancer cell lines by immunohistochemistry, western blot, reverse transcription-polymerase chain reaction (RT-PCR) or quantitative real-time RT-PCR assays. The effects of PDX1 on cell proliferation, apoptosis, clone formation and migration were evaluated using cancer cell lines after transient or stable transfection with PDX1-expressing vector. The ability of PDX1 stable transfectant in tumor formation in xenograft mice was assessed. RESULTS PDX1 was strongly expressed in normal gastric glands, but was absent in 29 of 39 of human gastric cancer and most gastric cancer cell lines. Negative correlation between PDX1 and Ki-67 expression was found in both gastric tissues and cell lines. Ectopic overexpression of PDX1 significantly inhibited cell proliferation and induced apoptosis, accompanied by the activation of caspases 3, 8, 9 and 10. Overexpression of PDX1 also impaired the ability of cancer cells in clonal formation and migration in vitro. Furthermore, stable transfection with PDX1 reduced the ability of cancer cells in tumor formation in nude mice. CONCLUSIONS PDX1 expression is lost in gastric cancers. Its effect on cell proliferation/apoptosis, migration and tumor formation in vitro and in vivo suggested that this protein functions as a putative tumor suppressor in gastric cancer.

Quality of Life and Psychological Impact in Patients With Noncardiac Chest Pain

Background Chest pain is common and data regarding noncardiac chest pain (NCCP) in Asia are lacking. Aim To determine the differences in clinical presentations, psychologic impact, and quality of life between patients with NCCP and cardiac chest pain (CCP), and to identify any factors that impacted on these patients. Methods Consecutive patients undergoing coronary angiography for the evaluation of chest pain were recruited in Hong Kong and Wuhan, China. One hundred and forty patients with abnormal and 141 patients with normal angiography were included in the study. The validated gastroesophageal reflux disease questionnaire, the Hospital Anxiety-Depression Scale, and the 12-item Short Form Health Survey (SF-12) were used for assessment. Results NCCP patients reported similar days-off work and impairment of their social life compared with those with CCP. No difference was found in the anxiety and depression scores between the 2 groups. NCCP patients with reflux symptoms had higher anxiety score (7.19 vs. 5.74, P=0.044), reported more interruption of their social life (26% vs. 5%, P<0.0001), and had taken more sick leaves (17% vs. 5%, P=0.018) compared with those without gastroesophageal reflux disease. Conclusions The quality of life and psychologic impact of patients with NCCP were as significant as those with CCP. NCCP patients with reflux symptoms were more anxious and were impaired in their productivity and social life.

An Inverse Correlation between Interleukin-6 and Select Gene Promoter Methylation in Patients with Gastric Cancer

Background: Both serum IL-6 levels and CpG island methylation have been shown to have prognostic significance in gastric cancer, it was suggested that an important link existed between IL-6 and methylation of cancers. Aim: To investigate the prognostic value of IL-6 serum level and the association between serum IL-6 levels and CpG island methylation at p16, DAPK, MGMT and E-cadherin in patients with gastric cancer. Patients and Methods: Methylation status was assessed by MSP in 75 surgical specimens of gastric adenocarcinoma. IL-6 serum levels were measured by chemiluminescent enzyme immunoassay (CLEIA). Results: Methylation of p16, DAPK, MGMT, and E-cadherin were present in 53, 48, 32, and 59% of patients. Patients with tumors methylated at p16 and DAPK had lower serum levels of IL-6 compared to unmethylated tumors (1.8 vs. 4.8 pg/ml, p = 0.01 for p16; 1.5 vs. 6.2 pg/ml, p = 0.0001 for DAPK). But there was no difference with MGMT and E-cadherin methylation status. Serum IL-6 levels were also associated with TNM stage (p = 0.001), depth of tumor invasion (p = 0.002), lymphatic invasion (p = 0.01), vascular invasion (p = 0.008), metastasis (p = 0.002) and signet cell histology (p = 0.001). Conclusion: IL-6 is of prognostic value for patients of gastric cancer. Low serum IL-6 levels were associated with p16 or DAPK gene methylation in patients with gastric cancer.

Accuracy of a new near patient test for the diagnosis of Helicobacter pylori infection in Chinese

Background and Aim: The performance of existing near patient tests for the diagnosis of Helicobacter pylori remains unsatisfactory. The aim of this study is to evaluate the accuracy of a new near patient test (Signify H. pylori) for the diagnosis of H. pylori and the usefulness of the Signify H. pylori test for a test and treat strategy.