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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.
Cancer letters 07/2010; 293(1):15-22. · 4.86 Impact Factor
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ABSTRACT: Resveratrol, a naturally occurring polyphenolic antioxidant, has been shown to exhibit chemoprophylactic effects on cancer development. Previously, we reported that 2,3',4,4',5'-pentamethoxy-trans-stilbene (PMS), a methoxylated resveratrol derivative, exerted a highly potent anti-proliferative effect on human colon cancer cells as compared with its parent compound. In the present study, the chemopreventive effect of PMS was evaluated in a mouse model of colitis-associated colon carcinogenesis.
Seven-week-old Balb/c mice were injected i.p. with 10 mg.kg(-1) azoxymethane (AOM). After 1 week, 3% dextran sodium sulphate (DSS) was administered in the drinking water for 7 days followed by 14 days of tap water for recovery, and this cycle was repeated twice.
Intragastric administration of PMS (25, 50 mg.kg(-1) body weight) for 16 weeks significantly reduced the multiplicity of colonic neoplasms by 15% and 35% (P < 0.01) respectively. Moreover, PMS at 50 mg.kg(-1) inhibited colon cancer cell proliferation and promoted apoptosis. Such changes were accompanied by reduction of Akt (protein kinase B) phosphorylation, inactivation of beta-catenin and down-regulation of inducible nitric oxide synthase. In parallel, in vitro studies also demonstrated that PMS inhibited proliferation and induced apoptosis in the murine colon adenocarcinoma cell line Colon26 with concomitant inhibition of Akt phosphorylation and inactivation of beta-catenin.
PMS effectively suppressed colon carcinogenesis in an AOM/DSS animal model and may merit further clinical investigation as a chemoprophylactic agent against colitis-associated colon cancer in humans.
British Journal of Pharmacology 07/2010; 160(6):1352-61. · 4.41 Impact Factor
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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.
Gut 07/2010; 59(7):969-74. · 10.11 Impact Factor
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ABSTRACT: Nicotine is shown to be one of the carcinogenic agents for gastric cancer. Perturbation of epithelial-mesenchymal transition (EMT) results in loss of intracellular adhesions leading to tumor progression. In this study, we examined the underlying mechanism of the long-term effects of nicotine on tumor progression in human gastric cancer cells. Nicotine activated 5-lipoxygenase (5-LOX) in three gastric cancer cell lines (MKN-45, MKN-28 and AGS). Cells treated with nicotine dose- and time-dependently induced cell proliferation, invasion and suppressed apoptosis. In addition, cell cycle progression analysis revealed that activation of 5-LOX modulated the G1/S phase transition regulatory proteins and caused cell proliferation. MK886 (5-LOX activating protein inhibitor) mediated the induction of apoptosis by elevation of caspase-3 and Bax/Bcl2 ratio. Abrogation of 5-LOX repressed featured molecular markers of EMT (inactivation of E-cadherin and activation of transcriptional repressor Snail). Blockade of 5-LOX signaling resulted in downregulation of cyclin D1, matrix metalloproteinase (MMP-7, -9), urokinase plasminogen activator (uPA) and its receptor (uPAR), and pro-apoptotic proteins. Furthermore, suppression of Snail and induction of E-cadherin is extracellular signal-regulated kinase (Erk)-dependent. Thus, we conclude that the promotion effect of nicotine on cancer cell progression and EMT is mediated by Erk/5-LOX signaling pathway.
Cancer letters 06/2010; 292(2):237-45. · 4.86 Impact Factor
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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.
Cancer letters 04/2010; 295(1):7-16. · 4.86 Impact Factor
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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 samples 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.
Journal of Cellular Physiology 04/2010; 223(1):178-86. · 3.87 Impact Factor
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Vincent Wai-Sun Wong,
Stephen Lam Chan,
Frankie Mo,
Tung-Ching Chan,
Herbert Ho-Fung Loong,
Grace Lai-Hung Wong,
Yanni Yan-Ni Lui,
Anthony Tak-Cheung Chan, Joseph Jao-Yiu Sung,
Winnie Yeo,
Henry Lik-Yuen Chan,
Tony Shu-Kam Mok
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ABSTRACT: Hepatitis B virus (HBV) infection is an important etiology for hepatocellular carcinoma (HCC). We aim to develop a simple clinical score in predicting the risk of HCC among HBV carriers.
We first evaluated 1,005 patients and found that the following five factors independently predicted HCC development: age, albumin, bilirubin, HBV DNA, and cirrhosis. These variables were used to construct a prediction score ranging from 0 to 44.5. The score was validated in another prospective cohort of 424 patients.
During a median follow-up of 10 years, 105 patients (10.%) in the training cohort and 45 patients (10.6%) in the validation cohort developed HCC. Cutoff values of 5 and 20 best discriminated HCC risk. By applying the cutoff value of 5, the score excluded future HCC development with high accuracy (negative predictive value = 97.8% and 97.3% in the training and validation cohorts, respectively). In the validation cohort, the 5-year HCC-free survival rates were 98.3%, 90.5%, and 78.9% in the low-, medium-, and high-risk groups, respectively. The hazard ratios for HCC in the medium- and high-risk groups were 12.8 and 14.6, respectively.
A simple prediction score constructed from routine clinical and laboratory parameters is accurate in predicting HCC development in HBV carriers. Future prospective validation is warranted.
Journal of Clinical Oncology 03/2010; 28(10):1660-5. · 18.37 Impact Factor
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ABSTRACT: Approximately 30%-40% of patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B treated with peginterferon and/or lamivudine achieve HBeAg seroconversion 6 months after the end of treatment. The durability and long-term effect of treatment are unknown. In this study, 85 HBeAg-positive patients who received peginterferon alfa-2b 1.5 microg/kg/week for 32 weeks and lamivudine 100 mg/day for 52 or 104 weeks were prospectively followed for 6.1 +/- 1.7 years posttreatment. Twenty-five (29%) patients had virologic response (HBeAg seroconversion and HBV DNA <10,000 copies/mL) at 5 years. The rate of HBeAg seroconversion rose progressively from 37% at the end of treatment to 60% at 5 years. Twenty-seven (32%) and 11 (13%) patients had undetectable HBV DNA (<100 copies/mL) at the end of peginterferon treatment and at 5 years, respectively. Two (2.4%) patients achieved hepatitis B surface antigen (HBsAg) seroclearance at 2.6 and 84 months posttreatment. Among virologic responders at the end of treatment, 82% and 57% and sustained HBeAg seroconversion and virologic response at 5 years. End-of-treatment serum quantitative HBsAg was significantly lower in patients with sustained virologic response at 5 years (median 1,431 IU/mL versus 2,689 IU/mL [P = 0.041]). At the last follow-up, the liver stiffness measurement by transient elastography was 5.8 +/- 2.7 kPa. Only two patients had liver stiffness suggestive of advanced fibrosis. Week 16 HBV DNA, end-of-treatment HBeAg seroconversion, and undetectable HBV DNA were independent factors associated with virologic response at 5 years. The duration of concomitant lamivudine treatment had no impact on any long-term response. CONCLUSION: Peginterferon has high durability in HBeAg-positive chronic hepatitis B patients with end-of-treatment virologic response.
Hepatology 02/2010; 51(6):1945-53. · 11.66 Impact Factor
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William Ka Kei Wu,
Chi Hin Cho,
Chung Wa Lee,
Ya Chun Wu,
Le Yu,
Zhi Jie Li,
Clover Ching Man Wong,
Hai Tao Li,
Lin Zhang,
Shun Xiang Ren,
Chun Tao Che,
Kaichun Wu,
Daiming Fan,
Jun Yu, Joseph Jao Yiu Sung
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ABSTRACT: The ubiquitin-proteasome system and macroautophagy are two complementary pathways for protein degradation. Emerging evidence suggests that proteasome inhibition might be a promising approach for the treatment of cancer. In this study, we show that proteasome inhibitor MG-132 suppressed gastric cancer cell proliferation and induced macroautophagy. The induction of macroautophagy was evidenced by the formation of LC3(+) autophagosomes and the accumulation of acidic vesicular organelles and autolysosomes and was accompanied by the suppression of mammalian target of rapamycin complex 1 activity. Abolition of macroautophagy by knockdown of Class III phosphatidylinositol-3 kinase Vps34 or ATG5/7 sensitized gastric cancer cells to the antiproliferative effect of MG-132 by promoting G(2)/M cell cycle arrest. In addition, MG-132 increased ERK phosphorylation whose inhibition by MEK inhibitor significantly enhanced the antiproliferative effect of proteasome inhibition. To conclude, this study demonstrates that macroautophagy and ERK phosphorylation serve as protective mechanisms to counteract the antiproliferative effect of proteasome inhibition. This discovery may have implications for the application of proteasome-directed therapy for the treatment of cancer.
Autophagy 02/2010; 6(2):228-38. · 7.45 Impact Factor
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Vincent Wai-Sun Wong,
Julien Vergniol,
Grace Lai-Hung Wong,
Juliette Foucher,
Henry Lik-Yuen Chan,
Brigitte Le Bail,
Paul Cheung-Lung Choi,
Mathurin Kowo,
Anthony Wing-Hung Chan,
Wassil Merrouche, Joseph Jao-Yiu Sung,
Victor de Lédinghen
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ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases in affluent countries. Accurate noninvasive tests for liver injury are urgently needed. The aim of this study was to evaluate the accuracy of transient elastography for the diagnosis of fibrosis and cirrhosis in patients with NAFLD and to study factors associated with discordance between transient elastography and histology. Two hundred forty-six consecutive patients from two ethnic groups had successful liver stiffness measurement and satisfactory liver biopsy specimens. The area under the receiver-operating characteristics curve (AUROC) of transient elastography for F3 or higher and F4 disease was 0.93 and 0.95, respectively, and was significantly higher than that of the aspartate aminotransferase-to-alanine aminotransferase ratio, aspartate aminotransferase-to-platelet ratio index, FIB-4, BARD, and NAFLD fibrosis scores (AUROC ranged from 0.62 to 0.81, P < 0.05 for all comparisons). At a cutoff value of 7.9 kPa, the sensitivity, specificity, and positive and negative predictive values for F3 or greater disease were 91%, 75%, 52%, and 97%, respectively. Liver stiffness was not affected by hepatic steatosis, necroinflammation, or body mass index. Discordance of at least two stages between transient elastography and histology was observed in 33 (13.4%) patients. By multivariate analysis, liver biopsy length less than 20 mm and F0-2 disease were associated with discordance. CONCLUSION: Transient elastography is accurate in most NAFLD patients. Unsatisfactory liver biopsy specimens rather than transient elastography technique account for most cases of discordance. With high negative predictive value and modest positive predictive value, transient elastography is useful as a screening test to exclude advanced fibrosis. Liver biopsy may be considered in NAFLD patients with liver stiffness of at least 7.9 kPa.
Hepatology 02/2010; 51(2):454-62. · 11.66 Impact Factor
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ABSTRACT: Gastrojejunal anastomosis is commonly performed for palliative management of malignant gastric outlet obstruction and bariatric surgery. Natural orifice transluminal endoscopic surgery revolutionized the surgical approach to intra-abdominal surgery. This study explored the possibility of performing gastrojejunostomy (GJ) by using a hybrid natural orifice transluminal endoscopic surgery approach.
To develop a surgical technique for the performance of transgastric endoscopic GJ (TGEJ) in a porcine model.
Prospective series of animal experiments.
University hospital animal laboratory.
Thirteen female domestic pigs.
With the animals under general anesthesia, the endoscope is passed through the gastrotomy and a segment of small bowel is retrieved into the stomach. An enterotomy is then created, and an EndoGIA stapler is introduced through an intragastric port and passed between the small bowel and stomach wall. A GJ is formed after firing of the EndoGIA stapler. The pigs are allowed to resume their diet 1 day after the operation and are allowed to survive for 2 weeks before they are euthanized. The patency of the GJ is confirmed with a repeat endoscopy, contrast study, and postmortem examination.
A total of 13 TEGJs were performed, 11 of which were successful. The mean operative time was 53.6 +/- 45.7 minutes. The mean time for gastrotomy was 4.7 minutes, and that for GJ was 42.5 minutes. One TEGJ was converted to open surgery because of malpositioning of the intragastric port, and the other failed because the enterotomy was too extensive. Ten of 11 pigs survived for 2 weeks, and endoscopic examination with contrast study confirmed that all the gastrojejunostomies were patent. On postmortem examination, the average size of the GJ was 30 mm.
The length between duodenojejunal flexure and the site chosen to perform the GJ could not be determined.
TEGJ is technically feasible with a patent and sizable anastomosis.
Gastrointestinal endoscopy 12/2009; 71(2):390-3. · 6.71 Impact Factor
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Vincent Wai-Sun Wong,
Grace Lai-Hung Wong,
Jun Yu,
Paul Cheung-Lung Choi,
Anthony Wing-Hung Chan,
Hoi-Yun Chan,
Eagle Siu-Hong Chu,
Alfred Sze-Lok Cheng,
Angel Mei-Ling Chim,
Francis Ka-Leung Chan, Joseph Jao-Yiu Sung,
Henry Lik-Yuen Chan
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ABSTRACT: OBJECTIVES: 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.
The American Journal of Gastroenterology 10/2009; 105(1):132-138. · 7.28 Impact Factor
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Vincent Wai-Sun Wong,
Grace Lai-Hung Wong,
Jun Yu,
Paul Cheung-Lung Choi,
Anthony Wing-Hung Chan,
Hoi-Yun Chan,
Eagle Siu-Hong Chu,
Alfred Sze-Lok Cheng,
Angel Mei-Ling Chim,
Francis Ka-Leung Chan, Joseph Jao-Yiu Sung,
Henry Lik-Yuen Chan
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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.
The American Journal of Gastroenterology 10/2009; 105(1):132-8. · 7.28 Impact Factor
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ABSTRACT: Histologic analyses of liver fibrosis have been limited by small sample sizes and the predominance of samples from patients with active hepatitis.
We performed a prospective study of transient elastography in treatment-naive patients with chronic hepatitis B, to investigate the relationship between hepatitis B virus (HBV) genotype and liver fibrosis. A validated liver stiffness measurement algorithm was used to define insignificant fibrosis and advanced fibrosis.
Of 1106 patients, 711 (64%) were older than age 40, 370 (34%) had positive test results for hepatitis B e antigen (HBeAg), and 386 (35%) had increased serum levels of alanine aminotransferase. Of the patients, 524 (49%) had genotype B and 582 (51%) had genotype C HBV infection. Patients with genotype C infection had insignificant fibrosis less often (42% vs 55%; P < .0001) and advanced fibrosis more often (25% vs 19%; P = .015) than those infected with genotype B HBV. The difference in the severity of liver fibrosis between the 2 HBV genotypes was most marked among patients older than age 40 and those who tested negative for HBeAg. The mean age of patients infected by genotype C was greater than that of patients infected by genotype B HBV (41 vs 36 y). Among patients who were older than age 40 and tested negative for HBeAg, those with genotype C infection had higher levels of HBV DNA and alanine aminotransferase than those with genotype B HBV.
Genotype C HBV was associated with more severe liver fibrosis than genotype B HBV, probably because of delayed HBeAg seroconversion and prolonged active disease.
Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 09/2009; 7(12):1361-6. · 5.64 Impact Factor
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ABSTRACT: Protein homeostasis relies on a balance between protein synthesis and protein degradation. The ubiquitin-proteasome system is a major catabolic pathway for protein degradation. In this respect, proteasome inhibition has been used therapeutically for the treatment of cancer. Whether inhibition of protein degradation by proteasome inhibitor can repress protein translation via a negative feedback mechanism, however, is unknown. In this study, proteasome inhibitor MG-132 lowered the proliferation of colon cancer cells HT-29 and SW1116. In this connection, MG-132 reduced the phosphorylation of mammalian target of rapamycin (mTOR) at Ser2448 and Ser2481 and the phosphorylation of its downstream targets 4E-BP1 and p70/p85 S6 kinases. Further analysis revealed that MG-132 inhibited protein translation as evidenced by the reductions of (35)S-methionine incorporation and polysomes/80S ratio. Knockdown of raptor, a structural component of mTOR complex 1, mimicked the anti-proliferative effect of MG-132. To conclude, we demonstrate that the inhibition of protein degradation by proteasome inhibitor represses mTOR signaling and protein translation in colon cancer cells.
Biochemical and Biophysical Research Communications 07/2009; 386(4):598-601. · 2.48 Impact Factor
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ABSTRACT: Neonatal maternal separation (NMS) could trigger long-term changes in the central neuronal responses to nociceptive stimuli in rats. Stress-induced visceral hyperalgesia is closely associated with the dysfunction of descending pain modulatory systems. Brain-derived neurotrophic factor (BDNF) not only has an important role in long-term synaptic plasticity but also in facilitating descending pain. The present study aimed to investigate changes in the expression of BDNF and its receptor tyrosine kinase receptor B (TrkB) in the amygdala and the rostral ventromedial medulla (RVM) after NMS and colorectal distention (CRD) stimulation in rats. Male Wistar rat pups were subjected to 180 min of daily NMS or not handled for 13 consecutive days. Expression of BDNF and TrkB following NMS and CRD stimulation was determined using immunohistochemistry. The results revealed an increase in the expression of BDNF and TrkB in the amygdala after NMS. An interactive effect of NMS and CRD on the expression of TrkB, but not BDNF, was found in the RVM. Furthermore, a significant interactive effect of NMS and CRD on the colocalization coefficient of TrkB and phospho-extracellular signal-regulated kinase expression in both the amygdala and RVM were found. These data demonstrate that NMS increases BDNF and TrkB expression in the descending pain systems, which may contribute to the development of NMS-induced visceral hyperalgesia.
Neurosignals 07/2009; 17(3):213-21. · 2.11 Impact Factor
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ABSTRACT: The approach to salvage surgery after failed endoscopic therapy for a bleeding peptic ulcer is controversial. We aimed to compare the outcomes of salvage surgery after failed endoscopic therapy for bleeding peptic ulcers over a 10-year period.
Patients receiving salvage surgery for bleeding peptic ulcers were divided into 2 cohorts, the 1st from 1993 to 1998 and the 2nd from 1999 to 2004. The type of salvage surgery was defined as minimal if ulcer plication or an ulcerectomy was performed, and definitive if the patient received a vagotomy or gastrectomy.
One hundred and twenty-three patients received salvage surgery in the 1st cohort, while 42 patients received surgical hemostasis for the bleeding peptic ulcer in the 2nd cohort. Patients in the 2nd cohort consisted of a larger proportion of in-hospital bleeders (cohort 1: 12.2%, cohort 2: 42.9%; p < 0.005) and had a significantly higher proportion of comorbidities. A larger number of patients received minimal surgery in cohort 2 (cohort 1: 42.3%, cohort 2: 73.8%; p < 0.005).
With advances in therapeutic endoscopy, patients who developed failed endoscopic hemostasis are likely to be poor surgical candidates with multiple comorbidities. The approach to salvage surgery has inclined towards minimal surgery to hasten surgical hemostasis among these fragile patients.
Digestive surgery 07/2009; 26(3):243-8. · 1.37 Impact Factor
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ABSTRACT: Macroautophagy is a process by which cytoplasmic content and organelles are sequestered by double-membrane bound vesicles and subsequently delivered to lysosomes for degradation. Macroautophagy serves as a major intracellular pathway for protein degradation and as a pro-survival mechanism in time of stress by generating nutrients. In the present study, bafilomycin A(1), a vacuolar type H(+)-ATPase inhibitor, suppresses macroautophagy by preventing acidification of lysosomes in colon cancer cells. Diminished macroautophagy was evidenced by the accumulation of undegraded LC3 protein. Suppression of macroautophagy by bafilomycin A(1) induced G(0)/G(1) cell cycle arrest and apoptosis which were accompanied by the down-regulation of cyclin D(1) and cyclin E, the up-regulation of p21(Cip1) as well as cleavages of caspases-3, -7, -8, and -9 and PARP. Further investigation revealed that bafilomycin A(1) increased the phosphorylation of ERK, JNK, and p38. In this regard, p38 inhibitor partially reversed the anti-proliferative effect of bafilomycin A(1). To conclude, inhibition of macroautophagy by bafilomycin A(1) lowers G(1)-S transition and induces apoptosis in colon cancer cells. Our results not only indicate that inhibitors of macroautophagy may be used therapeutically to inhibit cancer growth, but also delineate the relationship between macroautophagy and apoptosis.
Biochemical and Biophysical Research Communications 06/2009; 382(2):451-6. · 2.48 Impact Factor
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Grace Lai-Hung Wong,
Vincent Wai-Sun Wong,
Yawen Chan,
Jessica Yuet-Ling Ching,
Kim Au,
Aric Josun Hui,
Larry Hin Lai,
Dorothy Kai-Lai Chow,
Danny Ka-Fai Siu,
Yan-Ni Lui,
Justin Che-Yuen Wu,
Ka-Fai To,
Lawrence Cheung-Tsui Hung,
Henry Lik-Yuen Chan, Joseph Jao-Yiu Sung,
Francis Ka-Leung Chan
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ABSTRACT: The long-term prognosis of peptic ulcers associated with neither Helicobacter pylori nor nonsteroidal anti-inflammatory drugs (NSAIDs) is unknown.
This 7-year prospective cohort study recruited patients with bleeding ulcers from January to December 2000. H pylori-negative idiopathic bleeding ulcers were defined as having tested negative for H pylori, having no exposure to aspirin or analgesics within 4 weeks before endoscopy, and having no other identifiable causative factors. After ulcers healed, patients were divided into 2 groups: patients with prior H pylori-negative idiopathic bleeding ulcers (H pylori-negative idiopathic ulcer cohort; n = 120) and those with H pylori-positive, NSAID-negative bleeding ulcers who received eradication therapy (H pylori ulcer cohort; n = 213). Both groups were followed for <or=7 years without gastroprotective therapy. The primary endpoints were recurrent ulcer bleeding and mortality.
The 7-year cumulative incidence of recurrent ulcer bleeding was 42.3% (95% CI, 36.5%-48.1%) in the H pylori-negative idiopathic ulcer cohort and 11.2% (95% CI, 8.8%-13.6%) in the H pylori ulcer cohort (a difference of 31.1%; 95% CI, 27.7%-34.5%; P < .0001). Significantly more patients died in the H pylori-negative idiopathic ulcer cohort (87.6%; 95% CI, 83.0%-92.2%) than in the H pylori ulcer cohort (37.3%; 95% CI, 34.0%-40.6%) with a difference of 50.3% (95% CI, 49.0%-51.6%; P < .0001).
Patients with history of H pylori-negative idiopathic bleeding ulcers have a high risk of recurrent ulcer bleeding and mortality.
Gastroenterology 06/2009; 137(2):525-31. · 11.68 Impact Factor
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ABSTRACT: At the recent National Institutes of Health Consensus Development Conference, the value of antiviral therapy for chronic hepatitis B in improving clinical outcome was hotly debated. In patients with chronic hepatitis B, antiviral therapy has proved effective in viral load reduction, alanine aminotransferase normalization and histological improvements. However, its efficacy in reducing decompensated liver disease, hepatocellular carcinoma and liver-related death remains unclear. To date, animal studies and observational studies, but very few randomized controlled trials, have shown improved clinical outcomes after antiviral therapy. The difficulties of conducting clinical trials using clinical endpoints are highlighted. Before more clinical outcome data are available, it is important to validate the clinical implications of surrogate markers including biochemical, virological and histological responses.
Journal of Antimicrobial Chemotherapy 06/2009; 64(2):223-6. · 5.07 Impact Factor
