科研论文

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  • Development of an in vitro cell culture model for human noroviruses and its clinical application

    • 摘要:

    • 作者:

      Wai keung Leung    Paul Chan    李礼舜    沈祖堯    

    • 刊名:

      Hong Kong Medical Journal

    • 在线出版时间:

      2010

  • IκBα polymorphism at promoter region (rs2233408) influences the susceptibility of gastric cancer in Chinese

    • 摘要:

      Background: Nuclear factor of kappa B inhibitor alpha (IκBα) protein is implicated in regulating a variety of cellular process from inflammation to tumorigenesis. The objective of this study was to investigate the susceptibility of rs2233408 T/C genotype in the promoter region of IκBα to gastric cancer and the association of this polymorphism with clinicopathologic variables in gastric cancer patients.Methods: A population-based case-control study was conducted between 1999 and 2006 in Guangdong Province, China. A total of 564 gastric cancer patients and 566 healthy controls were enrolled in this study. rs2233408 genotypes in IκBα were analyzed by TaqMan SNP genotyping assay.Results: Both rs2233408 T homozygote (TT) and T heterozygotes (TC and TT) had significantly reduced gastric cancer risk (TT: OR = 0.250, 95% CI = 0.069-0.909, P = 0.035; TC and TT: OR = 0.721, 95% CI = 0.530-0.981, P = 0.037), compared with rs2233408 C homozygote (CC). rs2233408 T heterozygotes were significantly associated with reduced risk of intestinal-type gastric cancer with ORs of 0.648 (95% CI = 0.459-0.916, P = 0.014), but not with the diffuse or mix type of gastric cancer. The association between rs2233408 T heterozygotes and gastric cancer appeared more apparent in the older patients (age>40) (OR = 0.674, 95% CI = 0.484-0.939, P = 0.02). rs2233408 T heterozygotes was associated with non-cardiac gastric cancer (OR = 0.594, 95% CI = 0.411-0.859, P = 0.006), but not with cardiac gastric cancer. However, rs2233408 polymorphism was not associated with the prognosis of gastric cancer patients.Conclusions: IκBα rs2233408 T heterozygotes were associated with reduced risk of gastric cancer, especially for the development of certain subtypes of gastric cancer in Chinese population. © 2010 Wang et al; licensee BioMed Central Ltd.

    • 作者:

      Shiyan Wang    Linwei Tian    曾志荣    Zhang Mingdong    Kaichun Wu    陈旻湖    樊代明    Pinjin Hu    沈祖堯     Jun Yu   

    • 刊名:

      BMC Gastroenterology

    • 在线出版时间:

      2010

  • Macroautophagy modulates cellular response to proteasome inhibitors in cancer therapy

    • 摘要:

      Macroautophagy and the ubiquitin-proteasome system are two complementary pathways for protein degradation. The former degrades long-lived proteins and damaged organelles while the later degrades short-lived proteins. Recent findings indicate that suppression of the ubiquitin-proteasome system by proteasome inhibitors induces macroautophagy through multiple pathways, including (1) accumulation of ubiquitinated proteins and activation of HDAC6; (2) activation of the IRE1-JNK pathway; (3) proteasomal stabilization of ATF4; (4) inhibition of mTOR complex 1 signaling; (5) reduced proteasomal degradation of LC3. Induction of macroautophagy attenuates the antitumor effect of proteasome inhibitors in various types of cancer. These findings suggest that inhibition of macroautophagy may represent a novel strategy to enhance cellular sensitivity to proteasome inhibition. © 2010 Elsevier Ltd. All rights reserved.

    • 作者:

      William ka kei Wu    Sakamoto Kathleen M.    Milani    Aldana-Masankgay Grace    樊代明    Kaichun Wu    Chungwa Lee    Chihin Cho    Yu Jun    沈祖堯    

    • 刊名:

      Drug Resistance Updates

    • 在线出版时间:

      2010

  • Macroautophagy and ERK phosphorylation counteract the antiproliferative effect of proteasome inhibitor in gastric cancer cells

    • 摘要:

      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/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 implication in the application of proteasome-directed therapy for the treatment of cancer. © 2010 Landes Bioscience.

    • 作者:

      William ka kei Wu    Chihin Cho    Chungwa Lee    Wu Ya Chun    Le Yu    Li Zhi Jie    Clover ching man Wong    Haitao Li    Zhang Lin    Ren Shun Xiang    Chuntao Che    Kaichun Wu    樊代明    Jun Yu    沈祖堯    

    • 刊名:

      Autophagy

    • 在线出版时间:

      2010

  • Dysregulation of cellular signaling in gastric cancer

    • 摘要:

      The pathogenesis of gastric cancer is complex and related to multiple factors. Dysregulation of intracellular signaling pathways represents a common pathogenic mechanism and may be amenable to drug targeting. Multiple well-established oncogenic pathways, such as those mediated by cell cycle regulators, nuclear factor-κB, cyclooxygenase-2 and epidermal growth factor receptor are implicated in gastric carcinogenesis. Emerging evidence also underscores the importance of signaling pathways involved in the developmental process, including transforming growth factor-β/bone morphogenetic protein signaling, Wnt/β-catenin signaling, Hedgehog signaling and Notch signaling. Understanding their biological significance will provide a rational basis for drug development. Their relative importance and cross-talk in gastric carcinogenesis, however, are still not completely understood and warrant further investigation. © 2010 Elsevier Ireland Ltd.

    • 作者:

      William ka kei Wu    Chihin Cho    Chungwa Lee    樊代明    Kaichun Wu    Jun Yu    沈祖堯    

    • 刊名:

      Cancer Letters

    • 在线出版时间:

      2010

  • Emerging roles of the host defense peptide LL-37 in human cancer and its potential therapeutic applications

    • 摘要:

      Human cathelicidin LL-37, a host defense peptide derived from leukocytes and epithelial cells, plays a crucial role in innate and adaptive immunity. Not only does LL-37 eliminate pathogenic microbes directly but also modulates host immune responses. Emerging evidence from tumor biology studies indicates that LL-37 plays a prominent and complex role in carcinogenesis. Although overexpression of LL-37 has been implicated in the development or progression of many human malignancies, including breast, ovarian and lung cancers, LL-37 suppresses tumorigenesis in gastric cancer. These data are beginning to unveil the intricate and contradictory functions of LL-37. The reasons for the tissue-specific function of LL-37 in carcinogenesis remain to be elucidated. Here, we review the relationship between LL-37, its fragments and cancer progression as well as discuss the potential therapeutic implications of targeting this peptide. © 2010 UICC.

    • 作者:

      William ka kei Wu    Guangshun Wang    Seth Coffelt    Betancourt Aline M.    Chungwa Lee    樊代明    Kaichun Wu    Jun Yu    沈祖堯     Chihin Cho   

    • 刊名:

      International Journal of Cancer

    • 在线出版时间:

      2010

  • MicroRNA dysregulation in gastric cancer: A new player enters the game

    • 摘要:

      Gastric carcinogenesis is a multistep process involving genetic and epigenetic alteration of protein-coding proto-oncogenes and tumor-suppressor genes. Recent discoveries have shed new light on the involvement of a class of noncoding RNA known as microRNA (miRNA) in gastric cancer. A substantial number of miRNAs show differential expression in gastric cancer tissues. Genes coding for these miRNAs have been characterized as novel proto-oncogenes and tumor-suppressor genes based on findings that these miRNAs control malignant phenotypes of gastric cancer cells. In this connection, miRNA dysregulation promotes cell-cycle progression, confers resistance to apoptosis, and enhances invasiveness and metastasis. Moreover, certain polymorphisms in miRNA genes are associated with increased risks for atrophic gastritis and gastric cancer, whereas circulating levels of miRNAs may serve as biomarkers for early diagnosis. Several miRNAs have also been shown to correlate with gastric cancer progression, and thus may be used as prognostic markers. Elucidating the biological aspects of miRNA dysregulation may help us better understand the pathogenesis of gastric cancer and promote the development of miRNA-directed therapeutics against this deadly disease. © 2010 Macmillan Publishers Limited All rights reserved.

    • 作者:

      William ka kei Wu    Chungwa Lee    Chihin Cho    樊代明    Kaichun Wu    Jun Yu    沈祖堯    

    • 刊名:

      Oncogene

    • 在线出版时间:

      2010

  • Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease

    • 摘要:

      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. Copyright © 2009 by the American Association for the Study of Liver Diseases.

    • 作者:

      Vincent Wong    Julien Vergniol    Grace Wong    Juliette Foucher    Henry lik yuen Chan    Brigitte Le-Bail    |蔡祥龙    Kowo    Anthony wing hong Chan    Wassil Merrouche    沈祖堯     de Lédinghen   

    • 刊名:

      Hepatology

    • 在线出版时间:

      2010

  • Quality assurance for Chinese herbal formulae: Standardization of IBS-20, a 20-herb preparation

    • 摘要:

      Background: The employment of well characterized test samples prepared from authenticated, high quality medicinal plant materials is key to reproducible herbal research. The present study aims to demonstrate a quality assurance program covering the acquisition, botanical validation, chemical standardization and good manufacturing practices (GMP) production of IBS-20, a 20-herb Chinese herbal formula under study as a potential agent for the treatment of irritable bowel syndrome.Methods: Purity and contaminant tests for the presence of toxic metals, pesticide residues, mycotoxins and microorganisms were performed. Qualitative chemical fingerprint analysis and quantitation of marker compounds of the herbs, as well as that of the IBS-20 formula was carried out with high-performance liquid chromatography (HPLC). Extraction and manufacture of the 20-herb formula were carried out under GMP. Chemical standardization was performed with liquid chromatography-mass spectrometry (LC-MS) analysis. Stability of the formula was monitored with HPLC in real time.Results: Quality component herbs, purchased from a GMP supplier were botanically and chemically authenticated and quantitative HPLC profiles (fingerprints) of each component herb and of the composite formula were established. An aqueous extract of the mixture of the 20 herbs was prepared and formulated into IBS-20, which was chemically standardized by LC-MS, with 20 chemical compounds serving as reference markers. The stability of the formula was monitored and shown to be stable at room temperature.Conclusion: A quality assurance program has been developed for the preparation of a standardized 20-herb formulation for use in the clinical studies for the treatment of irritable bowel syndrome (IBS). The procedures developed in the present study will serve as a protocol for other poly-herbal Chinese medicine studies. © 2010 Ip et al; licensee BioMed Central Ltd.

    • 作者:

      Siupo Ip    Ming Zhao    Yanfang Xian    Chen Meng L.    Zong Yuying    Tjong Yung-Wui    Tsai Sam-Hip    沈祖堯     Alan Bensoussan    Berman Brian    Fong Harry H. S.    Chuntao Che   

    • 刊名:

      Chinese Medicine

    • 在线出版时间:

      2010

  • Neonatal maternal separation elevates thalamic corticotropin releasing factor type 1 receptor expression response to colonic distension in rat

    • 摘要:

      OBJECTIVES: Early life psychological stress is an essential factor contributing to the development of irritable bowel syndrome (IBS), with corticotrophin releasing factor (CRF) having been implicated in this common gastrointestinal disorder. The aim of our study is to examine the effect of neonatal maternal separation (NMS), an early life stress model, on the brain CRF expression following visceral pain induced by colorectal distension (CRD) stimuli in male rats. METHODS: Male neonatal Sprague-Dawley rats were subjected to 3-hr daily maternal separation on postnatal day 2-21, with unseparated normal (N) rats serving as controls. Electromyogram signals (EMG) in response to phasic CRD were measured. The results demonstrated an increased pain response and EMG magnitudes in NMS rats as compared to N rats in response to CRD stimulation. The mRNA and protein expressions of CRF in hippocampus, cortex and thalamus of NMS and N group following the CRD stress were determined by real-time quantitative PCR and western-blotting studies respectively. RESULTS: There was an increased mRNA and protein level of CRF in thalamus of NMS rats but no apparent change in CRF expression in hippocampus and cortex of both groups. Furthermore, an increased expression of CRF type 1 receptor (CRF-Rl) was observed in the thalamus of NMS rats. CONCLUSION: These results suggested an up-regulation of thalamus CRF-R1 is associated with visceral hyperalgesia in the rat model of NMS. © 2010 Neuroendocrinology Letters.

    • 作者:

      Tjong Yung-Wui    Siupo Ip    Lixing Lao    胡志    Fong Harry H. S.    沈祖堯     Berman Brian    Chuntao Che   

    • 刊名:

      Neuroendocrinology Letters

    • 在线出版时间:

      2010

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