Graduate Institute of Clinical Medical Science

Medicine, Taiwan

Graduate Institute of Clinical Medical Science

Medicine, Taiwan

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Chang Y.-C.,Graduate Institute of Clinical Medical science | Chang Y.-C.,Chang Gung Memorial Hospital | Wu C.-H.,Chang Gung University | Yen T.-C.,Chang Gung Memorial Hospital | Ouyang P.,Chang Gung University
Journal of Biological Chemistry | Year: 2012

Centrosomal protein 55 (Cep55), which is localized to the centrosome in interphase cells and recruited to the midbody during cytokinesis, is a regulator required for the completion of cell abscission. Up-regulation of Cep55 and inactivation of p53 occur in the majority of human cancers, raising the possibility of a link between these two genes. In this study we evaluated the role of p53 in Cep55 regulation. We demonstrated that Cep55 expression levels are well correlated with cancer cell growth rate and that p53 is able to negatively regulate Cep55 protein and promoter activity. Down-regulation of expression of Cep55 was accompanied by repression of polo-like kinase 1 (Plk1) levels due to p53 induction. Overexpression of Plk1 and knockdown of p53 expression both enhanced the post-translational protein stability of Cep55. BI 2356, a selective Plk1 inhibitor, however, prevented Cep55 accumulation in p53 knockdown cells while persistently keeping Plk1 levels elevated. Our results, therefore, indicate the existence of a p53-Plk1-Cep55 axis in which p53 negatively regulates expression of Cep55, through Plk1 which, in turn, is a positive regulator of Cep55 protein stability. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.


Tsai Y.-F.,Chang Gung Memorial Hospital | Tsai Y.-F.,Graduate Institute of Clinical Medical science | Tsai Y.-F.,Chang Gung University | Lau Y.-T.,Chang Gung University | And 2 more authors.
Shock | Year: 2015

Resveratrol (RSV) has been shown to inhibit the inflammatory reaction and ameliorate the organ damage resulting from trauma-hemorrhage (TH). However, the effects of RSV on the metabolomic profiles under these conditions remain unclear. The aim of this study was to determine the metabolomic profiles of plasma in TH rats and to evaluate the therapeutic effects of RSV using high-performance liquid chromatography-mass spectrometry. Thirty male Sprague-Dawley rats were divided into sham operation (n = 10), sham-operation plus RSV treatment (n = 10), TH (n = 10), and TH plus RSV treatment (n = 10) groups. Plasma samples were obtained at 24 h after surgery. Electrospray ionization-tandem mass spectrometry was used to characterize the plasma metabolomes. The systemic analyses of plasma metabolomes and their targets were determined using a number of computational approaches, including principal component analysis, partial least squares discriminant analysis, and heat map analysis. Using these methods, the effects of RSV on the metabolomic profiles in animals that underwent trauma-hemorrhagic injury were determined. These approaches allowed a clear discrimination of the pathophysiological characteristics among the groups. The results demonstrate RSV treatment significantly reduced the metabolic derangements caused by TH. Compared with the sham-operated rats, the plasma levels of carnitine in the TH rats were relatively lower, but the levels of acetylcarnitine and butyrylcarnitine were higher, suggesting that RSV ameliorated the deranged carnitine metabolism in TH rats. There was a statistically significant increase in carnitine. In addition, RSV treatment reduced ketoacidosis and protein degradation, as evidenced by the attenuation of the elevated plasma branched-chain amino acid levels in the TH rats. Our study showed that the alterations of the metabolomic profiles in the rats subjected to trauma-hemorrhagic shock were attenuated by RSV treatment. In view of the metabolomic evidence, we conclude that RSV exerts beneficial effects in trauma-hemorrhagic shock injury and that these effects are partially mediated by improving energy metabolism and reducing protein degradation. © 2014 by the Shock Society.


Wang C.-H.,Industrial Technology Research Institute of Taiwan | Hwang Y.-S.,Chang Gung Memorial Hospital | Hwang Y.-S.,Graduate Institute of Clinical Medical science | Chiang P.-R.,National Tsing Hua University | And 5 more authors.
Biomacromolecules | Year: 2012

The antibody bevacizumab (Avastin) has been used clinically to treat intraocular neovascular diseases based on its antivascular endothelial growth factor (VEGF) character. The anti-VEGF strategy for retinal neovascular diseases is limited by the short half-life of bevacizumab and thus requires frequent injections. This Article reports the sustained release of bevacizumab from a biocompatible material that is composed of a triblock copolymer of poly(2-ethyl-2-oxazoline)-b-poly(ε-caprolactone)-b-poly(2-ethyl-2- oxazoline) (PEOz-PCL-PEOz). The amphiphilic PEOz-PCL-PEOz triblock copolymer was synthesized in three steps. First, the PEOz was polymerized by methyl p-toluenesulfonate and 2-ethyl-2-oxazoline (EOz), and the living end was terminated by potassium hydroxide methanolic solution. Subsequently, the hydroxyl-PEOz was used as a macroinitiator for the ring-opening polymerization of ε-caprolactone using a Tin(II) octoate catalyst to synthesize the telechelic hydroxylated PEOz-PCL. Finally, the PEOz-PCL-PEOz triblock copolymer was obtained using the 1,6-hexamethylene diisocyanateas a coupling reagent. The PEOz-PCL-PEOz was chemically and molecularly characterized by GPC, 1H NMR, and FTIR, and its aqueous solution (ECE hydrogel) showed a reversible sol (room temperature)-gel (physiological temperature) phase transition, which serves as an easy antibody-packing system with extended release. The biodegradability of ECE hydrogel was assessed by the porosity formation at different periods by scanning electron microscopy. The ECE hydrogel had no in vitro cytotoxicity on the human retinal pigment epithelial cell line by flow cytometry. The histomorphology and electrophysiology of the rabbit neuroretina were preserved after 2 months of intravitreal injection. In conclusion, the ECE hydrogel has a temperature-sensitive sol-gel phase transition and is effective in vitro. Its intraocular biocompatibility demonstrated its great potential to be widely used in biomedical applications for extended drug release. © 2011 American Chemical Society.


Chang Y.-L.,Graduate Institute of Clinical Medical science | Tsai Y.-F.,Chang Gung University | Tsai Y.-F.,Chang Gung Memorial Hospital | Wu Y.-C.,Chang Gung Memorial Hospital | Hsieh M.-J.,Chang Gung Memorial Hospital
Cancer Nursing | Year: 2014

Background: Little is known regarding the short-term quality of life (QoL) and predictive factors for QoL after esophagectomy for cancer in Eastern countries. Objective: The aims of this study were to assess QoL and symptoms within 1 and 6 months after surgery for esophageal cancer (EC) and to identify factors predictive of QoL within 6 months after esophagectomy in Taiwan. Methods: A longitudinal, prospective design was used, where convenience samples of 99 patients who had undergone esophagectomy for cancer were recruited from 2 medical centers in northern Taiwan. All participants responded to a questionnaire with a QLQ-C30 (Quality of Life Questionnaire-Cancer) core and a QLQ-OES18 (esophageal module of the European Organization for Research and Treatment [EORTC] QLQ-C30) module in structured interviews at baseline and 1 and 6 months after surgery. Results: The results showed significant decline in social function and global QoL; fatigue, insomnia, eating problems, reflux, and dry mouth were major problems within 6 months. Body mass index, body weight loss before surgery, activity performance status, and anastomosis site showed no significant association with the function and symptom aspect of QoL. Surgical complications, advanced cancer, neoadjuvant therapy before surgery, and tumor location other than at the EC junction had significant deleterious effects on several aspects of QoL. Conclusions: This study describes the demographics of EC and short-term changes in QoL and also the predictive impact factor for QoL after surgery for EC. Implications for practice: Knowledge of risk factors for poor postoperative QoL would be useful for health providers in detecting and prioritizing problems and treatment options in a busy clinical site. Copyright © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Wu C.-K.,National Taiwan University Hospital | Wu C.-K.,National Taiwan University | Lee J.-K.,National Taiwan University Hospital | Chiang F.-T.,National Taiwan University Hospital | And 8 more authors.
Critical Care Medicine | Year: 2011

OBJECTIVE: The inflammatory process is associated with cardiac diastolic dysfunction, which has been demonstrated to be an independent prognostic marker for the mortality of critically ill patients. We investigated the association among inflammatory cytokines (tumor necrosis factor-α and interleukin-6), diastolic heart failure, and the possible molecular mechanism. DESIGN: Prospective case-controlled cohort and molecular studies. SETTING: University hospital and research laboratory. SUBJECTS: Patients with a diagnosis of diastolic heart failure by echocardiography and matched control subjects from the general population (study group 1) and also subjects from the intensive care unit (study group 2). Sarcoplasmic reticulum Ca-ATPase (SERCA2) gene expression and diastolic calcium decay in HL-1 cardiomyocytes were used as molecular phenotypes of diastolic heart failure. INTERVENTIONS: Soluble plasma levels of tumor necrosis factor-α and interleukin-6 were measured in all subjects. An approximate 1.75-kb promoter of the SERCA2 gene was cloned to the pGL3 luciferase reporter. The effect of tumor necrosis factor-α and interleukin-6 on SERCA2 gene expression and diastolic calcium decay of HL-1 cardiomyocytes were investigated. MEASUREMENTS AND MAIN RESULTS: Patients with diastolic heart failure had significantly higher plasma levels of tumor necrosis factor-α and interleukin-6 than the control subjects. Significant correlations (p <.01 for each) were found for tumor necrosis factor-α and E/Em (r =.87) and E/A (r =-0.69), and for interleukin-6 and E/Em (r =.80) and E/A (r =-0.65). Cytokine levels were also correlated with diastolic function in critically ill patients (study group 2), and diastolic function improved significantly in association with decrease of cytokines. Tumor necrosis factor-α, interleukin-6, and sera from critically ill patients downregulated the expression of the SERCA2 gene. Tumor necrosis factor-α and interleukin-6 also delayed the diastolic calcium reuptake and decay in cardiomyocytes. CONCLUSIONS: Through downregulation of SERCA2 gene expression, inflammatory cytokines may cause cardiac diastolic dysfunction by decreasing diastolic calcium reuptake. Our study may suggest novel therapeutic strategies for diastolic heart failure and critically ill patients by modulating inflammatory reactions. Copyright © 2011 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.


Wong C.H.,Graduate Institute of Clinical Medical science | Lin L.C.,Tri Service General Hospital | Lee H.H.,Taipei Medical University | Liu C.-F.,National Taipei University of Nursing and Health Sciences
Journal of Alternative and Complementary Medicine | Year: 2012

Objectives: Pain induced by surgery is a dynamic symptom, which may be quite variable even in the same surgical procedures. The purpose of this study was to investigate the analgesic effect of far infrared rays on the patients during the postoperative period of total knee arthroplasty (TKA). The selection and application of analgesic methods after the orthopedic surgery are therefore valuable for advanced studies. Design: The quasi-experimental design with a total five consecutive days of far infrared ray (FIR) thermal therapy was employed in this study. Subjects: The study involved 41 participants assigned by register code entry on computer to either the intervention or the control group. Intervention: The FIR pads were applied on the acupoints of ST 37 (Shang Chu Hsu), ST 38 (Tiao Kou), ST 39 (Hsia Chu Hsu), and ST 40 (Feng Lung) of the patients involved in the experimental group from the third day to the fifth day after the TKA. Outcome measures: The analgesic effect was evaluated via the pain intensity of the numeric rating scale (NRS) level and serum concentration of interleukin-6 (IL-6) and endothelin-1 (ET-1). Results: The FIR showed that the significant effects are on relieving pain and lowering the levels of IL-6 and ET-1. The results cannot only be the reference for the postoperative pain relief of TKA, but it can also be the database of another clinical application. Conclusions: This study demonstrated that the FIR can lower the NRS of pain and thus reduce the discomfort experienced by the patient. Findings indicated that effective application of FIR decreased the serum level of IL-6 and ET-1, which represent the subjective indicator of pain. © 2012, Mary Ann Liebert, Inc.


Li C.-F.,Chi Mei Medical Center | Li C.-F.,National Health Research Institute | Li C.-F.,Southern Taiwan University of Science and Technology | Li C.-F.,National Sun Yat - sen University | And 14 more authors.
Clinical Cancer Research | Year: 2012

Purpose: Myxofibrosarcoma remains obscure in molecular determinants of clinical aggressiveness, for which we elucidated implications of SKP2 amplification. Experimental Design: Array comparative genomic hybridization was applied on samples and cell lines (NMFH-1 to OH931) to search causal genes of tumor progression. SKP2 gene dosage was determined in 82 independent tumors for clinical correlates. Stable SKP2 knockdown was achieved in myxofibrosarcoma cells to assess its oncogenic attributes and candidate mediators in prometastatic function. Pharmacologic assays were evaluated in vitro and in vivo for the therapeutic relevance of bortezomib. Results: DNA gains frequently involved 5p in which three amplicons were differentially overrepresented in samples behaving unfavorably, encompassing mRNA-upregulated TRIO, SKP2, and AMACR genes. Detected in NMFH-1 cells and 38% of tumors, SKP2 amplification was associated with SKP2 immunoexpression and adverse prognosticators and independently predictive of worse outcomes. Nevertheless, SKP2- expressing OH931cells and14% of such tumors lacked gene amplification. Knockdown of SKP2 suppressed proliferation, anchorage-independent growth, migration, and invasion of sarcoma cells and downregulated motility-promoting genes, including ITGB2, ACTN1, IGF1, and ENAH. In vitro, bortezomib downregulated SKP2 expression at the mRNA level with p27 kip1 accumulation, induced caspase activation, and decreased cell viability in myxofibrosarcoma cells but not in fibroblasts. In vivo, bortezomib inhibited growth of NMFH-1 xenografts, the cells of which displayed decreased SKP2 expression but increased p27 kip1 and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). Conclusions: As a predominant mechanism driving protein overexpression, SKP2 amplification confers tumor aggressiveness in myxofibrosarcoma. The sensitivity of myxofibrosarcoma cells to bortezomib with SKP2-repressing effect indicates the potentiality of ubiquitin-proteasome pathway as a therapeutic target. ©2012 AACR.


Chen W.-J.,Chang Gung University | Pang J.-H.S.,Graduate Institute of Clinical Medical science | Lin K.-H.,Chang Gung University | Lee D.-Y.,Chang Gung University | And 2 more authors.
Basic Research in Cardiology | Year: 2010

Propylthiouracil (PTU), independent of its antithyroid effect, is recently found to have an antiatherosclerotic effect. The aim of this study is to determine the impact of PTU on phenotypic modulation of vascular smooth muscle cells (VSMCs), as phenotypic modulation may contribute to the growth of atherosclerotic lesions and neointimal formation after arterial injury. Propylthiouracil reduced neointimal formation in balloon-injured rat carotid arteries. In vitro, PTU may convert VSMCs from a serum-induced dedifferentiation state to a differentiated state, as indicated by a spindle-shaped morphology and an increase in the expression of SMC differentiation marker contractile proteins, including calponin and smooth muscle (SM)-myosin heavy chain (SM-MHC). Transient transfection studies in VSMCs demonstrated that PTU induced the activity of SMC marker genes (calponin and SM-MHC) promoters, indicating that PTU up-regulates these genes expression predominantly at the transcriptional level. Furthermore, PTU enhanced the expression of PTEN and inhibition of PTEN by siRNA knockdown blocked PTU-induced activation of contractile proteins expression and promoter activity. In the rat carotid injury model, PTU reversed the down-regulation of contractile proteins and up-regulated PTEN in the neointima induced by balloon injury. Propylthiouracil promotes VSMC differentiation, at lest in part, via induction of the PTEN-mediated pathway. These findings suggest a possible mechanism by which PTU may contribute to its beneficial effects on atherogenesis and neointimal formation after arterial injury. © 2009 Springer-Verlag.


Huang W.-S.,China Medical University at Taichung | Huang W.-S.,Graduate Institute of Clinical Medical Science | Tsai C.-H.,China Medical University at Taichung | Tsai C.-H.,Graduate Institute of Clinical Medical Science | And 10 more authors.
Journal of Clinical Psychiatry | Year: 2013

Objective: To evaluate the relationship between the use of zolpidem and risk of subsequent stroke in Taiwanese patients. Method: This case-control study used data obtained from the National Health Insurance Research Database to determine whether the use of zolpidem is associated with an increased risk of stroke. The case group comprised 12,747 patients who were newly diagnosed with stroke between January 1, 2005, and December 31, 2009. We also randomly selected a 4-fold greater number of patients without stroke as a control group. Patients with ischemic and hemorrhagic stroke were frequency-matched with controls on sex, age, and year of index date. We measured the effect of zolpidem and determined the adjusted odds ratios (ORs) with 95% confidence intervals (CIs). Results: We found that exposure to zolpidem was associated with increased risk of ischemic stroke (OR = 1.37; 95% CI, 1.30-1.44). The risk of ischemic stroke increased significantly with increasing exposure to zolpidem; for average exposures of ≤ 70, 71-470, and > 470 mg per year, the ORs were 1.20, 1.41, and 1.50, respectively; the P value for the trend was < .0001. Regardless of whether people presented with a sleep disorder, the risk of stroke was still greatly increased with zolpidem exposure; the adjusted OR was 1.37 without sleep disorder and 1.41 with sleep disorder. Conclusions: This population-based study positively associated the use of zolpidem with increased risk of ischemic stroke. Our findings warrant further large-scale and in-depth investigations in this area. © Copyright 2013 Physicians Postgraduate Press, Inc.


Sun L.-M.,Zuoying Branch of Kaohsiung Armed Forces General Hospital | Lin M.-C.,E DA Hospital | Muo C.-H.,Data Management | Liang J.-A.,Graduate Institute of Clinical Medical Science | And 3 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2014

Patients or Other Participants: The study cohort consisted of 28 222 patients diagnosed with osteoporosis between January 1, 2000, and December 31, 2011.Weidentified 1925 cancer patients as the study group and 2 noncancer patients frequency matched according to age at index date, sex, comorbidity, index-year, and osteoporosis-year as the control group.Main Outcome Measures: Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression analysis.Results: Use of CNS inwomenwith osteoporosis significantly increased the risk of liver cancer (OR=1.94, 95% CI= 1.23-3.05) but decreased the risk of breast cancer (OR= 0.35, 95% CI= 0.15-0.80). Further analysis of monthly CNS dosages showed that the association between CNS and liver cancer is limited to higher-dose users.Conclusion: The findings of this population-based nested case-control study suggest that CNS use might increase the risk of liver cancer in female osteoporosis patients but decrease the risk of breast cancer. Our data do not completely support the decision to discontinue use of CNS in osteoporosis patients.Context: The concern regarding cancer risk has resulted in the recommendation to pull calcitonin nasal spray (CNS) from the market.Objective: We conducted a nested case-control study to evaluate the association between CNS use in osteoporosis patients in Taiwan and their subsequent risk of cancer.Design: This was a population-based nested case-control study.Setting: Data were obtained from the Taiwan National Health Insurance Research Database. Copyright © 2014 by the Endocrine Society.

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